Speciality
Spotlight

 




 


Endocrinology


   

  



  • De
    Lonlay-Debenay P, Poggi-Travert F, Fournet J-C, et
    al [Hopital des Enfants Malades, Paris; Universite
    de Louvain, Brussels, Belgium; Ospedale Bambino Gesu,
    Rome

    Clinical Features of 52 Neonates With
    Hyperinsulinism


    N
    Engl J Med 340: 1169-1175, 1999

            

    Congenital
    Hyperinsulinism can be caused either by diffuse
    abnormalities of pancreatic beta cells or by focal
    abnormalities involving adenomatous islet cell
    hyperplasia, whereas a pancreas with diffuse
    involvement will likely require total or near-total
    pancretectomy. Focal hyperplasia can be treated with
    partial pancreatectomy to excise the abnormal area.

       

    In
    all 52 neonates with hyperinsulinism who required
    surgery were studied. Preoperatively, patients
    underwent transheptic, catheterization to locate the
    site(s) of insulin hypersecretion. Intraoperatively,
    tissues from the head, isthmus, body, and tail of
    the pancreas were examined histologically to confirm
    the extent of the involvement. By this method, 30
    neonates had diffuse beta cell hyperfunction and
    underwent near-total pancreatectomy, whereas 22
    neonates had focal hyperplasia and typically
    underwent partial pancreatectomy. All patients were
    monitored postoperatively by measurement of plasma
    glucose levels and glycosylated hemoglobin levels as
    well as by oral glucose tolerance tests.

       

    Focal
    hyperinsulinism can be detected by preoperative
    pancreatic catheterazation and intraoperative
    historical examination. This disorder can be
    successfully treated with partial pancreatectomy
    with litte risk 
    of the development of diabetes mellitus in
    future.

       
             

  • N
    Fuenmanyor, E Moreira, LX Cubeddu, (Central Univ of
    Venezuela, Caracas)

    Salt
    Sensitivity is Associated with Insulin Resistance in
    Essential Hypertension.

    Am
    J Hypertens 11: 397-402, 1998.

       

    Patients with essential hypertension may be salt
    sensitive or salt resistant.
    Hypertension in salt sensitive patients is
    associated with insulin resistance.
    In salt sensitive patients, high salt intake
    leads to increase in blood pressure, induced
    hyperinsulinemia, and worsening of diabetes.

       

  • R
    Abs, J Verhelst, D Maiter, et al (Univ Hosp,
    Antwerp, Belgium; Middelheim Hosp, Antwerp, Belgium;
    Hopital Saint-Luc, Brussels, Belgium; et al)  

    Cabergoline
    in the Treatment of Acromegaly: A Study in 64
    patients.
      

    J
    Clin Endocrinol Metab 83: 374-378, 1998.


       

    Cabergoline,
    a new, long-acting dopamine agonist, is more
    effective and less toxic than bromocriptine in the
    treatment of hyperprolactinemia.  This agent may also be useful in the medical management of
    acromegaly.

       

  • CB
    Newman, S Melmed, A George, et al (New York Univ;
    Cedars-Sinai Med Ctr, Los Angeles; Univ of
    Pennsylvania, Philadelphia; et al)  

    Octreotide
    as Primary Therapy for Acromegaly.
     

     J
    Clin Endocrinol Metab 83:3034-3040, 1998.


         

    Conclusions
    – Octreotide was equally effective in patients
    receiving this agent for acromegaly as primary or
    secondary treatment. 
    These findings raise questions about the
    current practice of surgically resecting all newly
    diagnosed GH-secreting pituitary adenomas.

        

  • Perry
    IJ, Wannamethee SG, et al (Royal Free Hospital, London; Univ of Newcastle upon Tyne, England)


    Serum True Insulin Concentration and the Risk of Clinical Non-Insulin Dependent Diabetes During Long-term Follow-up


    Int J Epidemiol 28: 735-741, 1999

       


    Background : Substantial evidence indicates that insulin resistance with compensatory hyperinsulinemia is an early, modifiable defect in the pathogenesis of NIDDM. However, such evidence comes mainly from studies using insulin assays that cross-react with proinsulin and other insulin precursors. A specific assay was used to determine whether an increase in serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM.

       


    Method :A cohort of 5550 men without diabetes (age, 40 to 59 years) from 18 British towns was followed up for a mean 14.8 years.

       


    Findings: One hundred sixty-eight incident cases of clinically diagnosed NIDDM occurred during follow-up.

       


    Conclusion : In this cohort, increased circulating true insulin levels antedate clinically manifest NIDDM by more than a decade. This supports the idea that insulin resistance with compensatory true hyperinsulinemia plays an early role in the pathogenesis of this condition.

        


    Editor’s comment: True insulin levels also confirm what most diabetologists have always known, namely, that insulin resistance (with compensatory hyperinsulinaemia) underlies type 2 diabetes in most patients.

        

  • Kaiyala KJ, Prigeon RL, et al (Univ of Washington, Seattle; Veterans Affairs Puget Sound Health Care System, Seattle; Univ of Cincinnati, Ohio)


    Reduced b-cell Function Contributes to Impaired Glucose Tolerance in Dogs Made Obese by High-Fat Feeding.


    Am J Physiol 277: E659-E667, 1999.

        


    From the animal study, it was concluded that High-fat feeding produces insulin resistance that is not compensated for by increased insulin secretion. This contributes to the development of glucose intolerance. These effects may be especially harmful in individuals who are predisposed to type 2 diabetes mellitus.

       


    Editor’s comment : A high-fat diet is a major culprit in the obesity seen in the Western industrialized world. Obesity is very common among patients with type 2 diabetes. This study demonstrated that a high fat diet, apart from inducing increased body weight and perhaps insulin resistance, may be associated with b-cell lipotoxicity with resultant diminution of b-cell secretory capacity.

       

  • Kitabchi AE, Imseis RE, Bush AJ, et al (Univ of Tennessee, Memphis)


    Racial Differences in the Correlation Between Gonadal Androgens and Serum Insulin Levels


    Diabetes Care 22: 1524-1529, 1999

       


    Purpose: Previous studies in a group of predominantly African American women with obesity and hyperandrogenism found that serum insulin level was directly correlated with levels of gonadal androgens (i.e, testosterone and androstenedione). However, this correlation has not always been demonstrated in predominantly white samples. Possible racial differences in the correlation between gonadal androgen and insulin levels were assessed.

       


    Method: The study included 14 African American and 14 white premenopausal women. The 2 racial groups were similar in terms of age, body mass index, and waist-to-hip ratio.

        


    Conclusions: African American women show a direct correaltion between gonadal androgen levels and the responses of glucose, insulin, and C-peptide to a glucose tolerance test. The findings support a racial difference in the relationship between gonadal hyperandrogenism and hyperinsulinemia. The mechanisms underlying this racial difference, including the possible protective effect of lower levels of visceral fat in African American women, warrant further study.

        


    Editor’s comment: This raises a very important question regarding the role of androgens in glucose and insulin metabolism and the development of type 2 diabetes in blacks.

        

  • Ciampelli M, Fulghesu AM, et al (Catholic Univ of Sacred Heart, Rome; OASI Inst for Research, Troina, Italy)

    Impact of Insulin and Body Mass Index on
    Metabolic and Endocrine Variables in Polycystic
    Ovary Syndrome.


    Metabolism 48: 167-172, 1999

       


    Purpose: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by anovulation, hyperandrogenism, and hyperinsulinemia with insulin resistance. There is a firmly established link between insulin resistance and obesity, and obesity iS common among patients with PCOS. The relative contributions of insulin and obesity to the disorders associated with PCOS were examined.

       


    Method : The study included 110 consecutive Italian women with PCOS.

       


    Conclusion: For patients with PCOS, hyperinsulinemia appears to have a significant effect on the LH response to a GnRH stimulus. Obesity and hyperinsulinemia combined to have a synergistic, additive effect on the free androgen index. Changes in lipid profile appear to result from obesity alone.

       


    Editor’s comment: This study shows that the role of hyperinsulinemia in the regulation of gonadal hormones and gonadotropins is partly dependent on the presence of obesity.

        

  • Vaccaro O, Ruffa G, Imperators G, et al (Federico II Univ, Naples, Italy)


    Risk of Diabetes in the New Diagnostic Category of Impaired Fasting Glucose: A Prospective Analysis.


    Diabetes Care 22: 1490 – 1493, 1999.

       


    Introduction: the latest American Diabetes Association (ADA) recommendations suggest that fasting glucose should be used rather than the oral glucose tolerance test (OGTT) for diagnosis of diabetes and impaired fasting glucose (IFG). In contrast, the World Health Organisation (WHO) recommends the OGTT for diagnosis of diabetes. Impaired fasting glucose is a new diagnostic category, the clinical significance of which is unknown. This study assessed progression to diabetes among subjects with evidence of impaired glucose regulation on either fasting glucose or OGTT. The 2 tests were compared for their ability to identify subjects at high risk of diabetes.

        


    Conclusion: The results support the continued use of the OGTT in screening programs to identify patients at high risk of diabetes, as recommended by the WHO. This is in contrast to the ADA recommendation to use the fasting glucose only. To date, this is the only population-based study of risk of progression to diabetes among Caucasian subjects with impaired fasting glucose.

        


    Editor’s comment: The new category of IFG could not supplant our old friend OGTT. OGTT is here to stay!

       

  • Mannucci E, Bardini G, et al (Careggi Hosp, Florence, Italy)


    Comparison of ADA and WHO Screening Methods for Diabetes Mellitus in Obese Patients.


    Diabetic Med 16: 579-585, 1999

        


    Background: Fasting glucose may not be sensitive enough to use as a screening method for diabetes, especially in high-risk populations. The performance of fasting glycemia (FG) was compared with that of oral glucose tolerance testing (OGTT) in the diabetes mellitus (DM) screening of obese patients.

       


    Method : Five hundred twenty eight consecutive obese outpatients under FG and OGTT. 

        


    Conclusion: The sensitivity of FG exceeding 6.1 mmol/L is satisfactory for screening for diabetes but not for IGT. A FG threshold of more than 7 mmol/L is not sensitive enough for diabetes screening in obese patients.

        


    Editor’s comment: The severity of fasting hyperglycaemia determines the B-cell function and the degree of hypertriglyceridemia in both obese and nonobese subjects. However, the presence of insulin resistance in most obese patients confound the degree of metabolic derangements. Various diagnostic criteria did not take into consideration the impact of obesity. Is it time to classify diabetes not only on the basis of glucose levels but also according to the presence of obesity of surrogates for insulin resistance?

        

  • Kashiwazaki K, Hirano T, et al (Showa Univ, Japan; Toho Univ, Tokyo)


    Decreased Release of Lipoprotein Lipase is Associated with Vascular Endothelial Damage in NIDDM Patients with Microalbuminuria.


    Diabetes Care 21: 2016-2020, 1998

       


    Background: Plasma triglyceride level is a risk factor for coronary heart disease in pateints with diabetes. This makes it important to identify the mechanisms of hypertriglyceridemia in diabetes. One possibility is that generalized endothelial damage reduces lipoprotein lipase (LPL) bound to epithelium. To assess this potential mechanism, the association between heparin-releasable LPL and von Willebrand factor (vWF) a marker of endothelial damage was evaluated in pateints with diabetes who have microalbuminuria.

        


    Conclusions: The findings demonstrate generalized endothelial damage in microalbuminuric patients with NIDDM. This leads to reduced endothelium-bound LPL and thus to impaired catabolism of TG-rich lipoproteins.

       


    Editor’s comment: These results suggest that widespread endothelial damage occurred in NIDDM patients with microalbuminuria. LPL moiety bound to the endothelium is thereby decreased, which results in an impaired catabolism of TG-rich lipoproteins.

       

  • Barzilay
    JI, Spiekerman CF, et al (Emory Univ, Atlanta, Ga; Univ of Washington, Seattle; Univ of Pittsburgh, Pa; et al)


    Cardiovascular Disease in Older Adults with Glucose Disorders: Comparison of American Diabetes Association Criteria for Diabetes Mellitus with WHO Criteria.


    Lancet 354: 622-625, 1999

       


    The American Diabetes Association’s (ADA) 1997 criteria for diagnosis of diabetes rely mainly on fasting glucose values, avoiding the need for oral glucose tolerance testing. In contrast, World Health Organization (WHO) criteria still call for oral glucose tolerance testing and have a higher cutoff point for fasting glucose concentration. It remains unclear which set of criteria are most useful for identifying glucose disturbances in the elderly. This study compared the ADA and WHO criteria for their ability to detect cardiovascular disease among older adults with diabetes or glucose disturbances.

        


    The ADA diagnostic criteria, based on fasting glucose measurements, are not as sensitive in predicting cardiovascular disease associated with glucose disturbances in the elderly as the WHO criteria, based on oral glucose tolerance testing. The findings question the recommendation to rely on fasting glucose measurements to diagnose glucose disorders in the elderly population.

       


    Editor’s comment: Delayed return of glucose to baseline (prandial hyperglycaemia) is the hallmark of diabetes in older persons. For that reason, the American Diabetes Association’s new criteria for the diagnosis of diabetes mellitus made little sense. 

        


    Diabetes mellitus remains a risk factor for coronary artery disease events, even in women in nursing homes.

       

  • Mitchell BD, Almasy LA, et al (Southwest Found for Biomedical Research, San Antonio, Tex; Univ of Texas, San Antonio)


    Diabetes and Hypertension in Mexican American Families: Relation to Cardiovascular Risk


    Am J Epidemiol 149: 1047-1056, 1999

       


    Type 2 diabetes, hypertension, and cardiovascular disease show a strong familial tendency. The association between a family history of these illnesses and a large panel of cardiovascular risk factors was studied in a group of Mexican Americans.

       


    A total of 1431 participants were enrolled in the San Antonio Family Heart Study.

       


    Family history of diabetes, and to a lesser degree hypertension, is significantly associated with a spectrum of cardiovascular risk factors. These relationships probably reflect the pleiotropic effects of genes transmitted from affected persons to their offspring.

       


    Editor’s comment: Hypertension is found in 50% to 60% of patients with type 2 diabetes. In both diseases, the major cause of death is cardiovascular disease. This suggests that both hypertension and diabetes could have a common genetic background.

       

  • Rodriguez BL, Sharp DS, Lau N, et al (Univ of Hawaii, Manoa; Kuakini Med Ctr, Honolulu, Hawaii; Natl Heart, Lung, and Blood Inst, Honolulu, Hawaii; et al)


    Glucose Intolerance and 23-Year Risk of Coronary Heart Disease and Total Mortality: The Honolulu Heart Program.


    Diabetes Care 22: 1261-1265, 1999.

       


    Though the increased risk of total mortality and coronary heart disease (CHD) morbidity and mortality in diabetic patients is well documented, the relationship between glucose intolerance and these outcomes is still unclear. The associations between glucose intolerance assessed on entry to the Honolulu Heart Program and the 23 year incidence of CHD, CHD mortality, and total mortality were reported.

       


    A cohort of 8006 Japanese American men, aged 45 to 68 years were enrolled in the study in 1965 and followed up for 23 years.

       


    Conclusion : In this cohort of middle aged and older Japanese American men, glucose intolerance at baseline had a dose-response association with CHD incidence, CHD mortality and total mortality. This association persisted after adjustment for many other risk factors.

       


    Editors’ comment: The remarkable strength of this study is the 23-year duration of the follow-up (similar to the Framingham Cohort Study). Hyperglycemia symptomatic and asymptomatic remains a greater risk in the development of
    CHD.

       

  • Zavaroni I, Bonini L, et al (Parma Univ, Italy; Stanford Univ, Calif; Shaman Pharmaceuticals, South San Francisco)


    Hyperinsulinemia in a Normal Population as a Predictor of Non-Insulin-Dependent Diabetes Mellitus, Hypertension and Coronary Heart Disease: The Barilla Factory Revisited.


    Metabolism 48: 989-994, 1999

       


    Background- Previous research findings suggest that hyperinsulinemia, as a surrogate measure of resistance to insulin-mediated glucose disposal, is associated with higher concentrations of plasma glucose and triglyceride, a lower concentration of HDL cholesterol, and an increase in systolic and diastolic blood pressure. The capability of hyperinsulinemia to aid in the prediction of the development of glucose intolerance, hypertension, and coronary heart disease in a previously healthy population was investigated.

       


    Six hundred forty seven individuals who were free of disease at study enrollment were followed up between 1981 and 1993 to 1996.

       


    The untoward clinical effects of insulin resistance or compensatory hyperinsulinemia, glucose intolerance, hypertension and CHD can develop within 15 years. In this unselected population, hyperinsulinemia was an effective marker of subsequent CHD development.

       


    Editor’s comment: The data are consistent with the presence of syndrome X.

        

  • Guerrer-Romero F, Rodriguez-Moran M (Gen Hosp of the Mexican Social Security Inst, Durango, Mexico)


    Proteinuria is an Independent Risk Factor for Ischemic Stroke in Non-Insulin Dependent Diabetes Mellitus.


    Stroke 30: 1787-1791, 1999

        


    In patients with non-insulin-dependent diabetes mellitus (NIDDM), proteinuria is an independent risk factor for cardiovascular disease. The association between proteinuria and ischemic stroke in patients with NIDDM was investigated.

       


    Fifty-nine diabetic patients with first-ever ischemic stroke from thrombotic arterial occlusion and 180 diabetic patients without stroke were included in the case-control study. The 2 groups were matched by sex, age and diabetes duration.

       


    This case-control study provides evidence that proteinuria is an independent risk factor for ischemic stroke in patients with NIDDM. More research is needed.

        


    Editor’s comment: Proteinuria is a reflection of generalized vascular compromise and hematorrheologic deregulation and blood pressure changes.

       

  • Perucchini d, Fischer U, et al (Univ Hosp Zurich, Switzerland)


    Using Fasting Plasma Glucose Concentrations to Screen for Gestational Diabetes Mellitus: Prospective Population Based Study.


    BMJ 319: 812-815, 1999

       


    Identifying women who are susceptible to gestational diabetes can help prevent perinatal morbidity and improve long-term outcomes for the mother and baby. Whether measurement of fasting glucose concentration is easier than the 1 hour, 50-g glucose challenge test in the screening of gestational diabetes mellitus was investigated.

    12

    The measurement of FPG levels, with a cut-off value of 4.8 mmol/l or greater, is easier than the 50-g glucose challenge test in screening for gestational diabetes and obviates the need for the challenge test in 70% of women.

         


    Editor’s comment: If confirmed in large studies, this will save doctors and patients very precious time. Longitudinal studies to examine the fetal and maternal outcomes of the use of FPG > 4.8 mmol/ml and 50-g glucose are needed

       

  • Willms B, Ruge D (Diabetesklinik Bad Lauterberg, Germany)


    Comparison of Acarbose and Metformin in Patients with Type 2 Diabetes Mellitus Insufficiency Controlled with Diet and Sulphonylureas: A Randomized, Placebo-Controlled
    Study
    .

    Diabetic Med 16: 755-761, 1999.

        


    The efficacies of acarbose and metformin have been compared in patients with type 2 diabetes mellitus uncontrolled with diet alone. The safety and efficacy of these agents were assessed in diabetic patients in whom sulfonylurea therapy did not sufficiently control type 2 diabetes mellitus.

        


    Acarbose and metformin are equally effective in improving metabolic control in patients with diabetes that is insufficiently controlled with diet and sulfonylureas. Further studies are needed to determine the relative effects of metformin and acarbose on disease progression and long-term complications.

       


    Editor’s comment: The significant weight loss in the acarbose group versus the metformin group, in the face of comparable glycemic control and adverse gastrointestinal effects, is very encouraging. The only problem is whether the American patients with type 2 diabetes are willing to hang on long enough at the 300-mg/day dose of acarbose to realize the maximum potential of this drug.

       

  • Coon B, An L-L, Whitton JL, et al (The Scripps Research Inst, La Jolla, Calif)


    DNA Immunization to Prevent Autoimmune Diabetes


    J Clin Invest 104: 189-194, 1999

       


    In mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a transgene in b cells, IDDM develops only after LCMV infection. This model was used in an investigation of the potential of DNA vaccination to control autoimmune disease, with the use of islet self-antigens to induce regulatory lymphocytes and prevent autoimmune diabetes.

       


    DNA immunization with plasmids expressing self-antigens may be an attractive, novel approach to prevent autoimmune disorders. The antigens must be carefully preelected for their ability to induce regulatory lymphocytes in vivo.

       


    Editor’s comment: There may be a way to prevent type 1 diabetes with a vaccine of insulin B-chain NDA in the future. This novel approach to vaccination needs further confirmation in other rodents and ultimately in human beings.

       

  • Nielsen FS, Hansen HP, et al (Steno Diabetes Ctr, Gentofte, Denmark; Dept of Internal Medicine and Endocrinology F, Herlev, Denmark; Universite Louis Pasteur, Strasbourg, France)


    Increased Sympathetic Activity During Sleep and Nocturnal Hypertension in Type 2 Diabetic Patients with Diabetic Nephropathy.


    Diabetic Med 16: 555-562, 1999

       


    Morbidity and mortality from cardiovascular causes are excessive in patients with proteinuric type 2 diabetes. The putative factors involved in the blunted nocturnal blood pressure decreases in hypertensive patients with type 2 diabetes and diabetic nephropathy were investigated.

        


    Sustained adrenergic activity during sleep is correlated with blunted nocturnal blood pressure decrease in hypertensive patients with type 2 diabetes mellitus and diabetic nephropathy. This is probably mediated through a lack of peripheral vasodilation. Changes in extracellular fluid volume distribution and melatonin secretion have no effect.

        


    Editor’s comment: A blunted nocturnal blood pressure dip has been associated with microabluminuria. The mechanism of the blunted nocturnal BP dip has remained uncertain. Increased nocturnal sympathetic activity during hours of sleep in hypertensive type 2 diabetic patients may offer an explanation. These findings in the present study lend support for potential use of sympathetic blocking agents such as clonidine in these patients. Ultimately, the question to be address is whether reduction in sympathetic activity at night, with concomitant reduction in blood pressure, will ameliorate the progression of
    microalbuminuria.

        

  • Golden
    SH, Peart-Vigilance c, et al (Johns Hopkins Med Institutions, Baltimore, Md)


    Perioperative Glycemic Contrl and the Risk of Infectious Complications in a Cohort of Adults with Diabetes.


    Diabetes Care 22: 1408-1414, 1999

          


    Diabetes increases the risk of various types of infectious complications, although the reasons for this increase are unclear. One possibility is that hyperglycemia increases risks through short-term effects on immune function, pathogen growth, or vascular permeability. Patients with diabetes undergoing coronary surgery were studied to determine the effects of perioperative glycemic control on the risk of infectious complications after surgery.

           


    The study included 411 adult patients with any type of diabetes who underwent coronary artery bypass surgery during a 6-year period.

          


    Hyperglycemia appears to be an independent predictor of the short-term risk of infectious complications in patients with diabetes undergoing coronary artery surgery. The risk of infection is significantly elevated for patients whose mean glucose concentration during the 36 hours after surgery exceeds 200mg d/L. The results support published recommendations for stricter glycemic control for patients with diabetes during the perioperative period.

       


    Editor’s comment: This study re-emphasises the importance of perioperative glycemic control in adults with diabetes. He presumes that the same benefits may be applicable to children with diabetes who are undergoing major surgery also.

          

  • GB Thompson, CS Grant, JA van Heerden et al (Mayo Found, Rochester,
    Minn):

    Laparoscopic versus open posterior
    adrenalectomy: A case control study of 100 patients.


    Surgery 122: 1132-1136, 1997.

          


    Few large studies have compared laparoscopic adrenalectomy (LA) with conventional open anterior or posterior adrenalectomy (PA).

         


    Laparoscopic adrenalectomy is a safe and effective procedure that is superior to PA with respect to patient satisfaction, length of hospital stay, return to normal activities, analgesic requirements and late complications. Compared with PA, LA operating times and hospital stays are slightly longer. LA is more expensive and technically more demanding.

         

  • Patel PC, Pellitteri PK, Patel NM, et al (Penn State Geisinger Health System, Danville,Pa)

    Use of a Rapid Intraoperative Parathyroid Hormone Assay in the Surgical Management of Parathyroid Disease.

    Arch Otolaryngol Head Neck Surg 124: 559-562, 1998.

        

    During parathyroid surgery patients underwent neck exploration and the parathyroid hormone assay is done by preremoval of parathyroids and postoperative, during operative procedure, thus guiding whether enough functioning of parathyroid tissue is received. If adenoma is suspected then preoperative 99mTc-sestamibi scanning was used to localize.

        

    Thus combination of preoperative scanning and intraoperative parathyroid hormone assay can guide unilateral exploration of neck.

         

  • Levine
    JA, Eberhardt NL, Jensen MD (Mayo Clinic and Mayo
    Found, Rochester, Minn)

    Role
    of Nonexercise Activity Thermogenesis in Resistance
    to Fat Gain in Humans.

    Science
    283: 212-214, 1999.

        

    Methods and Findings:
    For 8 weeks, 16 persons were fed 100 kcal/d more
    than weight-maintenance requirements.
    Two thirds of the increase in total daily
    energy expenditure resulted from increased
    nonexercise activity thermogenesis (NEAT), which is
    associated with fidgeting, maintaining posture, and
    other physical activities of daily living.
    Changes in NEAT explained the 10-fold
    differences in fat storage observed.
    These changes also directly predicted
    resistance to fat gain with overeating.

        

    Conclusions:
    These data suggest that the activation of NEAT
    dissipates excess energy to preserve leanness in
    persons who
    are overeating. Failure
    to activate NEAT may result in fat gain.

        

    Editorial
    comments:

    The use of doubly labeled water, a novel stable
    isotope technique, permitted the measurement of NEAT
    in response to overfeeding.

          

  • Gu
    K, Cowie CC, Harris MI (Natl Inst of Diabetes and
    Digestive and Kidney Diseases, Bethesda, Md)

    Diabetes and Decline in Heart Disease
    Mortality in US Adults.


    J.a.m.a.
    281: 1291-1297, 1999

        

    Methods:
    Patients with and without diabetes, age 35 to 74
    years, were followed up prospectively for
    age-specific mortality rates/1000 person-years, age
    adjusted and stratified by cohort, diabetes status,
    and sex.

        

    Conclusion:
    the decline in mortality rates for all causes, heart
    disease, and ischemic heart disease is lower for
    patients with diabetes than for those without
    diabetes, particularly if they are female.

        

    Editorial
    comments
    :
    Despite the decrease in the mortality rate from
    coronary heart disease in the United States over the
    past 30 years, it is unclear whether patients with
    diabetes have followed these trends. 
    The findings show that mortality from all
    causes, heart disease, and ischemic disease has
    decreased slightly in men with diabetes, and it has
    actually increased in women. 
    One possible explanation for these findings
    is that patients with diabetes may have benefited
    less from improved medical treatment of heart
    disease.  Moreover,
    the fact that mortality rates actually increased in
    women may suggest that women are being treated less
    aggressively for their diabetes than men. 
    It should be noted, however, that this study
    could not differentiate between the types of
    diabetes and could not identify individuals with
    undiagnosed diabetes. 
    Given the increasing prevalence of diabetes
    in the US population, it is possible that diabetes
    may constitute an even more important factor
    associated with heart disease mortality.

        

  • Guven
    S, El-Bershawi A, etal (Med College of Wisconsin,
    Milwaukee)

    Plasma Leptin and Insulin Levels in
    Weight-Reduced Obese Women with Normal Body Mass
    Index: Relationships with Body Composition and
    Insulin.


    Diabetes
    48: 347-352, 1999

        

    Study
    Design
    : The fasting plasma leptin and insulin
    levels were determined from 22 currently obese, 20
    weight reduced obese (with a normal BMI of at least
    1 year’s duration), and 29 never-obese women. All
    of the women were premenopausal.
    A subset of 14 currently obese, 9
    weight-reduced obese, and 20 never-obese women had
    plasma leptin evaluated in relation to body
    composition and insulin dynamics. Dual-energy x-ray absorptiometry was used to assess total body fat,
    and CT scanning was used to detect abdominal
    visceral and subcutaneous fat components of these
    women. The
    minimal model procedure was used to obtain
    quantitative data on insulin sensitivity.

         

    Conclusion:
    For premenopausal women, plasma leptin levels are
    elevated in weight-reduced obese women with a normal
    BMI.  This
    elevated leptin level may be caused by the larger
    amount of fat in the subcutaneous compartment of
    these women, compared with never-obese women. The
    normalization of visceral fat mass that accompanied
    weight loss for these women was associated with
    normalization of the insulin response.

        

    Editorial
    comment:

    The major finding is that for weight-reduced women,
    the insulin sensitivity index and first phase
    insulin response were comparable with those of
    never-obese women. 
    Despite the normalization of BMI in
    weight-reduced individuals, a higher leptin level
    persisted that was related to higher subcutaneous
    abdominal fat. 
    These results suggest that this depot is
    resistant to weight loss

         

  • Dvorak
    RV, DeNino WF, et al (Univ of Vermont, Burlington)

    Phenotypic
    Characteristics Associated with Insulin Resistance
    in Metabolically Obese but Normal Weight Young
    Women.

    Diabetes
    48: 2210-2214, 1999

        

    In
    a cohort of 71 healthy, nonobese women, aged 21 to
    35 years, 13 metabolically obese normal-weight (MONW)
    women were identified based on cut points for
    insulin sensitivity.
    These women had glucose disposal of less than
    8mg/min-1/kg-1 of fat-free mass.
    Body composition, body fat distribution,
    cardiorespiratory fitness, physical activity energy
    expenditure, glucose tolerance, serum lipid profile,
    and dietary intake were assessed.

        

    Editorial
    comments: Metabolically obese means despite having a
    normal body weight and a normal body mass index (21
    to 23) these young women had slightly higher levels
    of fat mass (31% body fat), were less physically
    active (as measured from doubly-labeled water), and
    had higher levels of intraabdominal fat (determined
    by CT).

          

  • Samaras
    K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp,
    London; St. Vincent’s Hosp, Darlinghurst, New
    South Wales, Australia)

    Genetic
    and Envirnomental Influences on Total-Body and
    Central Abdominal Fat: The Effect of Physical
    Activity in Female Twins

    Ann
    Intern Med 130: 873-882,1 999

        

    Methods:
    Nine hundred seventy healthy female twins, aged 39
    to 70 years were studied.
    Two hundred forty-one pairs were monozygotic,
    and 228 were dizygotic.
    Fifty six percent of the women were of normal
    weight, 30% were overweight, 7% were obese, and 7%
    were underweight.

         

    Conclusions  – For healthy middle-aged women, current physical activity
    predicts lower total-body and central abdominal
    adiposity.  After
    adjustments for genetic and environmental variables,
    the effects of physical activity are greater than
    those of other measured environmental factors.

         

    Editorial
    comments:

    This article shows the potentially powerful effects
    of regular physical activity in preventing increases
    in central obesity. The accumulation of central body fat has been shown to be a
    powerful predictor of type 2 diabetes and
    cardiovascular disease.

         

  • Recently
    there has been a lot of emphasis on genetic factors
    and obesity. Editor
    E.T. Poehlman
    has selected number of articles from the literature
    and grouped together to underscore that the
    susceptibility to obesity and obesity-related
    phenotypes may be partially explained by genetic
    polymorphisms involved in the regulation of energy
    expenditure, substrate metabolism, and body
    composition.

         

    The
    work of Heinonen
    et al (Univ of Turku, Finland; Univ Hosp of
    Helsinki; Unvi of Kuopio, Finland)
    Identification
    of a Three-Amino Acid Deletion in the
    a2B-Adrenergic
    Receptor That is Associated with Reduced Basal
    Metabolic Rate in Obese Subjects

    published in J
    Clin Endocrinol Metab 84: 2429-2433, 1999
    ,
    elegantly shows that a genetic polymorphism of the
    a2B
    subtype can partly explain the reduced resting
    metabolic rate in obese individuals. 
    A low resting metabolic rate may predict
    subsequent weight gain because of its large
    contribution to daily energy expenditure.

        

    b2-adrenergic
    receptor
    gene with Obesity, Hypertriglyceridaemia, and Diabetes
    Mellitus
    ,
    published in
    Diabetologia 42:98-101, 1999
    , supports the
    notion that the amino-terminal polymorphisms of the
    b2-adrenergic
    receptor gene could be involved in the pathogenesis
    of obesity and hypertriglyceridemia.

       

    The
    article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere,
    Finland; Univ of Kuopio, Finland
    ) Additive
    Effects of the Mutations in the B3-Adrenergic
    Receptor and Uncoupling Protein-1 Genes on Weight
    Loss and Weight Maintenance in Finnish Women
    ,
    published in J
    Clin Endocrinol Metab 83: 4246-4250, 1998
    , is
    particularly interesting.
    Its strength lies in the examination of
    various genetic variants to achieve successful
    weight loss and maintain a reduced body weight. This
    article specifically examined whether the
    simultaneous presence of the Trp64Arg mutation in
    the B3-adrenergic receptor and the A
    ®G
    mutation in the uncoupling protein (UCP-1) gene have
    associations with weight loss and subsequent weight
    maintenance. The finding that the individuals with
    both mutations had a lower weight reduction and
    gained weight back more rapidly raises new questions
    regarding the polygenetic nature of obesity and the
    search for genes that may predict differential
    response to weight reduction programs.

       

  • Gill
    Spyer, Andrew T Hattersley, et al (Department of
    Vascular Medicine and Diabetes Research, London)

    Hypoglycaemic
    counter-regulation at normal blood glucose
    concentrations in patients with well controlled
    type-2 diabetes.

    Lancet
    356, December 9, 2000, pg. 1970-74.

       

    Intensive
    treatment to achieve good glycaemic control in
    diabetic patients is limited by a high frequency of
    hypoglycaemia. 
    The glucose concentrations at which symptoms
    and release of counter-regulatory hormones takes
    place have not been studied in patients with well
    controlled type-2 diabetes.

       

    The
    findings were that symptom response took place at
    higher whole blood glucose concentrations in
    diabetic patients than in controls.

        

    Glucose
    thresholds for counter-regulatory hormone secretion
    are altered in well controlled type-2 diabetic
    patients, so that both symptoms and
    counter-regulatory hormone release can take place at
    normal glucose values. 
    This effect might protect type-2 diabetic
    patients against episodes of profound hypoglycaemia
    and make the achievement of normoglycaemia more
    challenging in clinical practice

        

  • Abi
    Berger,

    Gut
    cells engineered to produce insulin

    BMJ,
    16 December 2000, pg.1488

        

    Engineering
    non-pancreatic cells to produce insulin in response
    to a glucose load may one day be a successful
    approach in the treatment of diabetes.
    Canadian scientists have now shown that cells
    other than pancreatic cells can be induced to
    secrete appropriate levels of insulin in response to
    eating.

        

    Previous
    attempts at gene therapy have concentrated on
    manipulation of liver cells, but hepatocytes do not
    have the ability to store hormones.

        

    Dr.
    Cheung (Dept. of Medicine, Univ. of Alberta, Canada)
    and his team have shown that mice can be genetically
    engineered to produce human insulin from K cells
    located in the duodenum. K cells usually produce glucose dependent insulinotropic
    polypeptide (GIP), so they have an advantage over
    hepatocytes in that they are already glucose
    responsive endocrine cells and have the correct
    equipment to be able to store hormones.

        

    Dr.
    Cheung showed that when K cells are genetically
    engineered to produce insulin, normal glucose
    tolerance could be achieved in animals that have had
    their own pancreatic beta cells ablated.

         

  • Rodien
    P, Bremont C, Sanson M-LR, et al [Universite Libre
    de Bruxelles, Brussels, Belgium; Hopital Cochin,
    Paris; Centre National pour Ia Recherche
    Scientifique, Paris]

    Familial Gestational Hypethyroidism Caused
    by a Mutant Thyrotropin Receptor Hypersensitive to
    Human Chorionic Gonadotropin.


    N
    Engl J Med 339: 1823-1826, 1998

        

    Because
    of the structural similarity of chorionic
    gonadotropin and thyrotropin, some stimulation of
    the thyroid gland by human chorionic gonadotropin [hCG]
    is common in early pregnancy. 
    Hyperemesis gravidarum is characterized by
    excessive vomiting in ealy pregancy. 
    Some women with this condition have high
    serum thyroid hormone concentrations, and some have
    high serum chorionic gonadotropin concentrations.
    This case report described a woman with recurrent
    gestational hyperthyroidism and normal serum
    chorionic gonadotropin concentrations, who was
    heterozygous for a mutation in the thyrotropin
    receptor, rendering it hypersensitive to chorionic
    gonadotropin. The woman’s mother also carried this
    mutation.

        

    The
    gestational hyperthyroidism described in the women
    reported in this article has a different mechanism
    than that associated with molar pregnancies and at
    least in some women with hyperemesis gravidarum. In
    the latter two conditions, hyperthryroidism results
    from activation of the thyrotropin receptor by
    excessive quantities of normal chorionic
    gonadotropin or by chorionic gonadotropin molecules
    with increased thyrotropin like activity.
    Both conditions are thought to represent an
    exaggeration of normal thyroid stimulation caused by
    maximal chorionic gonadotropin production that
    occurs early in pregnancy in many normal women.

        

  • Sabri
    O, Zimny M, Schulz G, et al [ Aachen Univ, Germany]

    Success Rate of Radioiodine Therapy in
    Graves Disease : The Influence of Thyrostatic
    Medication.


    J
    Clin Endocrinol Metab 84: 1129-1233, 1999

        

    Studies
    conflict as to whether simultaneous thyrostatic
    medication reduces the effectiveness of iodine 131I
    therapy in patients with Graves’ disease.
    The effects of thyrostasis with carbimazole
    on the outcomes of ablative 131I therapy,
    aiming for a constant absorbed dose of 250 Gy, were
    examined.

       

    Conclusions
    – For patients with Graves’ disease, simultaneous
    thyrostatic medication greatly reduces the chances
    of successful treatment with 131I.
    Thyrostasis reduces success rate even if the 131I
    dose is increased to achieve a higher absorbed dose.
    Even in patients with hyperthyroidism, success rates
    of up to 100% can be achieved without thyrostasis.

       

    Editorial
    Comments – In fact, most patients can be treated
    with 131I and
    b-blockers
    without antithyroid drugs.

        

  • Nygaard
    B, Hegedus L, Ulriksen P, et al [ Univ of
    Copenhagen; Odense Univ Hosp, Denmark]

    Radioiodine Therapy for Multinodular Toxic
    Goiter


    Arch
    Intern Med 159: 1364-1368, 1999

        

    Methods
    – The 131I dose was calculated as 100 mCi,
    corrected to 100% uptake of 131I after 24
    hours, with a maximum single dose of 20 mCi. Thyroid
    function variable and thyroid size on US were
    examined before and at 3 weeks, and at 3 , 6, and 12
    months after treatment, then yearly thereafter.

       

    Editorial
    Comments – Since surgery and 131I are
    equally effective, the choice boils down to patient
    preference and the risks of therapy. An argument for
    surgery is that the rate of thyroid carcinoma is not
    negligible [6% in one surgical series] among
    hyperfunctional nodules. Yet, 131I is
    less invasive and is safe and highly effective and
    reaches retrosternal tissue. The bottom line is that
    a multinodular goiter causing hyperthyroidism or
    compressive symptoms is best treated with 131I.
    Even euthyroid multinodular goiter can be treated
    with 131I under special circumstances.
    Probably the main drawback is a transition to toxic
    autoimmune hyperthyroidism that occurs among a small
    number of patients with nodular goiter after 131I
    treatment.

         

  • Franklyn
    JA, Maisonneuve P, Sheppard M, et al [Univ of
    Birmingham, England; European Inst of Oncology,
    Milan, Italy]

    Cancer Incidence and Mortality After
    Radioiodine Treatment for Hyperthyroidism: A
    Population-based Cohort Study


    Lancer
    353: 2111-2115, 1999

       

    Introduction – Radioiodine is being used with
    increasing frequency as a first-line treatment for
    patients with hyperthyroidism. Concerns remain
    regarding the subsequent risk of cancer,
    particularly in patients treated at a young age.

        

    Methods
    – A polulation-based investigation was conducted of
    7417 patients treated in Birmingham, England,
    between 1950 and 1991. The details of all cancer
    diagnoses and deaths between 1971 and 1991 from the
    United Kingdom Office for National Statistics were
    compared with data regarding cancer incidence and
    mortality for England and Wales specific for age,
    sex and period.

        

    Results
    – During 72,073 person-years of follow-up, 634
    patients received a diagnosis of cancer, compared
    with an expected number of 761. The relative risk of
    cancer mortality was also reduced. Lower incidences
    were observed for cancers of the pancreas, bronchus,
    trachea, bladder, and lymphatic and hemopoietic
    systems. The mortality rate from cancers at these
    sites was also diminished. Findings were significant
    only for bronchus and tracheal sites.

        

    Conclusion
    – The reduction in overall cancer incidence and
    mortality for patients treated for hyperthyroidism
    with radioiodine is encouraging. The absolute risk
    of cancer of the small bowel and thyroid continues
    to be low. The increase in relative risk indicates
    the need for long – term follow-up among patients
    receiving radioiodine.

        

    Editorial
    comments – in the Chernobyl accident, thyroid cancer
    appeared almost entirely in children who were under
    age 5 years at the time of the accident. If there is
    a risk of thyroid cancer after treatment with 131I,
    it is small enough to be virtually negligible.

        

    Ron
    and her colleagues studied the cancer incidence
    among 35,593 hyperthyroid patients treated with 131I
    between 1946 and 1964 and who were in his original
    Co-operative Thyrotoxicosis Therapy Follow-up Study.
    They found that 131I was not linked to
    total cancer deaths or to
    any
    specific cancer with the exception of thyroid
    cancer, although in absolute terms the excess number
    of deaths was small. There seems little that,
    overall, 131I is safe therapy for
    hyperthyroidism and the benefits of therapy clearly
    outweigh any minimal risks that may exist.

         

  • Lonn
    L, Stenlof K, Ottosson M, et al [Univ of Goteborg,
    Sweden]

    Body Weight and Body Composition Changes After
    Treatment of Hyperthyroidism


    J
    Clin Endocrinol Metab 83: 4269-4273, 1998

         

    Methods – The study included 9 adult patients
    receiving treatment for hyperthyroidism, including
    surgery, antithyroid drugs, or radioiodine therapy.
    Body composition parameters were obtained with
    dual-energy x-ray absorptiometry [DXA] and CT before
    and 3 and 12 months after the patients attained a
    euthyroid state.

         

    Conclusions-
    The findings help in understanding the changes in
    body composition occurring after patients with
    hyperthyroidism are returned to a euthyroid state.
    During the first 3 months, the major changes are
    replenishment of skeletal muscle and intraperitoneal
    AT, though subcutaneous AT is not significantly
    increased until 12 months. No significant increases
    in bone tissue or visceral organs occur during this
    time.

        

  • Fukata
    S, kuma K, Sugawara M [Kuma Hosp Kobe, Japan; Univ
    of California Los Angeles]

    Granulocyte Colony-Stimulating Factor [ G-CSF]
    Does Not Improve Recovery From Antithyroid
    Drug-Induced Agranulocytosis : A Prospective Study


    Thyroid
    9: 29-31, 1999

        

    Methods – For ATD therapy 21 patients
    received methimazole [average daily dose, 24 mg],
    and 3 received propylthiouracil [ average daily
    dose, 270 mg]. Eighteen patients [75%] had
    agranulocytosis develop in less than 3 months of
    drug therapy. When agranulocytosis was detected on
    complete blood count, patients were asked to
    discontinue ATDs and were hospitalized immediately.
    The 14 patients in the G-CSF group received
    daily subcutaneous injections of 100 to 250 mg
    G-CSf until the neutrophil increased to 1000 /mL
    or higher. The 10 control subjects received
    antibiotic therapy only. Recovery time was defined
    as the number of days needed to exceed neutrophil
    counts of 500 mL
    or higher after diagnosis of agranulocytosis.

         

    Conclusion
    – The efficacy of G-CSF treatment of ATD-induced
    agranulocytosis was not supported by this
    prospective, randomized investigation.

        

    Editorial
    Comments – Most episodes occur during the first
    weeks of treatment. It tends to occur more often
    among patients receiving more than 30 mg of
    methimazole a day.

        

    Patients
    usually recover within 2 to 3 weeks of stopping the
    drug, although recovery is abrupt in some and others
    die despite aggressive management with isolation,
    antibiotics, and G-CSF. There is possibility G-CSF
    might be efficacious in an ambulatory setting,
    suggesting that if the neutrophil count rises to at
    least 500 /
    mL
    4 hours after it is given, the patient may not
    require hospitalization. G-CSF is expensive, but under desperate conditions when patients
    become quite ill with this iatrogenic problem,
    physicians are likely to continue its use.

         

  • Hintz
    G, Blombach O, Fink H, et al [Teaching Hosp of
    Luebeck Univ, Bad Oldesloe, Germany; Univ of Essen,
    Germany; Teaching Hosp of Duesseldorf Univ,
    Wuppertal, Germany]

    Risk
    of Iodine-Induced Thyrotoxicosis After Coronary
    Angiography : An Investigation in 788 Unselected
    Subjects

    Eur
    J Endocrinol 140: 264-267, 1999

        

    Background – Examination of the thyroid
    gland and measurement of thyroid hormone in blood
    before coronary angiography are common practices. Although there are no data on the individual risk of iodine-induced
    thyrotoxicosis [IIT] after contrast media
    contamination, many clinicians recommend preventive
    therapy with antithyroid agents.
    The individual risk for the development of
    IIT among residents of an iodine deficient region
    was determined.

        

    Methods
    – The study included 788 patients undergoing
    coronary angiography in a German community.

       

    Conclusions-
    In this population of unselected, euthyroid patients
    from an iodine-deficient area, short-term iodine
    contamination from contrast media rarely resulted in
    hyperthyroidism. Thus,
    prophylactic treatment with perchlorate or
    thiamazole is not generally recommended, as the risk
    of adverse effects from such therapy may outweigh
    the risk of IIT.

        

    Editorial
    Comments – Elderly persons, especially women with
    longstanding large nodular goiters, are at greatest
    risk, but in the absence of preexisting thyroid
    disease, elderly men are affected more often.

         

  • Bunevicius
    R, Kazanavicius G, Zalinkevicius R, et al [Kaunas
    Med Univ, Lithuania; Univ of North Carolina, Chapel
    Hill]

    Effects
    of Thyroxine as Compared With Thyroxine Plus
    Triiodothyronine in Patients with Hypothyroidism

    N
    Engl J Med 340: 424-429, 1999

        

    Background – Although both T4
    and T3 
    are secreted by the normal thyroid gland, T4
    alone is the usual treatment for hypothyroidism.
    Whether thyroid secretion of T3 is
    physiologically important was examined.

        

    Methods – Thirty-three patients with
    hypothyroidism were included in the study. For each
    of two 5-week periods, patients were given their
    usual dose of T4 or a regimen in which 50 mg
    of their usual dose was replaced by 12.5 mg
    of T3. The order of the treatments was
    randomly determined. At the end of each period,
    biochemical, physiologic, and psychological
    assessments were made.

        

    Conclusion
    – Partial substitution of T3 for T4
    may improve mood and neuropsychological function in
    patients with hypothyroidism. T3 normally
    secreted by the thyroid gland appears to have a
    specific effect.

        

    Editorial
    Comments – The dosage and formulation of T4
    have evolved since the 1960s [when we routinely over
    treated patients with 200 to 400 mg
    daily] to doses between 100 and 150 mg
    that we now know are adequate to restore thyrotropin
    secretion to normal in most patients.

        

    This
    short term study does not address other end points
    [noted in the editorial that accompanies the paper]
    Such as exercise tolerance and myocardial
    performance.  Daily
    T3 secretion is only 6
    mg,
    but 10
    mg
    per day was substituted in this study, less than in
    current formulations. Most patients feel well and
    have normal serum thyrotropin concentrations with T4
    replacements alone, and we should not rush into
    combined hormone therapy until the results of
    Bunevicius et al are verified and long term studies
    are done.

            

  • Perry
    IJ, Wannamethee SG, et al (Royal Free Hospital, London; Univ of Newcastle upon Tyne, England)

    Serum True Insulin Concentration and the Risk of Clinical Non-Insulin Dependent Diabetes During Long-term Follow-up

    Int J Epidemiol 28: 735-741, 1999

       


    Background : Substantial evidence indicates that insulin resistance with compensatory hyperinsulinemia is an early, modifiable defect in the pathogenesis of NIDDM. However, such evidence comes mainly from studies using insulin assays that cross-react with proinsulin and other insulin precursors. A specific assay was used to determine whether an increase in serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM.

        


    Method :A cohort of 5550 men without diabetes (age, 40 to 59 years) from 18 British towns was followed up for a mean 14.8 years.

         


    Findings: One hundred sixty-eight incident cases of clinically diagnosed NIDDM occurred during follow-up.

       


    Conclusion : In this cohort, increased circulating true insulin levels antedate clinically manifest NIDDM by more than a decade. This supports the idea that insulin resistance with compensatory true hyperinsulinemia plays an early role in the pathogenesis of this condition.

        


    Editor’s comment: True insulin levels also confirm what most diabetologists have always known, namely, that insulin resistance (with compensatory hyperinsulinaemia) underlies type 2 diabetes in most patients.

        

  • Kaiyala KJ, Prigeon RL, et al (Univ of Washington, Seattle; Veterans Affairs Puget Sound Health Care System, Seattle; Univ of Cincinnati, Ohio)

    Reduced b-cell Function Contributes to Impaired Glucose Tolerance in Dogs Made Obese by High-Fat Feeding.

    Am J Physiol 277: E659-E667, 1999.

       


    From the animal study, it was concluded that High-fat feeding produces insulin resistance that is not compensated for by increased insulin secretion. This contributes to the development of glucose intolerance. These effects may be especially harmful in individuals who are predisposed to type 2 diabetes mellitus.

       


    Editor’s comment : A high-fat diet is a major culprit in the obesity seen in the Western industrialized world. Obesity is very common among patients with type 2 diabetes. This study demonstrated that a high fat diet, apart from inducing increased body weight and perhaps insulin resistance, may be associated with b-cell lipotoxicity with resultant diminution of b-cell secretory capacity.

        

  • Kitabchi AE, Imseis RE, Bush AJ, et al (Univ of Tennessee, Memphis)

    Racial Differences in the Correlation Between Gonadal Androgens and Serum Insulin Levels

    Diabetes Care 22: 1524-1529, 1999

       


    Purpose: Previous studies in a group of predominantly African American women with obesity and hyperandrogenism found that serum insulin level was directly correlated with levels of gonadal androgens (i.e, testosterone and androstenedione). However, this correlation has not always been demonstrated in predominantly white samples. Possible racial differences in the correlation between gonadal androgen and insulin levels were assessed.

    Method: The study included 14 African American and 14 white premenopausal women. The 2 racial groups were similar in terms of age, body mass index, and waist-to-hip ratio.

       


    Conclusions: African American women show a direct correaltion between gonadal androgen levels and the responses of glucose, insulin, and C-peptide to a glucose tolerance test. The findings support a racial difference in the relationship between gonadal hyperandrogenism and hyperinsulinemia. The mechanisms underlying this racial difference, including the possible protective effect of lower levels of visceral fat in African American women, warrant further study.

        


    Editor’s comment: This raises a very important question regarding the role of androgens in glucose and insulin metabolism and the development of type 2 diabetes in blacks.

       

  • Ciampelli M, Fulghesu AM, et al (Catholic Univ of Sacred Heart, Rome; OASI Inst for Research, Troina, Italy)

    Impact of Insulin and Body Mass Index on Metabolic and Endocrine Variables in Polycystic Ovary Syndrome.

    Metabolism 48: 167-172, 1999

       


    Purpose: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by anovulation, hyperandrogenism, and hyperinsulinemia with insulin resistance. There is a firmly established link between insulin resistance and obesity, and obesity iS common among patients with PCOS. The relative contributions of insulin and obesity to the disorders associated with PCOS were examined.

       


    Method : The study included 110 consecutive Italian women with
    PCOS.

    Conclusion: For patients with PCOS, hyperinsulinemia appears to have a significant effect on the LH response to a GnRH stimulus. Obesity and hyperinsulinemia combined to have a synergistic, additive effect on the free androgen index. Changes in lipid profile appear to result from obesity alone.

        


    Editor’s comment: This study shows that the role of hyperinsulinemia in the regulation of gonadal hormones and gonadotropins is partly dependent on the presence of obesity.

        

  • Vaccaro O, Ruffa G, Imperators G, et al (Federico II Univ, Naples, Italy)

    Risk of Diabetes in the New Diagnostic Category of Impaired Fasting Glucose: A Prospective Analysis.

    Diabetes Care 22: 1490 – 1493, 1999.

       


    Introduction: the latest American Diabetes Association (ADA) recommendations suggest that fasting glucose should be used rather than the oral glucose tolerance test (OGTT) for diagnosis of diabetes and impaired fasting glucose (IFG). In contrast, the World Health Organisation (WHO) recommends the OGTT for diagnosis of diabetes. Impaired fasting glucose is a new diagnostic category, the clinical significance of which is unknown. This study assessed progression to diabetes among subjects with evidence of impaired glucose regulation on either fasting glucose or OGTT. The 2 tests were compared for their ability to identify subjects at high risk of diabetes.

        


    Conclusion: The results support the continued use of the OGTT in screening programs to identify patients at high risk of diabetes, as recommended by the WHO. This is in contrast to the ADA recommendation to use the fasting glucose only. To date, this is the only population-based study of risk of progression to diabetes among Caucasian subjects with impaired fasting glucose.

       


    Editor’s comment: The new category of IFG could not supplant our old friend OGTT. OGTT is here to stay!

        

  • Mannucci E, Bardini G, et al (Careggi Hosp, Florence, Italy)

    Comparison of ADA and WHO Screening Methods for Diabetes Mellitus in Obese Patients.

    Diabetic Med 16: 579-585, 1999

       


    Background: Fasting glucose may not be sensitive enough to use as a screening method for diabetes, especially in high-risk populations. The performance of fasting glycemia (FG) was compared with that of oral glucose tolerance testing (OGTT) in the diabetes mellitus (DM) screening of obese patients.

       


    Method : Five hundred twenty eight consecutive obese outpatients under FG and OGTT. 

       


    Conclusion: The sensitivity of FG exceeding 6.1 mmol/L is satisfactory for screening for diabetes but not for IGT. A FG threshold of more than 7 mmol/L is not sensitive enough for diabetes screening in obese patients.

       


    Editor’s comment: The severity of fasting hyperglycaemia determines the B-cell function and the degree of hypertriglyceridemia in both obese and nonobese subjects. However, the presence of insulin resistance in most obese patients confound the degree of metabolic derangements. Various diagnostic criteria did not take into consideration the impact of obesity. Is it time to classify diabetes not only on the basis of glucose levels but also according to the presence of obesity of surrogates for insulin resistance?

       

  • Kashiwazaki K, Hirano T, et al (Showa Univ, Japan; Toho Univ, Tokyo)

    Decreased Release of Lipoprotein Lipase is Associated with Vascular Endothelial Damage in NIDDM Patients with Microalbuminuria.

    Diabetes Care 21: 2016-2020, 1998

       


    Background: Plasma triglyceride level is a risk factor for coronary heart disease in pateints with diabetes. This makes it important to identify the mechanisms of hypertriglyceridemia in diabetes. One possibility is that generalized endothelial damage reduces lipoprotein lipase (LPL) bound to epithelium. To assess this potential mechanism, the association between heparin-releasable LPL and von Willebrand factor (vWF) – a marker of endothelial damage – was evaluated in pateints with diabetes who have microalbuminuria.

       


    Conclusions: The findings demonstrate generalized endothelial damage in microalbuminuric patients with NIDDM. This leads to reduced endothelium-bound LPL and thus to impaired catabolism of TG-rich lipoproteins.

       


    Editor’s comment: These results suggest that widespread endothelial damage occurred in NIDDM patients with microalbuminuria. LPL moiety bound to the endothelium is thereby decreased, which results in an impaired catabolism of TG-rich lipoproteins.

       

  • Barzilay
    JI, Spiekerman CF, et al (Emory Univ, Atlanta, Ga; Univ of Washington, Seattle; Univ of Pittsburgh, Pa; et al)

    Cardiovascular Disease in Older Adults with Glucose Disorders: Comparison of American Diabetes Association Criteria for Diabetes Mellitus with WHO Criteria.

    Lancet 354: 622-625, 1999

        


    The American Diabetes Association’s (ADA) 1997 criteria for diagnosis of diabetes rely mainly on fasting glucose values, avoiding the need for oral glucose tolerance testing. In contrast, World Health Organization (WHO) criteria still call for oral glucose tolerance testing and have a higher cutoff point for fasting glucose concentration. It remains unclear which set of criteria are most useful for identifying glucose disturbances in the elderly. This study compared the ADA and WHO criteria for their ability to detect cardiovascular disease among older adults with diabetes or glucose disturbances.

        


    The ADA diagnostic criteria, based on fasting glucose measurements, are not as sensitive in predicting cardiovascular disease associated with glucose disturbances in the elderly as the WHO criteria, based on oral glucose tolerance testing. The findings question the recommendation to rely on fasting glucose measurements to diagnose glucose disorders in the elderly population.

        


    Editor’s comment: Delayed return of glucose to baseline (prandial hyperglycaemia) is the hallmark of diabetes in older persons. For that reason, the American Diabetes Association’s new criteria for the diagnosis of diabetes mellitus made little sense. 

        


    Diabetes mellitus remains a risk factor for coronary artery disease events, even in women in nursing homes.

       

  • Mitchell BD, Almasy LA, et al (Southwest Found for Biomedical Research, San Antonio, Tex; Univ of Texas, San Antonio)

    Diabetes and Hypertension in Mexican American Families: Relation to Cardiovascular Risk

    Am J Epidemiol 149: 1047-1056, 1999

        


    Type 2 diabetes, hypertension, and cardiovascular disease show a strong familial tendency. The association between a family history of these illnesses and a large panel of cardiovascular risk factors was studied in a group of Mexican Americans.

        


    A total of 1431 participants were enrolled in the San Antonio Family Heart Study.

       


    Family history of diabetes, and to a lesser degree hypertension, is significantly associated with a spectrum of cardiovascular risk factors. These relationships probably reflect the pleiotropic effects of genes transmitted from affected persons to their offspring.

        


    Editor’s comment: Hypertension is found in 50% to 60% of patients with type 2 diabetes. In both diseases, the major cause of death is cardiovascular disease. This suggests that both hypertension and diabetes could have a common genetic background.

       

  • Rodriguez BL, Sharp DS, Lau N, et al (Univ of Hawaii, Manoa; Kuakini Med Ctr, Honolulu, Hawaii; Natl Heart, Lung, and Blood Inst, Honolulu, Hawaii; et al)

    Glucose Intolerance and 23-Year Risk of Coronary Heart Disease and Total Mortality: The Honolulu Heart Program.

    Diabetes Care 22: 1261-1265, 1999.

        


    Though the increased risk of total mortality and coronary heart disease (CHD) morbidity and mortality in diabetic patients is well documented, the relationship between glucose intolerance and these outcomes is still unclear. The associations between glucose intolerance assessed on entry to the Honolulu Heart Program and the 23 year incidence of CHD, CHD mortality, and total mortality were reported.

    10

    A cohort of 8006 Japanese American men, aged 45 to 68 years were enrolled in the study in 1965 and followed up for 23 years.

       


    Conclusion : In this cohort of middle aged and older Japanese American men, glucose intolerance at baseline had a dose-response association with CHD incidence, CHD mortality and total mortality. This association persisted after adjustment for many other risk factors.

       


    Editors’ comment: The remarkable strength of this study is the 23-year duration of the follow-up (similar to the Framingham Cohort Study). Hyperglycemia -symptomatic and asymptomatic – remains a greater risk in the development of
    CHD.

        

  • Zavaroni I, Bonini L, et al (Parma Univ, Italy; Stanford Univ, Calif; Shaman Pharmaceuticals, South San Francisco)

    Hyperinsulinemia in a Normal Population as a Predictor of Non-Insulin-Dependent Diabetes Mellitus, Hypertension and Coronary Heart Disease: The Barilla Factory Revisited.

    Metabolism 48: 989-994, 1999

        


    Background- Previous research findings suggest that hyperinsulinemia, as a surrogate measure of resistance to insulin-mediated glucose disposal, is associated with higher concentrations of plasma glucose and triglyceride, a lower concentration of HDL cholesterol, and an increase in systolic and diastolic blood pressure. The capability of hyperinsulinemia to aid in the prediction of the development of glucose intolerance, hypertension, and coronary heart disease in a previously healthy population was investigated.

        


    Six hundred forty seven individuals who were free of disease at study enrollment were followed up between 1981 and 1993 to 1996.

        


    The untoward clinical effects of insulin resistance or compensatory hyperinsulinemia, glucose intolerance, hypertension and CHD can develop within 15 years. In this unselected population, hyperinsulinemia was an effective marker of subsequent CHD development.

    11

    Editor’s comment: The data are consistent with the presence of syndrome X.

        

  • Guerrer-Romero F, Rodriguez-Moran M (Gen Hosp of the Mexican Social Security Inst, Durango, Mexico)

    Proteinuria is an Independent Risk Factor for Ischemic Stroke in Non-Insulin Dependent Diabetes Mellitus.

    Stroke 30: 1787-1791, 1999

        


    In patients with non-insulin-dependent diabetes mellitus (NIDDM), proteinuria is an independent risk factor for cardiovascular disease. The association between proteinuria and ischemic stroke in patients with NIDDM was investigated.

       


    Fifty-nine diabetic patients with first-ever ischemic stroke from thrombotic arterial occlusion and 180 diabetic patients without stroke were included in the case-control study. The 2 groups were matched by sex, age and diabetes duration.

       


    This case-control study provides evidence that proteinuria is an independent risk factor for ischemic stroke in patients with NIDDM. More research is needed.

       


    Editor’s comment: Proteinuria is a reflection of generalized vascular compromise and hematorrheologic deregulation and blood pressure changes.

       

  • Perucchini d, Fischer U, et al (Univ Hosp Zurich, Switzerland)

    Using Fasting Plasma Glucose Concentrations to Screen for Gestational Diabetes Mellitus: Prospective Population Based Study.

    BMJ 319: 812-815, 1999

       


    Identifying women who are susceptible to gestational diabetes can help prevent perinatal morbidity and improve long-term outcomes for the mother and baby. Whether measurement of fasting glucose concentration is easier than the 1 hour, 50-g glucose challenge test in the screening of gestational diabetes mellitus was investigated.

    12

    The measurement of FPG levels, with a cut-off value of 4.8 mmol/l or greater, is easier than the 50-g glucose challenge test in screening for gestational diabetes and obviates the need for the challenge test in 70% of women.

        


    Editor’s comment: If confirmed in large studies, this will save doctors and patients very precious time. Longitudinal studies to examine the fetal and maternal outcomes of the use of FPG > 4.8 mmol/ml and 50-g glucose are needed.

        

  • Willms B, Ruge D (Diabetesklinik Bad Lauterberg, Germany)

    Comparison of Acarbose and Metformin in Patients with Type 2 Diabetes Mellitus Insufficiency Controlled with Diet and Sulphonylureas: A Randomized, Placebo-Controlled Study.

    Diabetic Med 16: 755-761, 1999.

      


    The efficacies of acarbose and metformin have been compared in patients with type 2 diabetes mellitus uncontrolled with diet alone. The safety and efficacy of these agents were assessed in diabetic patients in whom sulfonylurea therapy did not sufficiently control type 2 diabetes mellitus.

       


    Acarbose and metformin are equally effective in improving metabolic control in patients with diabetes that is insufficiently controlled with diet and sulfonylureas. Further studies are needed to determine the relative effects of metformin and acarbose on disease progression and long-term complications.

       


    Editor’s comment: The significant weight loss in the acarbose group versus the metformin group, in the face of comparable glycemic control and adverse gastrointestinal effects, is very encouraging. The only problem is whether the American patients with type 2 diabetes are willing to hang on long enough at the 300-mg/day dose of acarbose to realize the maximum potential of this drug.

       

  • Coon B, An L-L, Whitton JL, et al (The Scripps Research Inst, La Jolla, Calif)

    DNA Immunization to Prevent Autoimmune Diabetes

    J Clin Invest 104: 189-194, 1999

        


    In mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a transgene in b cells, IDDM develops only after LCMV infection. This model was used in an investigation of the potential of DNA vaccination to control autoimmune disease, with the use of islet self-antigens to induce regulatory lymphocytes and prevent autoimmune diabetes.

       


    DNA immunization with plasmids expressing self-antigens may be an attractive, novel approach to prevent autoimmune disorders. The antigens must be carefully preelected for their ability to induce regulatory lymphocytes in vivo.

        


    Editor’s comment: There may be a way to prevent type 1 diabetes with a vaccine of insulin B-chain NDA in the future. This novel approach to vaccination needs further confirmation in other rodents and ultimately in human beings.

       

  • Nielsen FS, Hansen HP, et al (Steno Diabetes Ctr, Gentofte, Denmark; Dept of Internal Medicine and Endocrinology F, Herlev, Denmark; Universite Louis Pasteur, Strasbourg, France)

    Increased Sympathetic Activity During Sleep and Nocturnal Hypertension in Type 2 Diabetic Patients with Diabetic Nephropathy.

    Diabetic Med 16: 555-562, 1999

       


    Morbidity and mortality from cardiovascular causes are excessive in patients with proteinuric type 2 diabetes. The putative factors involved in the blunted nocturnal blood pressure decreases in hypertensive patients with type 2 diabetes and diabetic nephropathy were investigated.

       


    Sustained adrenergic activity during sleep is correlated with blunted nocturnal blood pressure decrease in hypertensive patients with type 2 diabetes mellitus and diabetic nephropathy. This is probably mediated through a lack of peripheral vasodilation. Changes in extracellular fluid volume distribution and melatonin secretion have no effect.

       


    Editor’s comment: A blunted nocturnal blood pressure dip has been associated with microabluminuria. The mechanism of the blunted nocturnal BP dip has remained uncertain. Increased nocturnal sympathetic activity during hours of sleep in hypertensive type 2 diabetic patients may offer an explanation. These findings in the present study lend support for potential use of sympathetic blocking agents such as clonidine in these patients. Ultimately, the question to be address is whether reduction in sympathetic activity at night, with concomitant reduction in blood pressure, will ameliorate the progression of
    microalbuminuria.

        

  • Golden
    SH, Peart-Vigilance c, et al (Johns Hopkins Med Institutions, Baltimore, Md)

    Perioperative Glycemic Contrl and the Risk of Infectious Complications in a Cohort of Adults with Diabetes.

    Diabetes Care 22: 1408-1414, 1999

        


    Diabetes increases the risk of various types of infectious complications, although the reasons for this increase are unclear. One possibility is that hyperglycemia increases risks through short-term effects on immune function, pathogen growth, or vascular permeability. Patients with diabetes undergoing coronary surgery were studied to determine the effects of perioperative glycemic control on the risk of infectious complications after surgery.

        


    The study included 411 adult patients with any type of diabetes who underwent coronary artery bypass surgery during a 6-year period.

        

    Hyperglycemia appears to be an independent predictor of the short-term risk of infectious complications in patients with diabetes undergoing coronary artery surgery. The risk of infection is significantly elevated for patients whose mean glucose concentration during the 36 hours after surgery exceeds 200mg d/L. The results support published recommendations for stricter glycemic control for patients with diabetes during the perioperative period.

        


    Editor’s comment: This study re-emphasises the importance of perioperative glycemic control in adults with diabetes. He presumes that the same benefits may be applicable to children with diabetes who are undergoing major surgery also.

       

  • R Abs, J Verhelst, D Maiter, et al (Univ Hosp, Antwerp, Belgium; Middelheim Hosp, Antwerp, Belgium; Hopital Saint-Luc, Brussels, Belgium; et al) Cabergoline in the Treatment of Acromegaly: A Study in 64 patients. J Clin Endocrinol Metab 83: 374-378, 1998.

        


    Cabergoline, a new, long-acting dopamine agonist, is more effective and less toxic than bromocriptine in the treatment of hyperprolactinemia. This agent may also be useful in the medical management of
    acromegaly.

       

  • CB Newman, S Melmed, A George, et al (New York Univ; Cedars-Sinai Med Ctr, Los Angeles; Univ of Pennsylvania, Philadelphia; et al) Octreotide as Primary Therapy for Acromegaly. J Clin Endocrinol Metab 83:3034-3040, 1998.

        


    Conclusions – Octreotide was equally effective in patients receiving this agent for acromegaly as primary or secondary treatment. These findings raise questions about the current practice of surgically resecting all newly diagnosed GH-secreting pituitary adenomas.

        

  • Levine JA, Eberhardt NL, Jensen MD (Mayo Clinic and Mayo Found, Rochester, Minn)

    Role of Nonexercise Activity Thermogenesis in Resistance to Fat Gain in Humans.

    Science
    283: 212-214, 1999.

        


    Methods and Findings: For 8 weeks, 16 persons were fed 100 kcal/d more than weight-maintenance requirements. Two thirds of the increase in total daily energy expenditure resulted from increased nonexercise activity thermogenesis (NEAT), which is associated with fidgeting, maintaining posture, and other physical activities of daily living. Changes in NEAT explained the 10-fold differences in fat storage observed. These changes also directly predicted resistance to fat gain with overeating.

         


    Conclusions: These data suggest that the activation of NEAT dissipates excess energy to preserve leanness in persons who are overeating. Failure to activate NEAT may result in fat gain.

        


    Editorial comments: The use of doubly labeled water, a novel stable isotope technique, permitted the measurement of NEAT in response to overfeeding.

        

  • Gu K, Cowie CC, Harris MI (Natl Inst of Diabetes and Digestive and Kidney Diseases, Bethesda, Md)

    Diabetes and Decline in Heart Disease Mortality in US Adults.

    J.A.M.A. 281: 1291-1297, 1999

        


    Methods: Patients with and without diabetes, age 35 to 74 years, were followed up prospectively for age-specific mortality rates/1000 person-years, age adjusted and stratified by cohort, diabetes status, and sex.

        


    Conclusion: the decline in mortality rates for all causes, heart disease, and ischemic heart disease is lower for patients with diabetes than for those without diabetes, particularly if they are female.

        


    Editorial comments: Despite the decrease in the mortality rate from coronary heart disease in the United States over the past 30 years, it is unclear whether patients with diabetes have followed these trends. The findings show that mortality from all causes, heart disease, and ischemic disease has decreased slightly in men with diabetes, and it has actually increased in women. One possible explanation for these findings is that patients with diabetes may have benefited less from improved medical treatment of heart disease. Moreover, the fact that mortality rates actually increased in women may suggest that women are being treated less aggressively for their diabetes than men. It should be noted, however, that this study could not differentiate between the types of diabetes and could not identify individuals with undiagnosed diabetes. Given the increasing prevalence of diabetes in the US population, it is possible that diabetes may constitute an even more important factor associated with heart disease mortality.

       

  • Guven S, El-Bershawi A, etal (Med College of Wisconsin, Milwaukee)

    Plasma Leptin and Insulin Levels in Weight-Reduced Obese Women with Normal Body Mass Index: Relationships with Body Composition and Insulin.

    Diabetes 48: 347-352, 1999

        


    Study Design: The fasting plasma leptin and insulin levels were determined from 22 currently obese, 20 weight reduced obese (with a normal BMI of at least 1 year’s duration), and 29 never-obese women. All of the women were premenopausal. A subset of 14 currently obese, 9 weight-reduced obese, and 20 never-obese women had plasma leptin evaluated in relation to body composition and insulin dynamics. Dual-energy x-ray absorptiometry was used to assess total body fat, and CT scanning was used to detect abdominal visceral and subcutaneous fat components of these women. The minimal model procedure was used to obtain quantitative data on insulin sensitivity.

        


    Conclusion: For premenopausal women, plasma leptin levels are elevated in weight-reduced obese women with a normal BMI. This elevated leptin level may be caused by the larger amount of fat in the subcutaneous compartment of these women, compared with never-obese women. The normalization of visceral fat mass that accompanied weight loss for these women was associated with normalization of the insulin response.

        


    Editorial comment: The major finding is that for weight-reduced women, the insulin sensitivity index and first phase insulin response were comparable with those of never-obese women. Despite the normalization of BMI in weight-reduced individuals, a higher leptin level persisted that was related to higher subcutaneous abdominal fat. These results suggest that this depot is resistant to weight loss.

        

  • Dvorak RV, DeNino WF, et al (Univ of Vermont, Burlington)

    Phenotypic Characteristics Associated with Insulin Resistance in Metabolically Obese but Normal Weight Young Women.

    Diabetes 48: 2210-2214, 1999

        


    In a cohort of 71 healthy, nonobese women, aged 21 to 35 years, 13 metabolically obese normal-weight (MONW) women were identified based on cut points for insulin sensitivity. These women had glucose disposal of less than 8mg/min-1/kg-1 of fat-free mass. Body composition, body fat distribution, cardiorespiratory fitness, physical activity energy expenditure, glucose tolerance, serum lipid profile, and dietary intake were assessed.

        


    Finding: the metabolically obese normal-weight group had a higher body fat percentage and higher subcutaneous and visceral abdominal adiposity than did the normal group. The MNOW group also had a lower physical acitivty energy expenditure. Cardiorespiratory fitness did not differ between groups.

        


    Editorial comments: Metabolically obese means despite having a normal body weight and a normal body mass index (21 to 23) these young women had slightly higher levels of fat mass (31% body fat), were less physically active (as measured from doubly-labeled water), and had higher levels of intraabdominal fat (determined by CT).

        

  • Samaras K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp, London; St. Vincent’s Hosp, Darlinghurst, New South Wales, Australia)

    Genetic and Envirnomental Influences on Total-Body and Central Abdominal Fat: The Effect of Physical Activity in Female Twins

    Ann Intern Med 130: 873-882,1 999

       


    Methods: Nine hundred seventy healthy female twins, aged 39 to 70 years were studied. Two hundred forty-one pairs were monozygotic, and 228 were dizygotic. Fifty six percent of the women were of normal weight, 30% were overweight, 7% were obese, and 7% were underweight.

        


    Conclusions – For healthy middle-aged women, current physical activity predicts lower total-body and central abdominal adiposity. After adjustments for genetic and environmental variables, the effects of physical activity are greater than those of other measured environmental factors.

       


    Editorial comments: This article shows the potentially powerful effects of regular physical activity in preventing increases in central obesity. The accumulation of central body fat has been shown to be a powerful predictor of type 2 diabetes and cardiovascular disease.

        

  • Recently there has been a lot of emphasis on genetic factors and obesity. Editor E.T. Poehlman has selected number of articles from the literature and grouped together to underscore that the susceptibility to obesity and obesity-related phenotypes may be partially explained by genetic polymorphisms involved in the regulation of energy expenditure, substrate metabolism, and body composition. 

        


    The work of Heinonen et al (Univ of Turku, Finland; Univ Hosp of Helsinki; Unvi of Kuopio, Finland) Identification of a Three-Amino Acid Deletion in the a2B-Adrenergic Receptor That is Associated with Reduced Basal Metabolic Rate in Obese Subjects published in J Clin Endocrinol Metab 84: 2429-2433, 1999, elegantly shows that a genetic polymorphism of the a2B subtype can partly explain the reduced resting metabolic rate in obese individuals. A low resting metabolic rate may predict subsequent weight gain because of its large contribution to daily energy expenditure. 

        


    The work by Ishiyama-Shigemoto et al (Kurume Univ, Japan) Association of Polymorphisms in the b2-Adrenergic Receptor Gene with Obesity, Hypertriglyceridaemia, and Diabetes Mellitus, published in Diabetologia 42:98-101, 1999, supports the notion that the amino-terminal polymorphisms of the b2-adrenergic receptor gene could be involved in the pathogenesis of obesity and hypertriglyceridemia.

       


    The article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere, Finland; Univ of Kuopio, Finland) Additive Effects of the Mutations in the B3-Adrenergic Receptor and Uncoupling Protein-1 Genes on Weight Loss and Weight Maintenance in Finnish Women, published in J Clin Endocrinol Metab 83: 4246-4250, 1998, is particularly interesting. Its strength lies in the examination of various genetic variants to achieve successful weight loss and maintain a reduced body weight. This article specifically examined whether the simultaneous presence of the Trp64Arg mutation in the B3-adrenergic receptor and the A®G mutation in the uncoupling protein (UCP-1) gene have associations with weight loss and subsequent weight maintenance. The finding that the individuals with both mutations had a lower weight reduction and gained weight back more rapidly raises new questions regarding the polygenetic nature of obesity and the search for genes that may predict differential response to weight reduction programs.

        

  • Gill
    Spyer, Andrew T Hattersley, et al (Department of Vascular Medicine and Diabetes Research, London)

    Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes.

    Lancet 356, December 9, 2000, pg. 1970-74.

        


    Intensive treatment to achieve good glycaemic control in diabetic patients is limited by a high frequency of hypoglycaemia. The glucose concentrations at which symptoms and release of counter-regulatory hormones takes place have not been studied in patients with well controlled type-2 diabetes.

       


    The findings were that symptom response took place at higher whole blood glucose concentrations in diabetic patients than in controls.

        


    Glucose thresholds for counter-regulatory hormone secretion are altered in well controlled type-2 diabetic patients, so that both symptoms and counter-regulatory hormone release can take place at normal glucose values. This effect might protect type-2 diabetic patients against episodes of profound hypoglycaemia and make the achievement of normoglycaemia more challenging in clinical practice.

       

  • Abi Berger, 

    Gut cells engineered to produce insulin

    BMJ, 16 December 2000, pg.1488

        


    Engineering non-pancreatic cells to produce insulin in response to a glucose load may one day be a successful approach in the treatment of diabetes. Canadian scientists have now shown that cells other than pancreatic cells can be induced to secrete appropriate levels of insulin in response to eating.

        


    Previous attempts at gene therapy have concentrated on manipulation of liver cells, but hepatocytes do not have the ability to store hormones.

       


    Dr. Cheung (Dept. of Medicine, Univ. of Alberta, Canada) and his team have shown that mice can be genetically engineered to produce human insulin from K cells located in the duodenum. K cells usually produce glucose dependent insulinotropic polypeptide (GIP), so they have an advantage over hepatocytes in that they are already glucose responsive endocrine cells and have the correct equipment to be able to store hormones.

       


    Dr. Cheung showed that when K cells are genetically engineered to produce insulin, normal glucose tolerance could be achieved in animals that have had their own pancreatic beta cells ablated.

        

  • Elizabeth Barrett-Connor and Deborah L Wingard

    Normal blood glucose and coronary risk

    Dose response effect seems consistent throughout the glycaemic continuum.


    BMJ, Vol.322; 6 Jan 2001, p.5


           


    Glycosylated haemoglobin is an accurate indicator of blood glucose level over the preceeding 6-12 weeks. It is a more precise predictor of coronary heart disease risk. Even in patients without diabetes a glycosylated haemoglobin level in the higher brackets has been shown to be an indicator of impending coronary disease. However lowering of glycosylated haemoglobin has not been shown to have any significant benefit in reducing cardiovascular risk.. Anti-hypertensive treatment is far more effective.

           

  • Andrew J Krentz, Clifford J Bailey et al

    Thiazolidinediones for type 2 diabetes

    New agents reduce insulin resistance but need long term clinical trials

    BMJ, Vol.321, July 29, 2000, pg. 252-253

           

    Insulin resistance (reduced action of insulin) is a prominent defect in type 2 diabetes. Before the introduction of troglitazone in 1997 metformin was the only drug able to sensitize target tissues to insulin. Troglitazone is superseded by more potent agents, rosiglitazone and pioglitazone. 

           


    Patients with insulin resistance have elevated serum TG and low HDL. This dyslipidemia contributes to risk of atherosclerotic cardiovascular disease. Thiazolidonediones increase HDL and rosiglitazone protects against endothelial dysfunction, lowers BP in insulin resistant and hypertensive rats.

           


    Clinical trials show that combination therapy using a thiazolidinedione with metformin (main action of which is to reduce glucose production by liver) or a sulphonylurea is particularly effective in lowering glucose concentrations.

            


    Extensive use of rosiglitazone and pioglitazone has produced little evidence that it has caused hepatic impairment. They are contraindicated in patients with liver damage. Cardiac failure is a contraindication and patients with reduced cardiac reserve need close monitoring. Pioglitazone induces cytochrome P450 (isoform CYP3A4) and the possibility of drug interactions e.g. with oral contraceptives.

            

  • Irene M Stratton, Amanda I Adler, et al 

    Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes
    (UKPDS 35): prospective observational study.


    BMJ, Vol.321, Aug.12, 2000, pg.405-412.

            

    The objective of the study was to determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complication in patients with type 2 diabetes. It was carried out in 4585 Asian Indian, white and Afro-Caribbean UKPDS (UK prospective diabetes study) patients. Incidence of clinical complications was significantly associated with
    glycaemia. Each 1% reduction in updated mean HbAtc was associated with reductions of risk of 21% for any end-point related to diabetes. The lowest risk being in those with HbAtc values in the normal range (<60%).

          

  • Editorial – Jaakko Tuomilehto

    Controlling glucose and blood pressure in type 2 diabetes. 

    Starting treatment earlier may reduce complications.

    BMJ. Vol.321, Aug.12, 2000, pg.394-395.

           

    The main questions have been when should we start treatment, what is the target level during treatment and what is the best method of treatment, since there are no obvious cut-off points for
    B.P. or glucose or cholesterol concentrations that would guide clinical decisions.

           


    Comparisons with observational data have shown that antihypertensive drugs reduce the risk of stroke as predicted, but the reduction in the risk of myocardial infarction is less than expected. Treatment of hypercholesterolaemia with statins reduces the risk of myocardial infarction as predicted, whereas the effect on the risk of stroke seems larger than expected.

           


    The results of UKPDS studies reveal that patients with type 2 diabetes whose hypertension is tightly controlled reduce their risk of macrovascular complications to a greater extent than estimated. The data clearly show that there are no natural thresholds under which the risk of microvascular and macrovascular complications in diabetes are fully prevented but the risk increases steadily with rising levels of risk factors. The lower the level of blood glucose,
    HbAtcc, or BP, the lower the risk of complications.

           


    It is difficult to maintain reductions in glucose concentrations and BP even when using multiple drugs that in short term trials have produced excellent results. This was also confirmed in the
    UKPDS. Thus, the alternative possibility would be to start treatment at lower levels than those currently used as thresholds.

           


    A large European epidemiological study showed that postprandial glucose concentration is a better predictor of mortality than is fasting glucose. Perhaps impaired glucose tolerance should be an indication for treatment. There is a need to carry out controlled clinical trials to find out whether lowering glucose concentrations at the levels of impaired glucose tolerance will reduce microvascular and macrovascular complications.

          

  • M.N.
    Alp, Ali Ozgen, I.Can et al, (Department of
    Ophthalmology, Numune Hospital Turkey; Department of
    Radiology, Hacettepe University, Ankara, Turkey)

    Colour Doppler Imaging of the orbital vasculature
    in Grave’s disease with computed tomographic
    correlation.

    Br.J.Ophthalmol 2000; 84:1027-1030.

          

    In patients with Graves’ ophthalmopathy orbital
    blood flow velocities are altered. This alteration
    may be detected by colour Doppler imaging.

           

    Some of these changes correlate with enlargement of
    the extraocular muscles. Orbital inflammation may
    lead to increased blood flow velocities.

          

  • A
    Fagot-Campagna, K.M.Venkat Narayan et al

    Type 2 diabetes in children

    BMJ, Vol.322, Feb.17,2001, pg.37-378

       

    Type 2 diabetes in children is being reported from USA, Canada, Japan, Hong-Kong, Australia, New Zealand, Libya and Bangladesh. Prevalence ranges from 4.1 per 1000 in US to 50.9 per 1000 in Pima Indians of Arizona.

        

    At diagnosis, the affected child may present with weight loss, ketosis and acidosis. Insulin and C-peptide levels are often raised and antibodies absent, which may help differentiate type I from type 2 diabetes, but insulin secretion may be blunted at diagnosis. Patients may have hypertension, hypertriglyceridemia, albuminuria, sleep apnoea and depression. Treatment varies considerably and several drugs used for glycaemia, blood pressure and lipid control are not approved for use in children.

       

    To respond to this emerging problem, we need to develop case definitions in children. Safety and efficacy of therapies used in adults is known but same information is not available for children. Also needed are well co-ordinated, multi-centre trials testing the feasibility of multiple risk factor reduction in children and its benefits for practical health outcomes, such as the early stages of vascular disease.

       

  • John Pickup and Harry Keen

    Editorial – Continuous subcutaneous insulin infusion in type I diabetes.

    BMJ, May 26, 2001, pg.1262-1263.



    About 25 years ago BMJ published an account of a new technique for achieving long-term strict blood glucose control in type I diabetes.



    Continuous subcutaneous insulin infusion, or insulin pump therapy, mimics physiological delivery of insulin. It is now used by at least 130,000 people worldwide, more than 80,000 in USA alone.



    There are misunderstandings about its effectiveness, safety and clinical use. A meta-analysis of studies showed that glycaemic control is slightly but significantly better during insulin pump therapy with a glycated Hb percentage about 0.5% lower than on optimized injection regimens. As to safety, there were initial reports of hypoglycaemic coma but in 2 recent trials severe hypoglycaemia was nearly 50% less than on multiple insulin injection therapy. Some studies have found less hypoglycaemia with monomeric lispro analogue than with regular human insulin as the pump insulin.



    High rates of ketoacidosis reported earlier were probably due to lack of experience, unsuitable pump insulin, with aggregation causing cannula blockage, and the use of less reliable pumps without alarms.



    Insulin pump therapy is not indicated in most people with type I diabetes, who can achieve good control with intensified insulin therapy. Real benefits are obtained in perhaps 1-2% of those with type I diabetes. Establishing simple clinical guidelines for using continuous subcutaneous insulin infusion will promote its wider, but selective and more rational availability.  

          

  • Israel in stem cell breakthroughs

    Scrip No.2667, August 8, 2001, p.22

         

    Researchers in Israel have made advances in stem cell research which could have applications for heart attack and diabetes patients. They have succeeded in producing heart cells from stem cells (cardiomyocytes) and insulin producing islet cells both in the laboratory stage. If they succeed, there will be major changes in the treatment of heart disease and diabetes.

       

  • Vahab Fatourechi 

    Adverse Effects of Subclinical Hyperthyroidism 

    Lancet, Vol.358, September 15, 2001, Pg.856

         


    Sensitive thyrotropin (sTSH) assays can measure very low concentrations (as low as 0.001 mU/L) of thyrotropin. Introduction of these assays has allowed clinicians to diagnose “subclinical hyperthyroidism” as a distinct disorder of a very low or undetactable thyrotropin concentration associated with normal concentrations of peripheral thyroid hormones. 

         


    Possible causes of a low serum thyrotropin concentration, such as treatment with dopamine, dobutamine, high doses of glucocorticoids or recovery from hyperthyroidism should be ruled out.

         


    The most common cause is excess thyroid-hormone therapy. Thyroid autonomy due to autonomous adenoma or nodular goitre, early or mild Graves’ disease, silent or postpartum thyroiditis, subacute thyroiditis, and ingestion of pharmacological amounts of iodine are other causes.

         


    For patients receiving thyroxine-replacement therapy, the dose must be adjusted to obtain a normal serum thyrotropin concentration.

         

  • Brent E. Wisse, and Michael Schwartz 

    Role of Melanocortins in Control of Obesity 

    Lancet, Vol.358, September 15, 2001, Pg. 857

         


    The discovery in 1994 that deficiency of the adipocyte hormone, leptin, underlies genetic obesity in ob/ob mice, provided compelling support for the hypothesis that humoral signals generated in proportion to body-fat mass provide afferent input to critical brain areas that control energy intake and expenditure. 

        


    Melanocortins are neuropeptides such as a-MSH that are derived from pro-opiomelanocortin (POMC) – precursor polypeptide. When released from axon terminals in the hypothalamus, these peptides reduce food intake while increasing energy expenditure, mainly via activation of the neuronal Mc4r melanocortin receptor subtype, although Mc3r may also play a role. Opposing the neuronal action of a-MSH in this system is the endogenous Mc3/4r antagonist, agouti-related peptide (AgRP). 

        


    Both a-MSH and antagonist AgRP are synthesised within adjacent but distinct subgroups of hypothalamic neurons that are sensitive to input from adiposity-related signals such as leptin.

         


    Efforts to introduce leptin as a treatment for obesity have proved disappointing, largely because obesity is associated with leptin resistance. Since drugs acting “downstream” of leptin may effectively bypass this resistance, they are particularly appealing. 

         


    Melanocortin receptor agonists are an example of this new class of drug and seem to promote weight loss even in leptin-resistant forms of obesity. Melanocortin receptors are expressed widely in the body, and are involved in functions as diverse as skin pigmentation (Mc1r) and secretion of adrenal hormones (Mc2r), an important challenge is to target neuronal melanocortin receptors selectively.

         

  • M Keston Jones

    Management of Nodular Thyroid Disease 

    BMJ Vol. 7308, 11 August 2001; Pg. 293-94

          

    Diagnosis of nodules in the thyroid gland has remained uncertain in spite of new diagnostic techniques.

         

    Fine needle aspiration cytology (FNBC) is commonly used. It is far from satisfactory. There are 3 limitations.

         

    Firstly, 20% of samples are initially unsatisfactory. Secondly, follicular adenomas cannot be distinguished from carcinomas. 

         

    Finally, there are a number of false negatives – missed carcinomas. In spite of these difficulties FNBC remains the commonest diagnostic procedure. 

           

  • A. Gupta, R. Gupta, B. Lal 

    Effect of Trigonella foenum-graecum (Fenugreek) Seeds on Glycaemic Control and Insulin Resistance in Type 2 Diabetes Mellitus: A Double Blind Placebo Controlled Study 

    JAPI, Vol.49, November 2001, Pg. 1057-1061

          

    Summary : A double-blind placebo controlled study was performed in mild to moderate type 2 diabetes mellitus patients to evaluate the effects of Fenugreek seeds on glycaemic control and insulin resistance (determined by HOMA model).

          

    A hydro-alcoholic extract of fenugreek seeds was used in the form of capsules, and patients were asked to take 2 capsules twice a day before meals, for 2 months. Twenty five newly diagnosed patients with type 2 diabetes (fasting glucose < 200 mg/dl) were randomly divided into 2 groups. Group 1 (n=12) received 1 gm/day hydro-alcoholic extract of fenugreek seeds and group 2 (n=13) received usual care (dietary control, exercise and placebo capsules).

          

    Conclusions of the study were that adjunct use of fenugreek seeds improve glycaemic control and decrease insulin resistance in mild type 2 diabetic patients. The serum triglycerides decreased and HDL-cholesterol increased significantly in the group treated with fenugreek seeds.

          

  • V. Mohan and M. Balasubramanyam 

    Editorial: Fenugreek and Insulin Resistance 

    JAPI, Vol.49, November 2001, Pg. 1055-1056

          

    Summary : The seeds of fenugreek comprising mucilaginous fibre (about 50% by weight) and steroid saponins (12% by weight) have been claimed to account for many of the beneficial effects of fenugreek. The steroid saponins are thought to inhibit cholesterol absorption and synthesis while the fibre may help lower blood sugar levels.

          

    The available data suggests that it could be used as an adjunct therapy of type 2 diabetes, but most studies have been performed on small number of patients. Therefore, toxicity testing and large multicentre randomized clinical studies are necessary.

          

    Recently, 4-hydroxyisoleucine, an amino acid extracted from fenugreek seeds has been shown to potentiate insulin secretion. Its action is very specific on beta-cells. Multiple beneficial effects of fenugreek on glucose and lipid metabolism indicate that it can serve as an effective supportive therapy in the clinical management of diabetes.

          

    One should be cautioned that fenugreek may react adversely with a variety of medications including glipizide, heparin, insulin, ticlopidine and warfarin.

          

  • Jay S. Skyler, William T. Cefalu, et al 

    Efficacy of Inhaled Human Insulin in Type 1 Diabetes Mellitus: A Randomised Proof-of-Concept Study

    Lancet Vol.357, February 3, 2001, Pg. 331-335

         

    Summary : Effective glycaemic control in type 1 diabetes mellitus usually requires two or more insulin injections daily. Inhaled intrapulmonary delivery of insulin offers a potential new way to deliver meal-related insulin, eliminating the need for preprandial injections.

            

    73 patients with type 1 diabetes mellitus were studied in an open-label, proof-of-concept, parallel-group randomised trial. Patients in the experimental group received preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection. 

            

    Patients in the control group received their usual insulin regimen of two to three injections per day. Participants monitored their blood glucose four times daily, and adjusted insulin doses weekly to achieve preprandial glucose targets of 5.6-8.9 mmol/L.

           

    The primary outcome measure was change in glycosylated haemoglobin
    (HbA1c) after 12 weeks. Secondary outcomes were fasting and postprandial glucose response to a mixed meal; hypoglycaemia frequency and severity; pulmonary function; and patients’ satisfaction.

            

    Changes in HbA1c were indistinguishable between groups (difference 0.2% [95% Cl
    – 0.2 to 0.5]). Changes in fasting and postprandial glucose concentrations, and occurrence and severity of hypoglycaemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function (ie, spirometry, lung volumes, diffusion capacity, and oxygen saturation).

            

    This proof-of-concept study shows that preprandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional preprandial insulin injections.

            

  • Edwin A. M. Gale 

    Commentary: Two Cheers for Inhaled Insulin

    Lancet Vol.357, February 3, 2001, Pg. 324-325

            

    Summary : Jay Skyler and colleagues have shown by comparison between inhaled insulin and conventional therapy in patients with type 1 diabetes, that one daily injection of long-acting insulin plus 3 preprandial inhalations gives glucose control similar to that of 2 or 3 insulin injections a day.

            

    First paper on inhaled insulin came out in 1924 and other routes, such as transdermal, oral, nasal, intestinal, and rectal, were also extensively investigated, but only a small and erratic fraction of the amount administered reaches circulation.

            

    Inhalation has emerged as the most promising route for non-invasive administration of peptides or proteins. Insulin with a molecular weight of 5700, is absorbed well. Inhaled insulin peaks rapidly like a fast-acting analogue injected under the skin and has a longer duration of effect.

             

    Intra-individual variability of absorption is similar to injected insulin. Some of the inhaled insulins in development contain bile salts, which enhance absorption, but the Pfizer preparation consists of dry insulin dispersed by aerosol into particles sufficiently fine to drift into distal twigs of respiratory tree.

             

    Absence of an absorption enhancer reduces risk of adverse reactions but may also reduce bioavailability. Cigarette smoking is an effective means of increasing absorption of insulin but the finding is best ignored. On present evidence inhalation delivers a small and reproducible fraction of inhaled dose safely and rapidly in the blood stream.

            

    Skyler’s study is a ‘proof of concept’, and inhaled insulin does not abolish the need for insulin injections, although it may allow people to get by on only one a day. Long-acting insulins are necessary in type I diabetes and still have to be given by injection.

            

    It is too early to conclude that inhaled insulin is as good as conventional insulin, as the sample size has been too small.

             

  • Gene-Jack Wang, Nora D. Volkow, et al

    Brain Dopamine and Obesity

    Lancet Vol.357, February 3, 2001, Pg. 354-357

           

    Summary : The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity, authors measured the availability of dopamine
    D2 receptors in brain. 

          

    Brain dopamine D2 receptor availability was measured with positron emission tomography [PET] and [C-11]raclopride (a radioligand for the dopamine
    D2 receptor). Striatal dopamine D2 receptor availability was significantly lower in the 10 obese individuals than in controls. The interpretation was that the availability of dopamine
    D2 receptor was decreased in obese individuals in proportion to their BMI (body-mass index). 

          

    Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.

            

  • Paul T. C. Harrison

    Endocrine Disrupters and Human Health

    BMJ Vol.323, December 8, 2001, Pg. 1317-1318

          

    The term environmental oestrogen has given way to the more encompassing term “environmental endocrine disrupter” defined as an exogenous substance that causes adverse health effects in an intact organism, or its progeny, subsequent to changes in endocrine function.

           

    Endocrine disrupters are potentially present in food as natural ‘phytoestrogens’ and chemical contaminants. Among specific chemicals implicated as endocrine disrupters phthalates may be of particular importance because of their ubiquity. Similarly bisphenol A has been shown to have high potential for endocrine disruption through its use in can linings.

           

    This is of major interest because of possible exposure of infants to these chemicals at critical stages of development. Phthalate and similar compounds continue to cause concern for testicular development. 

           

    The debate about phytoestrogens and women’s health continues. There is concern that any hormonally active substance can induce or exacerbate breast and uterine cancer, and on the other is the knowledge that these substances can be used as alternatives to hormone replacement therapy in the treatment of post-menopausal symptoms and osteoporosis.

             

  • Judy Siegel-Itzkovich, Jerusalem

    Scientists develop a “vaccine” against diabetes

    BMJ, Vol.323, 1 Dec. 2001, pg. 1272

       

    Scientists have developed the world’s first drug that successfully halts the immune system’s destruction of pancreatic b-cells in humans called DiaPep277, the drug offers the possibility of preventing type I diabetes in healthy people with a genetic risk of the disease and halting its progression in people whose b-cells have already begun to die.

       

    This peptide has undergone Phase II clinical trial on 35 patients. Mechanism of action may be changes in patients’ T cells. In children the destruction of pancreatic cells is very rapid taking place even in a couple of months.     

                                                        

  • Richard Stanhope                      

    Commentary – Use of a specific aromatase inhibitor in delayed puberty                    

    Lancet, vol.357, June 2, 2001, pg.1723                     

                                                                                                          

    Constitutional delay of puberty and growth may be diagnosed in short adolescents who have delayed puberty, a delayed bone age, and no underlying illness. The diagnosis however, should be made on clinical and anthropometric criteria since biochemical assessment is often misleading in delayed puberty and such patients require practical help rather than intensive investigation.

                                                                     

    In Lancet, Sanna Wickman and colleagues report the results of a randomised double-blind placebo-controlled trial of letrozole, a specific fourth-generation aromatase inhibitor, along with testosterone treatment in boys with constitutional delay of puberty and growth. In boys the spontaneous growth spurt occurs late in puberty
    – about 2 years after the start of sexual development.

                                                                                      

    Recent knowledge from the study of inborn errors of metabolism has shown that oestrogen is the predominant hormone that causes epiphyseal closure in both sexes. Men with mutations of the genes for oestrogen receptor

    a8 or P-450 aromatase continue to grow after the age of 20 and attain tall stature. Non-specific aromatase inhibitors, such as testolactone, have been used in paediatric endocrine practice for many years to block the conversion of testosterone to oestrogen. Wickman and colleagues have refined this intervention by the use of a specific aromatase inhibitor to mimic the effect of these inborn errors. When testosterone therapy is combined with an aromatase inhibitor, the former provides virilisation and a growth spurt, while the latter delays epiphyseal closure thus allowing growth over a longer time. Indeed, the effect of this double-edged therapeutic approach is magnified because combined therapy produces a higher serum testosterone and lower serum oestrogen concentration than would be attained by either agent alone. The overall effect is to advance pubertal development and improve the final-height
    potential.        

                                                

  • Sanna Wickman, Ilkka Sipila, et al        

    A specific aromatase ihibitor and potential increase in adult height in boys with delayed puberty: a  
    randomised controlled trial.          

    Lancet , June 2, 2001, 357, pg.1743-48                                               

                                                                     

    The role of oestrogens in the closure of growth plates in both sexes is unequivocal. Inhibition of oestrogen synthesis in boys with delayed puberty would delay maturation of the growth plates and ultimately result in increased adult height.                

                                                 

    A randomised, double-blind, placebo controlled study was done, in which authors treated boys with constitutional delay of puberty with testosterone and placebo, or testosterone and letrozole. Boys who decided to wait for the spontaneous progression of puberty without medical intervention composed the untreated group.                               

                                  

    Letrozole effectively inhibited oestrogen synthesis and delayed bone maturation. Progression of bone maturation was slower in the letrozole group than in the placebo group.                                      

                                                   

    Interpretation of the study suggests that if oestrogen action is inhibited in growing adolescents, adult height will increase. This finding provides a rationale for studies that aim to delay bone maturation in several growth disorders.                     

                                          

  • Sheila A. Doggrell (Department of Physiology and Pharmacology, The University of
    Queensland, Brisbane, Queensland, Australia) 

    Targets to Trials in Diabetic Complications 

    Drugs of Today, Vol. 37(11), November 2001, Pg. 739-748

         

    Diabetes is now the leading cause of end-stage renal disease, blindness, lower-extremity amputations and impotence. 

         

    Targets with potential for therapeutic intervention in diabetic complications

                      


    Genetic studies: Aldose reductase inhibitors

                               

    A candidate gene near the transcription site of the aldose reductase gene has been identified. Aldose reductase inhibitors have not been shown to be beneficial in diabetic complications. A possible explanation for this is that aldose reductase is only one pathway that leads to stimulation of MAPKs
    (mitogen-activated protein kinases), which may be common mediators of diabetic complications and thus inhibition of aldose reductase alone is not effective. 

                                          

    MAPKs (Mitogen-activated protein kinases) 

                                         

    Professor David Tomlinson (University of Manchester, U. K.) presented evidence that the MAPKs trigger all of the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy. Professor Tomlinson suggested that the damaging effects of glucose, regardless of pathway
    (sorbitol, nonenzymatic glycation of proteins, oxidative stress) were finally mediated by the MAPKs
    (ERK, JNK and p38).                              

                                    

    To support his hypothesis Professor Tomlinson provided experimental evidence using selective inhibitors of p38 (SB202190 and SB238063) and ERK (U0126) but stated that selective antagonists of JNK were not presently available. Some suggested that the MAPKs are far too widespread and involved in too many functions to be therapeutic without serious side effects and that signaling upstream of MAPKs would make more selective targets.     

                                                     

    Others suggested that in low doses MAPKs may have some therapeutic potential in diabetic complications. 

                      

    PKC (Protein kinase C)



    PKC is upstream in the MAP-kinase pathway. Inhibition of glomerular PKC activity by a specific inhibitor of the
    ß isoform (LY333531) has been shown to prevent diabetes-related vascular dysfunction and increases in albuminuria in an animal model (12).



    Activation of a specific isoform of PKC may be involved in retinopathy and this isoform is a potential target. The identification of a specific isoform of PKC associated with retinopathy increases the likelihood of having beneficial effects in retinopathy without excessive side effects. 



    TGF-?ß(Transforming growth factor-ß)



    The important role of TGF-?ß in mesangial and macro- and microvascular dysfunction was considered by Professor Kumar Sharma (Thomas Jefferson University, Philadelphia, U.S.A.). In an animal model of type II diabetes, the diabetic glomerular hypertrophy could be prevented with
    anti-TGF-ß antibodies. 



    The reported beneficial effects of the ACE inhibitor captopril and the AT1-receptor antagonist losartan in diabetic kidney disease may be partly due to inhibiting angiotensin II stimulation of
    TGF-ß. As TGF-?ß has beneficial effects at other sites, it seems an unlikely target for therapeutic intervention in diabetic complications, as these beneficial effects may also be inhibited. 



    However, if there is excessive production of TGF-?ß
    in diabetic complications, it may be possible to reduce the excessive effects without modifying the beneficial functions. 



    Another possible target is the interrupting of various downstream effects of
    TGF-ß. Thus, USF-1 (upstream stimulatory factor-1), GRE (glucose response element), IP3R (the inositol 1,4,5-triphosphate receptor) may be important therapeutic targets to combat diabetic complications. 



    Nitric oxide/tetrahydrobiopterin



    Diabetics have reduced vasodilatation and inadequate angiogenesis. These disturbed vascular responses appear to be the result of impaired synthesis of nitric oxide (NO). The roles of NO and tetrahydrobiopterin, an essential cofactor for NO synthase, in vascular dysfunction in diabetes were discussed by Dr. Cynthia Meininger. 



    There are several possible ways to improve the endothelial dysfunction in diabetes. Tetrahydrobiopterin supplements could be used. The nitrates and the NO-donor drugs also have the potential to overcome this dysfunction. 



    Antioxidants/superoxide dismutase



    Oxidative stress with superoxide production also contributes to the vascular dysfunction in diabetes. However, when vitamin E, an antioxidant, was used in the HOPE study it was ineffective. 



    They assessed whether vitamin E supplementation for three months would improve conduit and resistance vessel vasodilator function in 41 subjects with type I diabetes, in a double-blind, placebo-controlled, randomized study. 



    Vitamin E improved endothelial function assessed by brachial flow-mediated dilatation and by intraarterial acetylcholine. This improvement was associated with a decrease in LDL cholesterol oxidation. 



    Wound healing: VEGF



    Delayed wound healing, or an inability to carry out tissue repair processes, is a major complication of diabetes leading to an increased incidence of chronic wounds such as leg ulcers. 



    There are a number of factors involved in the healing impairment in diabetes. These include the acute effects of hyperglycemia, the long-term effects of advanced glycosylation of extracellular matrix proteins and changes in expression levels and availability of growth factors or cytokines. 



    VEGF is very important in angiogenesis but it is reduced in diabetic wounds. VEGF is detrimental in retinopathy. Thus, the local administration of VEGF to diabetic wounds will need careful testing of whether it is beneficial to the wounds without being detrimental to the eye. 



    Inhibition of advanced glycation endproducts (AGE) formation.



    ACE inhibition with ramipril decreased AGE levels in experimental diabetes and this effect may have contributed to the benefit of ramipril in diabetic patients in the HOPE trial.



    Connective tissue growth factor (CTGF) 



    CTGF is a potent inducer of extracellular matrix and its gene expression is increased in rodent models of diabetes. AGE induces CTGF through a non-PKC-dependent pathway, and AGE and CTGF induce fibronectin through a PKC-dependent mechanism. 



    Thus, CTGF may be a new target for consideration in the treatment of complications of diabetes. 



    Glucose transformer isoform 1 (GLUT-1) transporter



    As the GLUT-1 transporter is overexpressed in mesangial cells subject to mechanical stress, this is a potential site for pharmacological intervention in diabetic complications. 



    Nephrin



    Nephrin is a cytoskeletal protein that localizes to the slit pore of podocytes. In some proteinuric models, deficiencies in nephrin have been associated with increases in albuminuria. Nephrin is a potential target for pharmacological intervention in diabetes associated with hypertension. 

 



 

 

Speciality Spotlight

 

 
Endocrinology
   

  

  • De Lonlay-Debenay P, Poggi-Travert F, Fournet J-C, et al [Hopital des Enfants Malades, Paris; Universite de Louvain, Brussels, Belgium; Ospedale Bambino Gesu, Rome
    Clinical Features of 52 Neonates With Hyperinsulinism
    N Engl J Med 340: 1169-1175, 1999
            
    Congenital Hyperinsulinism can be caused either by diffuse abnormalities of pancreatic beta cells or by focal abnormalities involving adenomatous islet cell hyperplasia, whereas a pancreas with diffuse involvement will likely require total or near-total pancretectomy. Focal hyperplasia can be treated with partial pancreatectomy to excise the abnormal area.
       
    In all 52 neonates with hyperinsulinism who required surgery were studied. Preoperatively, patients underwent transheptic, catheterization to locate the site(s) of insulin hypersecretion. Intraoperatively, tissues from the head, isthmus, body, and tail of the pancreas were examined histologically to confirm the extent of the involvement. By this method, 30 neonates had diffuse beta cell hyperfunction and underwent near-total pancreatectomy, whereas 22 neonates had focal hyperplasia and typically underwent partial pancreatectomy. All patients were monitored postoperatively by measurement of plasma glucose levels and glycosylated hemoglobin levels as well as by oral glucose tolerance tests.
       
    Focal hyperinsulinism can be detected by preoperative pancreatic catheterazation and intraoperative historical examination. This disorder can be successfully treated with partial pancreatectomy with litte risk  of the development of diabetes mellitus in future.
       
             

  • N Fuenmanyor, E Moreira, LX Cubeddu, (Central Univ of Venezuela, Caracas)
    Salt Sensitivity is Associated with Insulin Resistance in Essential Hypertension.
    Am J Hypertens 11: 397-402, 1998.
       
    Patients with essential hypertension may be salt sensitive or salt resistant. Hypertension in salt sensitive patients is associated with insulin resistance. In salt sensitive patients, high salt intake leads to increase in blood pressure, induced hyperinsulinemia, and worsening of diabetes.
       

  • R Abs, J Verhelst, D Maiter, et al (Univ Hosp, Antwerp, Belgium; Middelheim Hosp, Antwerp, Belgium; Hopital Saint-Luc, Brussels, Belgium; et al)  
    Cabergoline in the Treatment of Acromegaly: A Study in 64 patients.  
    J Clin Endocrinol Metab 83: 374-378, 1998.
       
    Cabergoline, a new, long-acting dopamine agonist, is more effective and less toxic than bromocriptine in the treatment of hyperprolactinemia.  This agent may also be useful in the medical management of acromegaly.
       

  • CB Newman, S Melmed, A George, et al (New York Univ; Cedars-Sinai Med Ctr, Los Angeles; Univ of Pennsylvania, Philadelphia; et al)  
    Octreotide as Primary Therapy for Acromegaly. 
     J Clin Endocrinol Metab 83:3034-3040, 1998.

         
    Conclusions – Octreotide was equally effective in patients receiving this agent for acromegaly as primary or secondary treatment.  These findings raise questions about the current practice of surgically resecting all newly diagnosed GH-secreting pituitary adenomas.
        

  • Perry IJ, Wannamethee SG, et al (Royal Free Hospital, London; Univ of Newcastle upon Tyne, England)
    Serum True Insulin Concentration and the Risk of Clinical Non-Insulin Dependent Diabetes During Long-term Follow-up
    Int J Epidemiol 28: 735-741, 1999
       
    Background : Substantial evidence indicates that insulin resistance with compensatory hyperinsulinemia is an early, modifiable defect in the pathogenesis of NIDDM. However, such evidence comes mainly from studies using insulin assays that cross-react with proinsulin and other insulin precursors. A specific assay was used to determine whether an increase in serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM.
       
    Method :A cohort of 5550 men without diabetes (age, 40 to 59 years) from 18 British towns was followed up for a mean 14.8 years.
       
    Findings: One hundred sixty-eight incident cases of clinically diagnosed NIDDM occurred during follow-up.
       
    Conclusion : In this cohort, increased circulating true insulin levels antedate clinically manifest NIDDM by more than a decade. This supports the idea that insulin resistance with compensatory true hyperinsulinemia plays an early role in the pathogenesis of this condition.
        
    Editor’s comment: True insulin levels also confirm what most diabetologists have always known, namely, that insulin resistance (with compensatory hyperinsulinaemia) underlies type 2 diabetes in most patients.
        

  • Kaiyala KJ, Prigeon RL, et al (Univ of Washington, Seattle; Veterans Affairs Puget Sound Health Care System, Seattle; Univ of Cincinnati, Ohio)
    Reduced b-cell Function Contributes to Impaired Glucose Tolerance in Dogs Made Obese by High-Fat Feeding.
    Am J Physiol 277: E659-E667, 1999.
        
    From the animal study, it was concluded that High-fat feeding produces insulin resistance that is not compensated for by increased insulin secretion. This contributes to the development of glucose intolerance. These effects may be especially harmful in individuals who are predisposed to type 2 diabetes mellitus.
       
    Editor’s comment : A high-fat diet is a major culprit in the obesity seen in the Western industrialized world. Obesity is very common among patients with type 2 diabetes. This study demonstrated that a high fat diet, apart from inducing increased body weight and perhaps insulin resistance, may be associated with b-cell lipotoxicity with resultant diminution of b-cell secretory capacity.
       

  • Kitabchi AE, Imseis RE, Bush AJ, et al (Univ of Tennessee, Memphis)
    Racial Differences in the Correlation Between Gonadal Androgens and Serum Insulin Levels
    Diabetes Care 22: 1524-1529, 1999
       
    Purpose: Previous studies in a group of predominantly African American women with obesity and hyperandrogenism found that serum insulin level was directly correlated with levels of gonadal androgens (i.e, testosterone and androstenedione). However, this correlation has not always been demonstrated in predominantly white samples. Possible racial differences in the correlation between gonadal androgen and insulin levels were assessed.
       
    Method: The study included 14 African American and 14 white premenopausal women. The 2 racial groups were similar in terms of age, body mass index, and waist-to-hip ratio.
        
    Conclusions: African American women show a direct correaltion between gonadal androgen levels and the responses of glucose, insulin, and C-peptide to a glucose tolerance test. The findings support a racial difference in the relationship between gonadal hyperandrogenism and hyperinsulinemia. The mechanisms underlying this racial difference, including the possible protective effect of lower levels of visceral fat in African American women, warrant further study.
        
    Editor’s comment: This raises a very important question regarding the role of androgens in glucose and insulin metabolism and the development of type 2 diabetes in blacks.
        

  • Ciampelli M, Fulghesu AM, et al (Catholic Univ of Sacred Heart, Rome; OASI Inst for Research, Troina, Italy)
    Impact of Insulin and Body Mass Index on Metabolic and Endocrine Variables in Polycystic Ovary Syndrome.
    Metabolism 48: 167-172, 1999
       
    Purpose: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by anovulation, hyperandrogenism, and hyperinsulinemia with insulin resistance. There is a firmly established link between insulin resistance and obesity, and obesity iS common among patients with PCOS. The relative contributions of insulin and obesity to the disorders associated with PCOS were examined.
       
    Method : The study included 110 consecutive Italian women with PCOS.
       
    Conclusion: For patients with PCOS, hyperinsulinemia appears to have a significant effect on the LH response to a GnRH stimulus. Obesity and hyperinsulinemia combined to have a synergistic, additive effect on the free androgen index. Changes in lipid profile appear to result from obesity alone.
       
    Editor’s comment: This study shows that the role of hyperinsulinemia in the regulation of gonadal hormones and gonadotropins is partly dependent on the presence of obesity.
        

  • Vaccaro O, Ruffa G, Imperators G, et al (Federico II Univ, Naples, Italy)
    Risk of Diabetes in the New Diagnostic Category of Impaired Fasting Glucose: A Prospective Analysis.
    Diabetes Care 22: 1490 – 1493, 1999.
       
    Introduction: the latest American Diabetes Association (ADA) recommendations suggest that fasting glucose should be used rather than the oral glucose tolerance test (OGTT) for diagnosis of diabetes and impaired fasting glucose (IFG). In contrast, the World Health Organisation (WHO) recommends the OGTT for diagnosis of diabetes. Impaired fasting glucose is a new diagnostic category, the clinical significance of which is unknown. This study assessed progression to diabetes among subjects with evidence of impaired glucose regulation on either fasting glucose or OGTT. The 2 tests were compared for their ability to identify subjects at high risk of diabetes.
        
    Conclusion: The results support the continued use of the OGTT in screening programs to identify patients at high risk of diabetes, as recommended by the WHO. This is in contrast to the ADA recommendation to use the fasting glucose only. To date, this is the only population-based study of risk of progression to diabetes among Caucasian subjects with impaired fasting glucose.
        
    Editor’s comment: The new category of IFG could not supplant our old friend OGTT. OGTT is here to stay!
       

  • Mannucci E, Bardini G, et al (Careggi Hosp, Florence, Italy)
    Comparison of ADA and WHO Screening Methods for Diabetes Mellitus in Obese Patients.
    Diabetic Med 16: 579-585, 1999
        
    Background: Fasting glucose may not be sensitive enough to use as a screening method for diabetes, especially in high-risk populations. The performance of fasting glycemia (FG) was compared with that of oral glucose tolerance testing (OGTT) in the diabetes mellitus (DM) screening of obese patients.
       
    Method : Five hundred twenty eight consecutive obese outpatients under FG and OGTT. 
        
    Conclusion: The sensitivity of FG exceeding 6.1 mmol/L is satisfactory for screening for diabetes but not for IGT. A FG threshold of more than 7 mmol/L is not sensitive enough for diabetes screening in obese patients.
        
    Editor’s comment: The severity of fasting hyperglycaemia determines the B-cell function and the degree of hypertriglyceridemia in both obese and nonobese subjects. However, the presence of insulin resistance in most obese patients confound the degree of metabolic derangements. Various diagnostic criteria did not take into consideration the impact of obesity. Is it time to classify diabetes not only on the basis of glucose levels but also according to the presence of obesity of surrogates for insulin resistance?
        

  • Kashiwazaki K, Hirano T, et al (Showa Univ, Japan; Toho Univ, Tokyo)
    Decreased Release of Lipoprotein Lipase is Associated with Vascular Endothelial Damage in NIDDM Patients with Microalbuminuria.
    Diabetes Care 21: 2016-2020, 1998
       
    Background: Plasma triglyceride level is a risk factor for coronary heart disease in pateints with diabetes. This makes it important to identify the mechanisms of hypertriglyceridemia in diabetes. One possibility is that generalized endothelial damage reduces lipoprotein lipase (LPL) bound to epithelium. To assess this potential mechanism, the association between heparin-releasable LPL and von Willebrand factor (vWF) a marker of endothelial damage was evaluated in pateints with diabetes who have microalbuminuria.
        
    Conclusions: The findings demonstrate generalized endothelial damage in microalbuminuric patients with NIDDM. This leads to reduced endothelium-bound LPL and thus to impaired catabolism of TG-rich lipoproteins.
       
    Editor’s comment: These results suggest that widespread endothelial damage occurred in NIDDM patients with microalbuminuria. LPL moiety bound to the endothelium is thereby decreased, which results in an impaired catabolism of TG-rich lipoproteins.
       

  • Barzilay JI, Spiekerman CF, et al (Emory Univ, Atlanta, Ga; Univ of Washington, Seattle; Univ of Pittsburgh, Pa; et al)
    Cardiovascular Disease in Older Adults with Glucose Disorders: Comparison of American Diabetes Association Criteria for Diabetes Mellitus with WHO Criteria.
    Lancet 354: 622-625, 1999
       
    The American Diabetes Association’s (ADA) 1997 criteria for diagnosis of diabetes rely mainly on fasting glucose values, avoiding the need for oral glucose tolerance testing. In contrast, World Health Organization (WHO) criteria still call for oral glucose tolerance testing and have a higher cutoff point for fasting glucose concentration. It remains unclear which set of criteria are most useful for identifying glucose disturbances in the elderly. This study compared the ADA and WHO criteria for their ability to detect cardiovascular disease among older adults with diabetes or glucose disturbances.
        
    The ADA diagnostic criteria, based on fasting glucose measurements, are not as sensitive in predicting cardiovascular disease associated with glucose disturbances in the elderly as the WHO criteria, based on oral glucose tolerance testing. The findings question the recommendation to rely on fasting glucose measurements to diagnose glucose disorders in the elderly population.
       
    Editor’s comment: Delayed return of glucose to baseline (prandial hyperglycaemia) is the hallmark of diabetes in older persons. For that reason, the American Diabetes Association’s new criteria for the diagnosis of diabetes mellitus made little sense. 
        
    Diabetes mellitus remains a risk factor for coronary artery disease events, even in women in nursing homes.
       

  • Mitchell BD, Almasy LA, et al (Southwest Found for Biomedical Research, San Antonio, Tex; Univ of Texas, San Antonio)
    Diabetes and Hypertension in Mexican American Families: Relation to Cardiovascular Risk
    Am J Epidemiol 149: 1047-1056, 1999
       
    Type 2 diabetes, hypertension, and cardiovascular disease show a strong familial tendency. The association between a family history of these illnesses and a large panel of cardiovascular risk factors was studied in a group of Mexican Americans.
       
    A total of 1431 participants were enrolled in the San Antonio Family Heart Study.
       
    Family history of diabetes, and to a lesser degree hypertension, is significantly associated with a spectrum of cardiovascular risk factors. These relationships probably reflect the pleiotropic effects of genes transmitted from affected persons to their offspring.
       
    Editor’s comment: Hypertension is found in 50% to 60% of patients with type 2 diabetes. In both diseases, the major cause of death is cardiovascular disease. This suggests that both hypertension and diabetes could have a common genetic background.
       

  • Rodriguez BL, Sharp DS, Lau N, et al (Univ of Hawaii, Manoa; Kuakini Med Ctr, Honolulu, Hawaii; Natl Heart, Lung, and Blood Inst, Honolulu, Hawaii; et al)
    Glucose Intolerance and 23-Year Risk of Coronary Heart Disease and Total Mortality: The Honolulu Heart Program.
    Diabetes Care 22: 1261-1265, 1999.
       
    Though the increased risk of total mortality and coronary heart disease (CHD) morbidity and mortality in diabetic patients is well documented, the relationship between glucose intolerance and these outcomes is still unclear. The associations between glucose intolerance assessed on entry to the Honolulu Heart Program and the 23 year incidence of CHD, CHD mortality, and total mortality were reported.
       
    A cohort of 8006 Japanese American men, aged 45 to 68 years were enrolled in the study in 1965 and followed up for 23 years.
       
    Conclusion : In this cohort of middle aged and older Japanese American men, glucose intolerance at baseline had a dose-response association with CHD incidence, CHD mortality and total mortality. This association persisted after adjustment for many other risk factors.
       
    Editors’ comment: The remarkable strength of this study is the 23-year duration of the follow-up (similar to the Framingham Cohort Study). Hyperglycemia symptomatic and asymptomatic remains a greater risk in the development of CHD.
       

  • Zavaroni I, Bonini L, et al (Parma Univ, Italy; Stanford Univ, Calif; Shaman Pharmaceuticals, South San Francisco)
    Hyperinsulinemia in a Normal Population as a Predictor of Non-Insulin-Dependent Diabetes Mellitus, Hypertension and Coronary Heart Disease: The Barilla Factory Revisited.
    Metabolism 48: 989-994, 1999
       
    Background- Previous research findings suggest that hyperinsulinemia, as a surrogate measure of resistance to insulin-mediated glucose disposal, is associated with higher concentrations of plasma glucose and triglyceride, a lower concentration of HDL cholesterol, and an increase in systolic and diastolic blood pressure. The capability of hyperinsulinemia to aid in the prediction of the development of glucose intolerance, hypertension, and coronary heart disease in a previously healthy population was investigated.
       
    Six hundred forty seven individuals who were free of disease at study enrollment were followed up between 1981 and 1993 to 1996.
       
    The untoward clinical effects of insulin resistance or compensatory hyperinsulinemia, glucose intolerance, hypertension and CHD can develop within 15 years. In this unselected population, hyperinsulinemia was an effective marker of subsequent CHD development.
       
    Editor’s comment: The data are consistent with the presence of syndrome X.
        

  • Guerrer-Romero F, Rodriguez-Moran M (Gen Hosp of the Mexican Social Security Inst, Durango, Mexico)
    Proteinuria is an Independent Risk Factor for Ischemic Stroke in Non-Insulin Dependent Diabetes Mellitus.
    Stroke 30: 1787-1791, 1999
        
    In patients with non-insulin-dependent diabetes mellitus (NIDDM), proteinuria is an independent risk factor for cardiovascular disease. The association between proteinuria and ischemic stroke in patients with NIDDM was investigated.
       
    Fifty-nine diabetic patients with first-ever ischemic stroke from thrombotic arterial occlusion and 180 diabetic patients without stroke were included in the case-control study. The 2 groups were matched by sex, age and diabetes duration.
       
    This case-control study provides evidence that proteinuria is an independent risk factor for ischemic stroke in patients with NIDDM. More research is needed.
        
    Editor’s comment: Proteinuria is a reflection of generalized vascular compromise and hematorrheologic deregulation and blood pressure changes.
       

  • Perucchini d, Fischer U, et al (Univ Hosp Zurich, Switzerland)
    Using Fasting Plasma Glucose Concentrations to Screen for Gestational Diabetes Mellitus: Prospective Population Based Study.
    BMJ 319: 812-815, 1999
       
    Identifying women who are susceptible to gestational diabetes can help prevent perinatal morbidity and improve long-term outcomes for the mother and baby. Whether measurement of fasting glucose concentration is easier than the 1 hour, 50-g glucose challenge test in the screening of gestational diabetes mellitus was investigated.
    12
    The measurement of FPG levels, with a cut-off value of 4.8 mmol/l or greater, is easier than the 50-g glucose challenge test in screening for gestational diabetes and obviates the need for the challenge test in 70% of women.
         
    Editor’s comment: If confirmed in large studies, this will save doctors and patients very precious time. Longitudinal studies to examine the fetal and maternal outcomes of the use of FPG > 4.8 mmol/ml and 50-g glucose are needed
       

  • Willms B, Ruge D (Diabetesklinik Bad Lauterberg, Germany)
    Comparison of Acarbose and Metformin in Patients with Type 2 Diabetes Mellitus Insufficiency Controlled with Diet and Sulphonylureas: A Randomized, Placebo-Controlled Study.
    Diabetic Med 16: 755-761, 1999.
        
    The efficacies of acarbose and metformin have been compared in patients with type 2 diabetes mellitus uncontrolled with diet alone. The safety and efficacy of these agents were assessed in diabetic patients in whom sulfonylurea therapy did not sufficiently control type 2 diabetes mellitus.
        
    Acarbose and metformin are equally effective in improving metabolic control in patients with diabetes that is insufficiently controlled with diet and sulfonylureas. Further studies are needed to determine the relative effects of metformin and acarbose on disease progression and long-term complications.
       
    Editor’s comment: The significant weight loss in the acarbose group versus the metformin group, in the face of comparable glycemic control and adverse gastrointestinal effects, is very encouraging. The only problem is whether the American patients with type 2 diabetes are willing to hang on long enough at the 300-mg/day dose of acarbose to realize the maximum potential of this drug.
       

  • Coon B, An L-L, Whitton JL, et al (The Scripps Research Inst, La Jolla, Calif)
    DNA Immunization to Prevent Autoimmune Diabetes
    J Clin Invest 104: 189-194, 1999
       
    In mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a transgene in b cells, IDDM develops only after LCMV infection. This model was used in an investigation of the potential of DNA vaccination to control autoimmune disease, with the use of islet self-antigens to induce regulatory lymphocytes and prevent autoimmune diabetes.
       
    DNA immunization with plasmids expressing self-antigens may be an attractive, novel approach to prevent autoimmune disorders. The antigens must be carefully preelected for their ability to induce regulatory lymphocytes in vivo.
       
    Editor’s comment: There may be a way to prevent type 1 diabetes with a vaccine of insulin B-chain NDA in the future. This novel approach to vaccination needs further confirmation in other rodents and ultimately in human beings.
       

  • Nielsen FS, Hansen HP, et al (Steno Diabetes Ctr, Gentofte, Denmark; Dept of Internal Medicine and Endocrinology F, Herlev, Denmark; Universite Louis Pasteur, Strasbourg, France)
    Increased Sympathetic Activity During Sleep and Nocturnal Hypertension in Type 2 Diabetic Patients with Diabetic Nephropathy.
    Diabetic Med 16: 555-562, 1999
       
    Morbidity and mortality from cardiovascular causes are excessive in patients with proteinuric type 2 diabetes. The putative factors involved in the blunted nocturnal blood pressure decreases in hypertensive patients with type 2 diabetes and diabetic nephropathy were investigated.
        
    Sustained adrenergic activity during sleep is correlated with blunted nocturnal blood pressure decrease in hypertensive patients with type 2 diabetes mellitus and diabetic nephropathy. This is probably mediated through a lack of peripheral vasodilation. Changes in extracellular fluid volume distribution and melatonin secretion have no effect.
        
    Editor’s comment: A blunted nocturnal blood pressure dip has been associated with microabluminuria. The mechanism of the blunted nocturnal BP dip has remained uncertain. Increased nocturnal sympathetic activity during hours of sleep in hypertensive type 2 diabetic patients may offer an explanation. These findings in the present study lend support for potential use of sympathetic blocking agents such as clonidine in these patients. Ultimately, the question to be address is whether reduction in sympathetic activity at night, with concomitant reduction in blood pressure, will ameliorate the progression of microalbuminuria.
        

  • Golden SH, Peart-Vigilance c, et al (Johns Hopkins Med Institutions, Baltimore, Md)
    Perioperative Glycemic Contrl and the Risk of Infectious Complications in a Cohort of Adults with Diabetes.
    Diabetes Care 22: 1408-1414, 1999
          
    Diabetes increases the risk of various types of infectious complications, although the reasons for this increase are unclear. One possibility is that hyperglycemia increases risks through short-term effects on immune function, pathogen growth, or vascular permeability. Patients with diabetes undergoing coronary surgery were studied to determine the effects of perioperative glycemic control on the risk of infectious complications after surgery.
           
    The study included 411 adult patients with any type of diabetes who underwent coronary artery bypass surgery during a 6-year period.
          
    Hyperglycemia appears to be an independent predictor of the short-term risk of infectious complications in patients with diabetes undergoing coronary artery surgery. The risk of infection is significantly elevated for patients whose mean glucose concentration during the 36 hours after surgery exceeds 200mg d/L. The results support published recommendations for stricter glycemic control for patients with diabetes during the perioperative period.
       
    Editor’s comment: This study re-emphasises the importance of perioperative glycemic control in adults with diabetes. He presumes that the same benefits may be applicable to children with diabetes who are undergoing major surgery also.
          

  • GB Thompson, CS Grant, JA van Heerden et al (Mayo Found, Rochester, Minn):
    Laparoscopic versus open posterior adrenalectomy: A case control study of 100 patients.
    Surgery 122: 1132-1136, 1997.
          
    Few large studies have compared laparoscopic adrenalectomy (LA) with conventional open anterior or posterior adrenalectomy (PA).
         
    Laparoscopic adrenalectomy is a safe and effective procedure that is superior to PA with respect to patient satisfaction, length of hospital stay, return to normal activities, analgesic requirements and late complications. Compared with PA, LA operating times and hospital stays are slightly longer. LA is more expensive and technically more demanding.
         

  • Patel PC, Pellitteri PK, Patel NM, et al (Penn State Geisinger Health System, Danville,Pa)
    Use of a Rapid Intraoperative Parathyroid Hormone Assay in the Surgical Management of Parathyroid Disease.
    Arch Otolaryngol Head Neck Surg 124: 559-562, 1998.
        
    During parathyroid surgery patients underwent neck exploration and the parathyroid hormone assay is done by preremoval of parathyroids and postoperative, during operative procedure, thus guiding whether enough functioning of parathyroid tissue is received. If adenoma is suspected then preoperative 99mTc-sestamibi scanning was used to localize.
        
    Thus combination of preoperative scanning and intraoperative parathyroid hormone assay can guide unilateral exploration of neck.
         

  • Levine JA, Eberhardt NL, Jensen MD (Mayo Clinic and Mayo Found, Rochester, Minn)
    Role of Nonexercise Activity Thermogenesis in Resistance to Fat Gain in Humans.
    Science 283: 212-214, 1999.
        
    Methods and Findings: For 8 weeks, 16 persons were fed 100 kcal/d more than weight-maintenance requirements. Two thirds of the increase in total daily energy expenditure resulted from increased nonexercise activity thermogenesis (NEAT), which is associated with fidgeting, maintaining posture, and other physical activities of daily living. Changes in NEAT explained the 10-fold differences in fat storage observed. These changes also directly predicted resistance to fat gain with overeating.
        
    Conclusions: These data suggest that the activation of NEAT dissipates excess energy to preserve leanness in persons who are overeating. Failure to activate NEAT may result in fat gain.
        
    Editorial comments: The use of doubly labeled water, a novel stable isotope technique, permitted the measurement of NEAT in response to overfeeding.
          

  • Gu K, Cowie CC, Harris MI (Natl Inst of Diabetes and Digestive and Kidney Diseases, Bethesda, Md)
    Diabetes and Decline in Heart Disease Mortality in US Adults.
    J.a.m.a. 281: 1291-1297, 1999
        
    Methods: Patients with and without diabetes, age 35 to 74 years, were followed up prospectively for age-specific mortality rates/1000 person-years, age adjusted and stratified by cohort, diabetes status, and sex.
        
    Conclusion: the decline in mortality rates for all causes, heart disease, and ischemic heart disease is lower for patients with diabetes than for those without diabetes, particularly if they are female.
        
    Editorial comments: Despite the decrease in the mortality rate from coronary heart disease in the United States over the past 30 years, it is unclear whether patients with diabetes have followed these trends.  The findings show that mortality from all causes, heart disease, and ischemic disease has decreased slightly in men with diabetes, and it has actually increased in women.  One possible explanation for these findings is that patients with diabetes may have benefited less from improved medical treatment of heart disease.  Moreover, the fact that mortality rates actually increased in women may suggest that women are being treated less aggressively for their diabetes than men.  It should be noted, however, that this study could not differentiate between the types of diabetes and could not identify individuals with undiagnosed diabetes.  Given the increasing prevalence of diabetes in the US population, it is possible that diabetes may constitute an even more important factor associated with heart disease mortality.
        

  • Guven S, El-Bershawi A, etal (Med College of Wisconsin, Milwaukee)
    Plasma Leptin and Insulin Levels in Weight-Reduced Obese Women with Normal Body Mass Index: Relationships with Body Composition and Insulin.
    Diabetes 48: 347-352, 1999
        
    Study Design: The fasting plasma leptin and insulin levels were determined from 22 currently obese, 20 weight reduced obese (with a normal BMI of at least 1 year’s duration), and 29 never-obese women. All of the women were premenopausal. A subset of 14 currently obese, 9 weight-reduced obese, and 20 never-obese women had plasma leptin evaluated in relation to body composition and insulin dynamics. Dual-energy x-ray absorptiometry was used to assess total body fat, and CT scanning was used to detect abdominal visceral and subcutaneous fat components of these women. The minimal model procedure was used to obtain quantitative data on insulin sensitivity.
         
    Conclusion: For premenopausal women, plasma leptin levels are elevated in weight-reduced obese women with a normal BMI.  This elevated leptin level may be caused by the larger amount of fat in the subcutaneous compartment of these women, compared with never-obese women. The normalization of visceral fat mass that accompanied weight loss for these women was associated with normalization of the insulin response.
        
    Editorial comment: The major finding is that for weight-reduced women, the insulin sensitivity index and first phase insulin response were comparable with those of never-obese women.  Despite the normalization of BMI in weight-reduced individuals, a higher leptin level persisted that was related to higher subcutaneous abdominal fat.  These results suggest that this depot is resistant to weight loss
         

  • Dvorak RV, DeNino WF, et al (Univ of Vermont, Burlington)
    Phenotypic Characteristics Associated with Insulin Resistance in Metabolically Obese but Normal Weight Young Women.
    Diabetes 48: 2210-2214, 1999
        
    In a cohort of 71 healthy, nonobese women, aged 21 to 35 years, 13 metabolically obese normal-weight (MONW) women were identified based on cut points for insulin sensitivity. These women had glucose disposal of less than 8mg/min-1/kg-1 of fat-free mass. Body composition, body fat distribution, cardiorespiratory fitness, physical activity energy expenditure, glucose tolerance, serum lipid profile, and dietary intake were assessed.
        
    Editorial comments: Metabolically obese means despite having a normal body weight and a normal body mass index (21 to 23) these young women had slightly higher levels of fat mass (31% body fat), were less physically active (as measured from doubly-labeled water), and had higher levels of intraabdominal fat (determined by CT).
          

  • Samaras K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp, London; St. Vincent’s Hosp, Darlinghurst, New South Wales, Australia)
    Genetic and Envirnomental Influences on Total-Body and Central Abdominal Fat: The Effect of Physical Activity in Female Twins
    Ann Intern Med 130: 873-882,1 999
        
    Methods: Nine hundred seventy healthy female twins, aged 39 to 70 years were studied. Two hundred forty-one pairs were monozygotic, and 228 were dizygotic. Fifty six percent of the women were of normal weight, 30% were overweight, 7% were obese, and 7% were underweight.
         
    Conclusions  – For healthy middle-aged women, current physical activity predicts lower total-body and central abdominal adiposity.  After adjustments for genetic and environmental variables, the effects of physical activity are greater than those of other measured environmental factors.
         
    Editorial comments: This article shows the potentially powerful effects of regular physical activity in preventing increases in central obesity. The accumulation of central body fat has been shown to be a powerful predictor of type 2 diabetes and cardiovascular disease.
         

  • Recently there has been a lot of emphasis on genetic factors and obesity. Editor E.T. Poehlman has selected number of articles from the literature and grouped together to underscore that the susceptibility to obesity and obesity-related phenotypes may be partially explained by genetic polymorphisms involved in the regulation of energy expenditure, substrate metabolism, and body composition.
         
    The work of Heinonen et al (Univ of Turku, Finland; Univ Hosp of Helsinki; Unvi of Kuopio, Finland) Identification of a Three-Amino Acid Deletion in the
    a2B-Adrenergic Receptor That is Associated with Reduced Basal Metabolic Rate in Obese Subjects published in J Clin Endocrinol Metab 84: 2429-2433, 1999, elegantly shows that a genetic polymorphism of the a2B subtype can partly explain the reduced resting metabolic rate in obese individuals.  A low resting metabolic rate may predict subsequent weight gain because of its large contribution to daily energy expenditure.
        
    b2-adrenergic receptor gene with Obesity, Hypertriglyceridaemia, and Diabetes Mellitus, published in Diabetologia 42:98-101, 1999, supports the notion that the amino-terminal polymorphisms of the b2-adrenergic receptor gene could be involved in the pathogenesis of obesity and hypertriglyceridemia.
       
    The article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere, Finland; Univ of Kuopio, Finland) Additive Effects of the Mutations in the B3-Adrenergic Receptor and Uncoupling Protein-1 Genes on Weight Loss and Weight Maintenance in Finnish Women, published in J Clin Endocrinol Metab 83: 4246-4250, 1998, is particularly interesting. Its strength lies in the examination of various genetic variants to achieve successful weight loss and maintain a reduced body weight. This article specifically examined whether the simultaneous presence of the Trp64Arg mutation in the B3-adrenergic receptor and the A®G mutation in the uncoupling protein (UCP-1) gene have associations with weight loss and subsequent weight maintenance. The finding that the individuals with both mutations had a lower weight reduction and gained weight back more rapidly raises new questions regarding the polygenetic nature of obesity and the search for genes that may predict differential response to weight reduction programs.
       

  • Gill Spyer, Andrew T Hattersley, et al (Department of Vascular Medicine and Diabetes Research, London)
    Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes.
    Lancet 356, December 9, 2000, pg. 1970-74.
       
    Intensive treatment to achieve good glycaemic control in diabetic patients is limited by a high frequency of hypoglycaemia.  The glucose concentrations at which symptoms and release of counter-regulatory hormones takes place have not been studied in patients with well controlled type-2 diabetes.
       
    The findings were that symptom response took place at higher whole blood glucose concentrations in diabetic patients than in controls.
        
    Glucose thresholds for counter-regulatory hormone secretion are altered in well controlled type-2 diabetic patients, so that both symptoms and counter-regulatory hormone release can take place at normal glucose values.  This effect might protect type-2 diabetic patients against episodes of profound hypoglycaemia and make the achievement of normoglycaemia more challenging in clinical practice
        

  • Abi Berger,
    Gut cells engineered to produce insulin
    BMJ, 16 December 2000, pg.1488
        
    Engineering non-pancreatic cells to produce insulin in response to a glucose load may one day be a successful approach in the treatment of diabetes. Canadian scientists have now shown that cells other than pancreatic cells can be induced to secrete appropriate levels of insulin in response to eating.
        
    Previous attempts at gene therapy have concentrated on manipulation of liver cells, but hepatocytes do not have the ability to store hormones.
        
    Dr. Cheung (Dept. of Medicine, Univ. of Alberta, Canada) and his team have shown that mice can be genetically engineered to produce human insulin from K cells located in the duodenum. K cells usually produce glucose dependent insulinotropic polypeptide (GIP), so they have an advantage over hepatocytes in that they are already glucose responsive endocrine cells and have the correct equipment to be able to store hormones.
        
    Dr. Cheung showed that when K cells are genetically engineered to produce insulin, normal glucose tolerance could be achieved in animals that have had their own pancreatic beta cells ablated.
         

  • Rodien P, Bremont C, Sanson M-LR, et al [Universite Libre de Bruxelles, Brussels, Belgium; Hopital Cochin, Paris; Centre National pour Ia Recherche Scientifique, Paris]
    Familial Gestational Hypethyroidism Caused by a Mutant Thyrotropin Receptor Hypersensitive to Human Chorionic Gonadotropin.
    N Engl J Med 339: 1823-1826, 1998
        
    Because of the structural similarity of chorionic gonadotropin and thyrotropin, some stimulation of the thyroid gland by human chorionic gonadotropin [hCG] is common in early pregnancy.  Hyperemesis gravidarum is characterized by excessive vomiting in ealy pregancy.  Some women with this condition have high serum thyroid hormone concentrations, and some have high serum chorionic gonadotropin concentrations. This case report described a woman with recurrent gestational hyperthyroidism and normal serum chorionic gonadotropin concentrations, who was heterozygous for a mutation in the thyrotropin receptor, rendering it hypersensitive to chorionic gonadotropin. The woman’s mother also carried this mutation.
        
    The gestational hyperthyroidism described in the women reported in this article has a different mechanism than that associated with molar pregnancies and at least in some women with hyperemesis gravidarum. In the latter two conditions, hyperthryroidism results from activation of the thyrotropin receptor by excessive quantities of normal chorionic gonadotropin or by chorionic gonadotropin molecules with increased thyrotropin like activity. Both conditions are thought to represent an exaggeration of normal thyroid stimulation caused by maximal chorionic gonadotropin production that occurs early in pregnancy in many normal women.
        

  • Sabri O, Zimny M, Schulz G, et al [ Aachen Univ, Germany]
    Success Rate of Radioiodine Therapy in Graves Disease : The Influence of Thyrostatic Medication.
    J Clin Endocrinol Metab 84: 1129-1233, 1999
        
    Studies conflict as to whether simultaneous thyrostatic medication reduces the effectiveness of iodine 131I therapy in patients with Graves’ disease. The effects of thyrostasis with carbimazole on the outcomes of ablative 131I therapy, aiming for a constant absorbed dose of 250 Gy, were examined.
       
    Conclusions – For patients with Graves’ disease, simultaneous thyrostatic medication greatly reduces the chances of successful treatment with 131I. Thyrostasis reduces success rate even if the 131I dose is increased to achieve a higher absorbed dose. Even in patients with hyperthyroidism, success rates of up to 100% can be achieved without thyrostasis.
       
    Editorial Comments – In fact, most patients can be treated with 131I and b-blockers without antithyroid drugs.
        

  • Nygaard B, Hegedus L, Ulriksen P, et al [ Univ of Copenhagen; Odense Univ Hosp, Denmark]
    Radioiodine Therapy for Multinodular Toxic Goiter
    Arch Intern Med 159: 1364-1368, 1999
        
    Methods – The 131I dose was calculated as 100 mCi, corrected to 100% uptake of 131I after 24 hours, with a maximum single dose of 20 mCi. Thyroid function variable and thyroid size on US were examined before and at 3 weeks, and at 3 , 6, and 12 months after treatment, then yearly thereafter.
       
    Editorial Comments – Since surgery and 131I are equally effective, the choice boils down to patient preference and the risks of therapy. An argument for surgery is that the rate of thyroid carcinoma is not negligible [6% in one surgical series] among hyperfunctional nodules. Yet, 131I is less invasive and is safe and highly effective and reaches retrosternal tissue. The bottom line is that a multinodular goiter causing hyperthyroidism or compressive symptoms is best treated with 131I. Even euthyroid multinodular goiter can be treated with 131I under special circumstances. Probably the main drawback is a transition to toxic autoimmune hyperthyroidism that occurs among a small number of patients with nodular goiter after 131I treatment.
         

  • Franklyn JA, Maisonneuve P, Sheppard M, et al [Univ of Birmingham, England; European Inst of Oncology, Milan, Italy]
    Cancer Incidence and Mortality After Radioiodine Treatment for Hyperthyroidism: A Population-based Cohort Study
    Lancer 353: 2111-2115, 1999
       
    Introduction – Radioiodine is being used with increasing frequency as a first-line treatment for patients with hyperthyroidism. Concerns remain regarding the subsequent risk of cancer, particularly in patients treated at a young age.
        
    Methods – A polulation-based investigation was conducted of 7417 patients treated in Birmingham, England, between 1950 and 1991. The details of all cancer diagnoses and deaths between 1971 and 1991 from the United Kingdom Office for National Statistics were compared with data regarding cancer incidence and mortality for England and Wales specific for age, sex and period.
        
    Results – During 72,073 person-years of follow-up, 634 patients received a diagnosis of cancer, compared with an expected number of 761. The relative risk of cancer mortality was also reduced. Lower incidences were observed for cancers of the pancreas, bronchus, trachea, bladder, and lymphatic and hemopoietic systems. The mortality rate from cancers at these sites was also diminished. Findings were significant only for bronchus and tracheal sites.
        
    Conclusion – The reduction in overall cancer incidence and mortality for patients treated for hyperthyroidism with radioiodine is encouraging. The absolute risk of cancer of the small bowel and thyroid continues to be low. The increase in relative risk indicates the need for long – term follow-up among patients receiving radioiodine.
        
    Editorial comments – in the Chernobyl accident, thyroid cancer appeared almost entirely in children who were under age 5 years at the time of the accident. If there is a risk of thyroid cancer after treatment with 131I, it is small enough to be virtually negligible.
        
    Ron and her colleagues studied the cancer incidence among 35,593 hyperthyroid patients treated with 131I between 1946 and 1964 and who were in his original Co-operative Thyrotoxicosis Therapy Follow-up Study. They found that 131I was not linked to total cancer deaths or to
    any specific cancer with the exception of thyroid cancer, although in absolute terms the excess number of deaths was small. There seems little that, overall, 131I is safe therapy for hyperthyroidism and the benefits of therapy clearly outweigh any minimal risks that may exist.
         

  • Lonn L, Stenlof K, Ottosson M, et al [Univ of Goteborg, Sweden]
    Body Weight and Body Composition Changes After Treatment of Hyperthyroidism
    J Clin Endocrinol Metab 83: 4269-4273, 1998
         
    Methods – The study included 9 adult patients receiving treatment for hyperthyroidism, including surgery, antithyroid drugs, or radioiodine therapy. Body composition parameters were obtained with dual-energy x-ray absorptiometry [DXA] and CT before and 3 and 12 months after the patients attained a euthyroid state.
         
    Conclusions- The findings help in understanding the changes in body composition occurring after patients with hyperthyroidism are returned to a euthyroid state. During the first 3 months, the major changes are replenishment of skeletal muscle and intraperitoneal AT, though subcutaneous AT is not significantly increased until 12 months. No significant increases in bone tissue or visceral organs occur during this time.
        

  • Fukata S, kuma K, Sugawara M [Kuma Hosp Kobe, Japan; Univ of California Los Angeles]
    Granulocyte Colony-Stimulating Factor [ G-CSF] Does Not Improve Recovery From Antithyroid Drug-Induced Agranulocytosis : A Prospective Study
    Thyroid 9: 29-31, 1999
        
    Methods – For ATD therapy 21 patients received methimazole [average daily dose, 24 mg], and 3 received propylthiouracil [ average daily dose, 270 mg]. Eighteen patients [75%] had agranulocytosis develop in less than 3 months of drug therapy. When agranulocytosis was detected on complete blood count, patients were asked to discontinue ATDs and were hospitalized immediately. The 14 patients in the G-CSF group received daily subcutaneous injections of 100 to 250 mg G-CSf until the neutrophil increased to 1000 /mL or higher. The 10 control subjects received antibiotic therapy only. Recovery time was defined as the number of days needed to exceed neutrophil counts of 500 mL or higher after diagnosis of agranulocytosis.
         
    Conclusion – The efficacy of G-CSF treatment of ATD-induced agranulocytosis was not supported by this prospective, randomized investigation.
        
    Editorial Comments – Most episodes occur during the first weeks of treatment. It tends to occur more often among patients receiving more than 30 mg of methimazole a day.
        
    Patients usually recover within 2 to 3 weeks of stopping the drug, although recovery is abrupt in some and others die despite aggressive management with isolation, antibiotics, and G-CSF. There is possibility G-CSF might be efficacious in an ambulatory setting, suggesting that if the neutrophil count rises to at least 500 /mL 4 hours after it is given, the patient may not require hospitalization. G-CSF is expensive, but under desperate conditions when patients become quite ill with this iatrogenic problem, physicians are likely to continue its use.
         

  • Hintz G, Blombach O, Fink H, et al [Teaching Hosp of Luebeck Univ, Bad Oldesloe, Germany; Univ of Essen, Germany; Teaching Hosp of Duesseldorf Univ, Wuppertal, Germany]
    Risk of Iodine-Induced Thyrotoxicosis After Coronary Angiography : An Investigation in 788 Unselected Subjects
    Eur J Endocrinol 140: 264-267, 1999
        
    Background – Examination of the thyroid gland and measurement of thyroid hormone in blood before coronary angiography are common practices. Although there are no data on the individual risk of iodine-induced thyrotoxicosis [IIT] after contrast media contamination, many clinicians recommend preventive therapy with antithyroid agents. The individual risk for the development of IIT among residents of an iodine deficient region was determined.
        
    Methods – The study included 788 patients undergoing coronary angiography in a German community.
       
    Conclusions- In this population of unselected, euthyroid patients from an iodine-deficient area, short-term iodine contamination from contrast media rarely resulted in hyperthyroidism. Thus, prophylactic treatment with perchlorate or thiamazole is not generally recommended, as the risk of adverse effects from such therapy may outweigh the risk of IIT.
        
    Editorial Comments – Elderly persons, especially women with longstanding large nodular goiters, are at greatest risk, but in the absence of preexisting thyroid disease, elderly men are affected more often.
         

  • Bunevicius R, Kazanavicius G, Zalinkevicius R, et al [Kaunas Med Univ, Lithuania; Univ of North Carolina, Chapel Hill]
    Effects of Thyroxine as Compared With Thyroxine Plus Triiodothyronine in Patients with Hypothyroidism
    N Engl J Med 340: 424-429, 1999
        
    Background – Although both T4 and T3  are secreted by the normal thyroid gland, T4 alone is the usual treatment for hypothyroidism. Whether thyroid secretion of T3 is physiologically important was examined.
        
    Methods – Thirty-three patients with hypothyroidism were included in the study. For each of two 5-week periods, patients were given their usual dose of T4 or a regimen in which 50 mg of their usual dose was replaced by 12.5 mg of T3. The order of the treatments was randomly determined. At the end of each period, biochemical, physiologic, and psychological assessments were made.
        
    Conclusion – Partial substitution of T3 for T4 may improve mood and neuropsychological function in patients with hypothyroidism. T3 normally secreted by the thyroid gland appears to have a specific effect.
        
    Editorial Comments – The dosage and formulation of T4 have evolved since the 1960s [when we routinely over treated patients with 200 to 400 mg daily] to doses between 100 and 150 mg that we now know are adequate to restore thyrotropin secretion to normal in most patients.
        
    This short term study does not address other end points [noted in the editorial that accompanies the paper] Such as exercise tolerance and myocardial performance.  Daily T3 secretion is only 6 mg, but 10 mg per day was substituted in this study, less than in current formulations. Most patients feel well and have normal serum thyrotropin concentrations with T4 replacements alone, and we should not rush into combined hormone therapy until the results of Bunevicius et al are verified and long term studies are done.
            

  • Perry IJ, Wannamethee SG, et al (Royal Free Hospital, London; Univ of Newcastle upon Tyne, England)
    Serum True Insulin Concentration and the Risk of Clinical Non-Insulin Dependent Diabetes During Long-term Follow-up
    Int J Epidemiol 28: 735-741, 1999
       
    Background : Substantial evidence indicates that insulin resistance with compensatory hyperinsulinemia is an early, modifiable defect in the pathogenesis of NIDDM. However, such evidence comes mainly from studies using insulin assays that cross-react with proinsulin and other insulin precursors. A specific assay was used to determine whether an increase in serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM.
        
    Method :A cohort of 5550 men without diabetes (age, 40 to 59 years) from 18 British towns was followed up for a mean 14.8 years.
         
    Findings: One hundred sixty-eight incident cases of clinically diagnosed NIDDM occurred during follow-up.
       
    Conclusion : In this cohort, increased circulating true insulin levels antedate clinically manifest NIDDM by more than a decade. This supports the idea that insulin resistance with compensatory true hyperinsulinemia plays an early role in the pathogenesis of this condition.
        
    Editor’s comment: True insulin levels also confirm what most diabetologists have always known, namely, that insulin resistance (with compensatory hyperinsulinaemia) underlies type 2 diabetes in most patients.
        

  • Kaiyala KJ, Prigeon RL, et al (Univ of Washington, Seattle; Veterans Affairs Puget Sound Health Care System, Seattle; Univ of Cincinnati, Ohio)
    Reduced b-cell Function Contributes to Impaired Glucose Tolerance in Dogs Made Obese by High-Fat Feeding.
    Am J Physiol 277: E659-E667, 1999.
       
    From the animal study, it was concluded that High-fat feeding produces insulin resistance that is not compensated for by increased insulin secretion. This contributes to the development of glucose intolerance. These effects may be especially harmful in individuals who are predisposed to type 2 diabetes mellitus.
       
    Editor’s comment : A high-fat diet is a major culprit in the obesity seen in the Western industrialized world. Obesity is very common among patients with type 2 diabetes. This study demonstrated that a high fat diet, apart from inducing increased body weight and perhaps insulin resistance, may be associated with b-cell lipotoxicity with resultant diminution of b-cell secretory capacity.
        

  • Kitabchi AE, Imseis RE, Bush AJ, et al (Univ of Tennessee, Memphis)
    Racial Differences in the Correlation Between Gonadal Androgens and Serum Insulin Levels
    Diabetes Care 22: 1524-1529, 1999
       
    Purpose: Previous studies in a group of predominantly African American women with obesity and hyperandrogenism found that serum insulin level was directly correlated with levels of gonadal androgens (i.e, testosterone and androstenedione). However, this correlation has not always been demonstrated in predominantly white samples. Possible racial differences in the correlation between gonadal androgen and insulin levels were assessed.
    Method: The study included 14 African American and 14 white premenopausal women. The 2 racial groups were similar in terms of age, body mass index, and waist-to-hip ratio.
       
    Conclusions: African American women show a direct correaltion between gonadal androgen levels and the responses of glucose, insulin, and C-peptide to a glucose tolerance test. The findings support a racial difference in the relationship between gonadal hyperandrogenism and hyperinsulinemia. The mechanisms underlying this racial difference, including the possible protective effect of lower levels of visceral fat in African American women, warrant further study.
        
    Editor’s comment: This raises a very important question regarding the role of androgens in glucose and insulin metabolism and the development of type 2 diabetes in blacks.
       

  • Ciampelli M, Fulghesu AM, et al (Catholic Univ of Sacred Heart, Rome; OASI Inst for Research, Troina, Italy)
    Impact of Insulin and Body Mass Index on Metabolic and Endocrine Variables in Polycystic Ovary Syndrome.
    Metabolism 48: 167-172, 1999
       
    Purpose: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by anovulation, hyperandrogenism, and hyperinsulinemia with insulin resistance. There is a firmly established link between insulin resistance and obesity, and obesity iS common among patients with PCOS. The relative contributions of insulin and obesity to the disorders associated with PCOS were examined.
       
    Method : The study included 110 consecutive Italian women with PCOS.
    Conclusion: For patients with PCOS, hyperinsulinemia appears to have a significant effect on the LH response to a GnRH stimulus. Obesity and hyperinsulinemia combined to have a synergistic, additive effect on the free androgen index. Changes in lipid profile appear to result from obesity alone.
        
    Editor’s comment: This study shows that the role of hyperinsulinemia in the regulation of gonadal hormones and gonadotropins is partly dependent on the presence of obesity.
        

  • Vaccaro O, Ruffa G, Imperators G, et al (Federico II Univ, Naples, Italy)
    Risk of Diabetes in the New Diagnostic Category of Impaired Fasting Glucose: A Prospective Analysis.
    Diabetes Care 22: 1490 – 1493, 1999.
       
    Introduction: the latest American Diabetes Association (ADA) recommendations suggest that fasting glucose should be used rather than the oral glucose tolerance test (OGTT) for diagnosis of diabetes and impaired fasting glucose (IFG). In contrast, the World Health Organisation (WHO) recommends the OGTT for diagnosis of diabetes. Impaired fasting glucose is a new diagnostic category, the clinical significance of which is unknown. This study assessed progression to diabetes among subjects with evidence of impaired glucose regulation on either fasting glucose or OGTT. The 2 tests were compared for their ability to identify subjects at high risk of diabetes.
        
    Conclusion: The results support the continued use of the OGTT in screening programs to identify patients at high risk of diabetes, as recommended by the WHO. This is in contrast to the ADA recommendation to use the fasting glucose only. To date, this is the only population-based study of risk of progression to diabetes among Caucasian subjects with impaired fasting glucose.
       
    Editor’s comment: The new category of IFG could not supplant our old friend OGTT. OGTT is here to stay!
        

  • Mannucci E, Bardini G, et al (Careggi Hosp, Florence, Italy)
    Comparison of ADA and WHO Screening Methods for Diabetes Mellitus in Obese Patients.
    Diabetic Med 16: 579-585, 1999
       
    Background: Fasting glucose may not be sensitive enough to use as a screening method for diabetes, especially in high-risk populations. The performance of fasting glycemia (FG) was compared with that of oral glucose tolerance testing (OGTT) in the diabetes mellitus (DM) screening of obese patients.
       
    Method : Five hundred twenty eight consecutive obese outpatients under FG and OGTT. 
       
    Conclusion: The sensitivity of FG exceeding 6.1 mmol/L is satisfactory for screening for diabetes but not for IGT. A FG threshold of more than 7 mmol/L is not sensitive enough for diabetes screening in obese patients.
       
    Editor’s comment: The severity of fasting hyperglycaemia determines the B-cell function and the degree of hypertriglyceridemia in both obese and nonobese subjects. However, the presence of insulin resistance in most obese patients confound the degree of metabolic derangements. Various diagnostic criteria did not take into consideration the impact of obesity. Is it time to classify diabetes not only on the basis of glucose levels but also according to the presence of obesity of surrogates for insulin resistance?
       

  • Kashiwazaki K, Hirano T, et al (Showa Univ, Japan; Toho Univ, Tokyo)
    Decreased Release of Lipoprotein Lipase is Associated with Vascular Endothelial Damage in NIDDM Patients with Microalbuminuria.
    Diabetes Care 21: 2016-2020, 1998
       
    Background: Plasma triglyceride level is a risk factor for coronary heart disease in pateints with diabetes. This makes it important to identify the mechanisms of hypertriglyceridemia in diabetes. One possibility is that generalized endothelial damage reduces lipoprotein lipase (LPL) bound to epithelium. To assess this potential mechanism, the association between heparin-releasable LPL and von Willebrand factor (vWF) – a marker of endothelial damage – was evaluated in pateints with diabetes who have microalbuminuria.
       
    Conclusions: The findings demonstrate generalized endothelial damage in microalbuminuric patients with NIDDM. This leads to reduced endothelium-bound LPL and thus to impaired catabolism of TG-rich lipoproteins.
       
    Editor’s comment: These results suggest that widespread endothelial damage occurred in NIDDM patients with microalbuminuria. LPL moiety bound to the endothelium is thereby decreased, which results in an impaired catabolism of TG-rich lipoproteins.
       

  • Barzilay JI, Spiekerman CF, et al (Emory Univ, Atlanta, Ga; Univ of Washington, Seattle; Univ of Pittsburgh, Pa; et al)
    Cardiovascular Disease in Older Adults with Glucose Disorders: Comparison of American Diabetes Association Criteria for Diabetes Mellitus with WHO Criteria.
    Lancet 354: 622-625, 1999
        
    The American Diabetes Association’s (ADA) 1997 criteria for diagnosis of diabetes rely mainly on fasting glucose values, avoiding the need for oral glucose tolerance testing. In contrast, World Health Organization (WHO) criteria still call for oral glucose tolerance testing and have a higher cutoff point for fasting glucose concentration. It remains unclear which set of criteria are most useful for identifying glucose disturbances in the elderly. This study compared the ADA and WHO criteria for their ability to detect cardiovascular disease among older adults with diabetes or glucose disturbances.
        
    The ADA diagnostic criteria, based on fasting glucose measurements, are not as sensitive in predicting cardiovascular disease associated with glucose disturbances in the elderly as the WHO criteria, based on oral glucose tolerance testing. The findings question the recommendation to rely on fasting glucose measurements to diagnose glucose disorders in the elderly population.
        
    Editor’s comment: Delayed return of glucose to baseline (prandial hyperglycaemia) is the hallmark of diabetes in older persons. For that reason, the American Diabetes Association’s new criteria for the diagnosis of diabetes mellitus made little sense. 
        
    Diabetes mellitus remains a risk factor for coronary artery disease events, even in women in nursing homes.
       

  • Mitchell BD, Almasy LA, et al (Southwest Found for Biomedical Research, San Antonio, Tex; Univ of Texas, San Antonio)
    Diabetes and Hypertension in Mexican American Families: Relation to Cardiovascular Risk
    Am J Epidemiol 149: 1047-1056, 1999
        
    Type 2 diabetes, hypertension, and cardiovascular disease show a strong familial tendency. The association between a family history of these illnesses and a large panel of cardiovascular risk factors was studied in a group of Mexican Americans.
        
    A total of 1431 participants were enrolled in the San Antonio Family Heart Study.
       
    Family history of diabetes, and to a lesser degree hypertension, is significantly associated with a spectrum of cardiovascular risk factors. These relationships probably reflect the pleiotropic effects of genes transmitted from affected persons to their offspring.
        
    Editor’s comment: Hypertension is found in 50% to 60% of patients with type 2 diabetes. In both diseases, the major cause of death is cardiovascular disease. This suggests that both hypertension and diabetes could have a common genetic background.
       

  • Rodriguez BL, Sharp DS, Lau N, et al (Univ of Hawaii, Manoa; Kuakini Med Ctr, Honolulu, Hawaii; Natl Heart, Lung, and Blood Inst, Honolulu, Hawaii; et al)
    Glucose Intolerance and 23-Year Risk of Coronary Heart Disease and Total Mortality: The Honolulu Heart Program.
    Diabetes Care 22: 1261-1265, 1999.
        
    Though the increased risk of total mortality and coronary heart disease (CHD) morbidity and mortality in diabetic patients is well documented, the relationship between glucose intolerance and these outcomes is still unclear. The associations between glucose intolerance assessed on entry to the Honolulu Heart Program and the 23 year incidence of CHD, CHD mortality, and total mortality were reported.
    10
    A cohort of 8006 Japanese American men, aged 45 to 68 years were enrolled in the study in 1965 and followed up for 23 years.
       
    Conclusion : In this cohort of middle aged and older Japanese American men, glucose intolerance at baseline had a dose-response association with CHD incidence, CHD mortality and total mortality. This association persisted after adjustment for many other risk factors.
       
    Editors’ comment: The remarkable strength of this study is the 23-year duration of the follow-up (similar to the Framingham Cohort Study). Hyperglycemia -symptomatic and asymptomatic – remains a greater risk in the development of CHD.
        

  • Zavaroni I, Bonini L, et al (Parma Univ, Italy; Stanford Univ, Calif; Shaman Pharmaceuticals, South San Francisco)
    Hyperinsulinemia in a Normal Population as a Predictor of Non-Insulin-Dependent Diabetes Mellitus, Hypertension and Coronary Heart Disease: The Barilla Factory Revisited.
    Metabolism 48: 989-994, 1999
        
    Background- Previous research findings suggest that hyperinsulinemia, as a surrogate measure of resistance to insulin-mediated glucose disposal, is associated with higher concentrations of plasma glucose and triglyceride, a lower concentration of HDL cholesterol, and an increase in systolic and diastolic blood pressure. The capability of hyperinsulinemia to aid in the prediction of the development of glucose intolerance, hypertension, and coronary heart disease in a previously healthy population was investigated.
        
    Six hundred forty seven individuals who were free of disease at study enrollment were followed up between 1981 and 1993 to 1996.
        
    The untoward clinical effects of insulin resistance or compensatory hyperinsulinemia, glucose intolerance, hypertension and CHD can develop within 15 years. In this unselected population, hyperinsulinemia was an effective marker of subsequent CHD development.
    11
    Editor’s comment: The data are consistent with the presence of syndrome X.
        

  • Guerrer-Romero F, Rodriguez-Moran M (Gen Hosp of the Mexican Social Security Inst, Durango, Mexico)
    Proteinuria is an Independent Risk Factor for Ischemic Stroke in Non-Insulin Dependent Diabetes Mellitus.
    Stroke 30: 1787-1791, 1999
        
    In patients with non-insulin-dependent diabetes mellitus (NIDDM), proteinuria is an independent risk factor for cardiovascular disease. The association between proteinuria and ischemic stroke in patients with NIDDM was investigated.
       
    Fifty-nine diabetic patients with first-ever ischemic stroke from thrombotic arterial occlusion and 180 diabetic patients without stroke were included in the case-control study. The 2 groups were matched by sex, age and diabetes duration.
       
    This case-control study provides evidence that proteinuria is an independent risk factor for ischemic stroke in patients with NIDDM. More research is needed.
       
    Editor’s comment: Proteinuria is a reflection of generalized vascular compromise and hematorrheologic deregulation and blood pressure changes.
       

  • Perucchini d, Fischer U, et al (Univ Hosp Zurich, Switzerland)
    Using Fasting Plasma Glucose Concentrations to Screen for Gestational Diabetes Mellitus: Prospective Population Based Study.
    BMJ 319: 812-815, 1999
       
    Identifying women who are susceptible to gestational diabetes can help prevent perinatal morbidity and improve long-term outcomes for the mother and baby. Whether measurement of fasting glucose concentration is easier than the 1 hour, 50-g glucose challenge test in the screening of gestational diabetes mellitus was investigated.
    12
    The measurement of FPG levels, with a cut-off value of 4.8 mmol/l or greater, is easier than the 50-g glucose challenge test in screening for gestational diabetes and obviates the need for the challenge test in 70% of women.
        
    Editor’s comment: If confirmed in large studies, this will save doctors and patients very precious time. Longitudinal studies to examine the fetal and maternal outcomes of the use of FPG > 4.8 mmol/ml and 50-g glucose are needed.
        

  • Willms B, Ruge D (Diabetesklinik Bad Lauterberg, Germany)
    Comparison of Acarbose and Metformin in Patients with Type 2 Diabetes Mellitus Insufficiency Controlled with Diet and Sulphonylureas: A Randomized, Placebo-Controlled Study.
    Diabetic Med 16: 755-761, 1999.
      
    The efficacies of acarbose and metformin have been compared in patients with type 2 diabetes mellitus uncontrolled with diet alone. The safety and efficacy of these agents were assessed in diabetic patients in whom sulfonylurea therapy did not sufficiently control type 2 diabetes mellitus.
       
    Acarbose and metformin are equally effective in improving metabolic control in patients with diabetes that is insufficiently controlled with diet and sulfonylureas. Further studies are needed to determine the relative effects of metformin and acarbose on disease progression and long-term complications.
       
    Editor’s comment: The significant weight loss in the acarbose group versus the metformin group, in the face of comparable glycemic control and adverse gastrointestinal effects, is very encouraging. The only problem is whether the American patients with type 2 diabetes are willing to hang on long enough at the 300-mg/day dose of acarbose to realize the maximum potential of this drug.
       

  • Coon B, An L-L, Whitton JL, et al (The Scripps Research Inst, La Jolla, Calif)
    DNA Immunization to Prevent Autoimmune Diabetes
    J Clin Invest 104: 189-194, 1999
        
    In mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a transgene in b cells, IDDM develops only after LCMV infection. This model was used in an investigation of the potential of DNA vaccination to control autoimmune disease, with the use of islet self-antigens to induce regulatory lymphocytes and prevent autoimmune diabetes.
       
    DNA immunization with plasmids expressing self-antigens may be an attractive, novel approach to prevent autoimmune disorders. The antigens must be carefully preelected for their ability to induce regulatory lymphocytes in vivo.
        
    Editor’s comment: There may be a way to prevent type 1 diabetes with a vaccine of insulin B-chain NDA in the future. This novel approach to vaccination needs further confirmation in other rodents and ultimately in human beings.
       

  • Nielsen FS, Hansen HP, et al (Steno Diabetes Ctr, Gentofte, Denmark; Dept of Internal Medicine and Endocrinology F, Herlev, Denmark; Universite Louis Pasteur, Strasbourg, France)
    Increased Sympathetic Activity During Sleep and Nocturnal Hypertension in Type 2 Diabetic Patients with Diabetic Nephropathy.
    Diabetic Med 16: 555-562, 1999
       
    Morbidity and mortality from cardiovascular causes are excessive in patients with proteinuric type 2 diabetes. The putative factors involved in the blunted nocturnal blood pressure decreases in hypertensive patients with type 2 diabetes and diabetic nephropathy were investigated.
       
    Sustained adrenergic activity during sleep is correlated with blunted nocturnal blood pressure decrease in hypertensive patients with type 2 diabetes mellitus and diabetic nephropathy. This is probably mediated through a lack of peripheral vasodilation. Changes in extracellular fluid volume distribution and melatonin secretion have no effect.
       
    Editor’s comment: A blunted nocturnal blood pressure dip has been associated with microabluminuria. The mechanism of the blunted nocturnal BP dip has remained uncertain. Increased nocturnal sympathetic activity during hours of sleep in hypertensive type 2 diabetic patients may offer an explanation. These findings in the present study lend support for potential use of sympathetic blocking agents such as clonidine in these patients. Ultimately, the question to be address is whether reduction in sympathetic activity at night, with concomitant reduction in blood pressure, will ameliorate the progression of microalbuminuria.
        

  • Golden SH, Peart-Vigilance c, et al (Johns Hopkins Med Institutions, Baltimore, Md)
    Perioperative Glycemic Contrl and the Risk of Infectious Complications in a Cohort of Adults with Diabetes.
    Diabetes Care 22: 1408-1414, 1999
        
    Diabetes increases the risk of various types of infectious complications, although the reasons for this increase are unclear. One possibility is that hyperglycemia increases risks through short-term effects on immune function, pathogen growth, or vascular permeability. Patients with diabetes undergoing coronary surgery were studied to determine the effects of perioperative glycemic control on the risk of infectious complications after surgery.
        
    The study included 411 adult patients with any type of diabetes who underwent coronary artery bypass surgery during a 6-year period.
        
    Hyperglycemia appears to be an independent predictor of the short-term risk of infectious complications in patients with diabetes undergoing coronary artery surgery. The risk of infection is significantly elevated for patients whose mean glucose concentration during the 36 hours after surgery exceeds 200mg d/L. The results support published recommendations for stricter glycemic control for patients with diabetes during the perioperative period.
        
    Editor’s comment: This study re-emphasises the importance of perioperative glycemic control in adults with diabetes. He presumes that the same benefits may be applicable to children with diabetes who are undergoing major surgery also.
       

  • R Abs, J Verhelst, D Maiter, et al (Univ Hosp, Antwerp, Belgium; Middelheim Hosp, Antwerp, Belgium; Hopital Saint-Luc, Brussels, Belgium; et al) Cabergoline in the Treatment of Acromegaly: A Study in 64 patients. J Clin Endocrinol Metab 83: 374-378, 1998.
        
    Cabergoline, a new, long-acting dopamine agonist, is more effective and less toxic than bromocriptine in the treatment of hyperprolactinemia. This agent may also be useful in the medical management of acromegaly.
       

  • CB Newman, S Melmed, A George, et al (New York Univ; Cedars-Sinai Med Ctr, Los Angeles; Univ of Pennsylvania, Philadelphia; et al) Octreotide as Primary Therapy for Acromegaly. J Clin Endocrinol Metab 83:3034-3040, 1998.
        
    Conclusions – Octreotide was equally effective in patients receiving this agent for acromegaly as primary or secondary treatment. These findings raise questions about the current practice of surgically resecting all newly diagnosed GH-secreting pituitary adenomas.
        

  • Levine JA, Eberhardt NL, Jensen MD (Mayo Clinic and Mayo Found, Rochester, Minn)
    Role of Nonexercise Activity Thermogenesis in Resistance to Fat Gain in Humans.
    Science
    283: 212-214, 1999.
        
    Methods and Findings: For 8 weeks, 16 persons were fed 100 kcal/d more than weight-maintenance requirements. Two thirds of the increase in total daily energy expenditure resulted from increased nonexercise activity thermogenesis (NEAT), which is associated with fidgeting, maintaining posture, and other physical activities of daily living. Changes in NEAT explained the 10-fold differences in fat storage observed. These changes also directly predicted resistance to fat gain with overeating.
         
    Conclusions: These data suggest that the activation of NEAT dissipates excess energy to preserve leanness in persons who are overeating. Failure to activate NEAT may result in fat gain.
        
    Editorial comments: The use of doubly labeled water, a novel stable isotope technique, permitted the measurement of NEAT in response to overfeeding.
        

  • Gu K, Cowie CC, Harris MI (Natl Inst of Diabetes and Digestive and Kidney Diseases, Bethesda, Md)
    Diabetes and Decline in Heart Disease Mortality in US Adults.
    J.A.M.A. 281: 1291-1297, 1999
        
    Methods: Patients with and without diabetes, age 35 to 74 years, were followed up prospectively for age-specific mortality rates/1000 person-years, age adjusted and stratified by cohort, diabetes status, and sex.
        
    Conclusion: the decline in mortality rates for all causes, heart disease, and ischemic heart disease is lower for patients with diabetes than for those without diabetes, particularly if they are female.
        
    Editorial comments: Despite the decrease in the mortality rate from coronary heart disease in the United States over the past 30 years, it is unclear whether patients with diabetes have followed these trends. The findings show that mortality from all causes, heart disease, and ischemic disease has decreased slightly in men with diabetes, and it has actually increased in women. One possible explanation for these findings is that patients with diabetes may have benefited less from improved medical treatment of heart disease. Moreover, the fact that mortality rates actually increased in women may suggest that women are being treated less aggressively for their diabetes than men. It should be noted, however, that this study could not differentiate between the types of diabetes and could not identify individuals with undiagnosed diabetes. Given the increasing prevalence of diabetes in the US population, it is possible that diabetes may constitute an even more important factor associated with heart disease mortality.
       

  • Guven S, El-Bershawi A, etal (Med College of Wisconsin, Milwaukee)
    Plasma Leptin and Insulin Levels in Weight-Reduced Obese Women with Normal Body Mass Index: Relationships with Body Composition and Insulin.
    Diabetes 48: 347-352, 1999
        
    Study Design: The fasting plasma leptin and insulin levels were determined from 22 currently obese, 20 weight reduced obese (with a normal BMI of at least 1 year’s duration), and 29 never-obese women. All of the women were premenopausal. A subset of 14 currently obese, 9 weight-reduced obese, and 20 never-obese women had plasma leptin evaluated in relation to body composition and insulin dynamics. Dual-energy x-ray absorptiometry was used to assess total body fat, and CT scanning was used to detect abdominal visceral and subcutaneous fat components of these women. The minimal model procedure was used to obtain quantitative data on insulin sensitivity.
        
    Conclusion: For premenopausal women, plasma leptin levels are elevated in weight-reduced obese women with a normal BMI. This elevated leptin level may be caused by the larger amount of fat in the subcutaneous compartment of these women, compared with never-obese women. The normalization of visceral fat mass that accompanied weight loss for these women was associated with normalization of the insulin response.
        
    Editorial comment: The major finding is that for weight-reduced women, the insulin sensitivity index and first phase insulin response were comparable with those of never-obese women. Despite the normalization of BMI in weight-reduced individuals, a higher leptin level persisted that was related to higher subcutaneous abdominal fat. These results suggest that this depot is resistant to weight loss.
        

  • Dvorak RV, DeNino WF, et al (Univ of Vermont, Burlington)
    Phenotypic Characteristics Associated with Insulin Resistance in Metabolically Obese but Normal Weight Young Women.
    Diabetes 48: 2210-2214, 1999
        
    In a cohort of 71 healthy, nonobese women, aged 21 to 35 years, 13 metabolically obese normal-weight (MONW) women were identified based on cut points for insulin sensitivity. These women had glucose disposal of less than 8mg/min-1/kg-1 of fat-free mass. Body composition, body fat distribution, cardiorespiratory fitness, physical activity energy expenditure, glucose tolerance, serum lipid profile, and dietary intake were assessed.
        
    Finding: the metabolically obese normal-weight group had a higher body fat percentage and higher subcutaneous and visceral abdominal adiposity than did the normal group. The MNOW group also had a lower physical acitivty energy expenditure. Cardiorespiratory fitness did not differ between groups.
        
    Editorial comments: Metabolically obese means despite having a normal body weight and a normal body mass index (21 to 23) these young women had slightly higher levels of fat mass (31% body fat), were less physically active (as measured from doubly-labeled water), and had higher levels of intraabdominal fat (determined by CT).
        

  • Samaras K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp, London; St. Vincent’s Hosp, Darlinghurst, New South Wales, Australia)
    Genetic and Envirnomental Influences on Total-Body and Central Abdominal Fat: The Effect of Physical Activity in Female Twins
    Ann Intern Med 130: 873-882,1 999
       
    Methods: Nine hundred seventy healthy female twins, aged 39 to 70 years were studied. Two hundred forty-one pairs were monozygotic, and 228 were dizygotic. Fifty six percent of the women were of normal weight, 30% were overweight, 7% were obese, and 7% were underweight.
        
    Conclusions – For healthy middle-aged women, current physical activity predicts lower total-body and central abdominal adiposity. After adjustments for genetic and environmental variables, the effects of physical activity are greater than those of other measured environmental factors.
       
    Editorial comments: This article shows the potentially powerful effects of regular physical activity in preventing increases in central obesity. The accumulation of central body fat has been shown to be a powerful predictor of type 2 diabetes and cardiovascular disease.
        

  • Recently there has been a lot of emphasis on genetic factors and obesity. Editor E.T. Poehlman has selected number of articles from the literature and grouped together to underscore that the susceptibility to obesity and obesity-related phenotypes may be partially explained by genetic polymorphisms involved in the regulation of energy expenditure, substrate metabolism, and body composition. 
        
    The work of Heinonen et al (Univ of Turku, Finland; Univ Hosp of Helsinki; Unvi of Kuopio, Finland) Identification of a Three-Amino Acid Deletion in the a2B-Adrenergic Receptor That is Associated with Reduced Basal Metabolic Rate in Obese Subjects published in J Clin Endocrinol Metab 84: 2429-2433, 1999, elegantly shows that a genetic polymorphism of the a2B subtype can partly explain the reduced resting metabolic rate in obese individuals. A low resting metabolic rate may predict subsequent weight gain because of its large contribution to daily energy expenditure. 
        
    The work by Ishiyama-Shigemoto et al (Kurume Univ, Japan) Association of Polymorphisms in the b2-Adrenergic Receptor Gene with Obesity, Hypertriglyceridaemia, and Diabetes Mellitus, published in Diabetologia 42:98-101, 1999, supports the notion that the amino-terminal polymorphisms of the b2-adrenergic receptor gene could be involved in the pathogenesis of obesity and hypertriglyceridemia.
       
    The article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere, Finland; Univ of Kuopio, Finland) Additive Effects of the Mutations in the B3-Adrenergic Receptor and Uncoupling Protein-1 Genes on Weight Loss and Weight Maintenance in Finnish Women, published in J Clin Endocrinol Metab 83: 4246-4250, 1998, is particularly interesting. Its strength lies in the examination of various genetic variants to achieve successful weight loss and maintain a reduced body weight. This article specifically examined whether the simultaneous presence of the Trp64Arg mutation in the B3-adrenergic receptor and the A®G mutation in the uncoupling protein (UCP-1) gene have associations with weight loss and subsequent weight maintenance. The finding that the individuals with both mutations had a lower weight reduction and gained weight back more rapidly raises new questions regarding the polygenetic nature of obesity and the search for genes that may predict differential response to weight reduction programs.
        

  • Gill Spyer, Andrew T Hattersley, et al (Department of Vascular Medicine and Diabetes Research, London)
    Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes.
    Lancet 356, December 9, 2000, pg. 1970-74.
        
    Intensive treatment to achieve good glycaemic control in diabetic patients is limited by a high frequency of hypoglycaemia. The glucose concentrations at which symptoms and release of counter-regulatory hormones takes place have not been studied in patients with well controlled type-2 diabetes.
       
    The findings were that symptom response took place at higher whole blood glucose concentrations in diabetic patients than in controls.
        
    Glucose thresholds for counter-regulatory hormone secretion are altered in well controlled type-2 diabetic patients, so that both symptoms and counter-regulatory hormone release can take place at normal glucose values. This effect might protect type-2 diabetic patients against episodes of profound hypoglycaemia and make the achievement of normoglycaemia more challenging in clinical practice.
       

  • Abi Berger, 
    Gut cells engineered to produce insulin
    BMJ, 16 December 2000, pg.1488
        
    Engineering non-pancreatic cells to produce insulin in response to a glucose load may one day be a successful approach in the treatment of diabetes. Canadian scientists have now shown that cells other than pancreatic cells can be induced to secrete appropriate levels of insulin in response to eating.
        
    Previous attempts at gene therapy have concentrated on manipulation of liver cells, but hepatocytes do not have the ability to store hormones.
       
    Dr. Cheung (Dept. of Medicine, Univ. of Alberta, Canada) and his team have shown that mice can be genetically engineered to produce human insulin from K cells located in the duodenum. K cells usually produce glucose dependent insulinotropic polypeptide (GIP), so they have an advantage over hepatocytes in that they are already glucose responsive endocrine cells and have the correct equipment to be able to store hormones.
       
    Dr. Cheung showed that when K cells are genetically engineered to produce insulin, normal glucose tolerance could be achieved in animals that have had their own pancreatic beta cells ablated.
        

  • Elizabeth Barrett-Connor and Deborah L Wingard
    Normal blood glucose and coronary risk
    Dose response effect seems consistent throughout the glycaemic continuum.
    BMJ, Vol.322; 6 Jan 2001, p.5
           
    Glycosylated haemoglobin is an accurate indicator of blood glucose level over the preceeding 6-12 weeks. It is a more precise predictor of coronary heart disease risk. Even in patients without diabetes a glycosylated haemoglobin level in the higher brackets has been shown to be an indicator of impending coronary disease. However lowering of glycosylated haemoglobin has not been shown to have any significant benefit in reducing cardiovascular risk.. Anti-hypertensive treatment is far more effective.
           

  • Andrew J Krentz, Clifford J Bailey et al
    Thiazolidinediones for type 2 diabetes
    New agents reduce insulin resistance but need long term clinical trials
    BMJ, Vol.321, July 29, 2000, pg. 252-253
           
    Insulin resistance (reduced action of insulin) is a prominent defect in type 2 diabetes. Before the introduction of troglitazone in 1997 metformin was the only drug able to sensitize target tissues to insulin. Troglitazone is superseded by more potent agents, rosiglitazone and pioglitazone. 
           
    Patients with insulin resistance have elevated serum TG and low HDL. This dyslipidemia contributes to risk of atherosclerotic cardiovascular disease. Thiazolidonediones increase HDL and rosiglitazone protects against endothelial dysfunction, lowers BP in insulin resistant and hypertensive rats.
           
    Clinical trials show that combination therapy using a thiazolidinedione with metformin (main action of which is to reduce glucose production by liver) or a sulphonylurea is particularly effective in lowering glucose concentrations.
            
    Extensive use of rosiglitazone and pioglitazone has produced little evidence that it has caused hepatic impairment. They are contraindicated in patients with liver damage. Cardiac failure is a contraindication and patients with reduced cardiac reserve need close monitoring. Pioglitazone induces cytochrome P450 (isoform CYP3A4) and the possibility of drug interactions e.g. with oral contraceptives.
            

  • Irene M Stratton, Amanda I Adler, et al 
    Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
    BMJ, Vol.321, Aug.12, 2000, pg.405-412.
            
    The objective of the study was to determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complication in patients with type 2 diabetes. It was carried out in 4585 Asian Indian, white and Afro-Caribbean UKPDS (UK prospective diabetes study) patients. Incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbAtc was associated with reductions of risk of 21% for any end-point related to diabetes. The lowest risk being in those with HbAtc values in the normal range (<60%).
          

  • Editorial – Jaakko Tuomilehto
    Controlling glucose and blood pressure in type 2 diabetes. 
    Starting treatment earlier may reduce complications.
    BMJ. Vol.321, Aug.12, 2000, pg.394-395.
           
    The main questions have been when should we start treatment, what is the target level during treatment and what is the best method of treatment, since there are no obvious cut-off points for B.P. or glucose or cholesterol concentrations that would guide clinical decisions.
           
    Comparisons with observational data have shown that antihypertensive drugs reduce the risk of stroke as predicted, but the reduction in the risk of myocardial infarction is less than expected. Treatment of hypercholesterolaemia with statins reduces the risk of myocardial infarction as predicted, whereas the effect on the risk of stroke seems larger than expected.
           
    The results of UKPDS studies reveal that patients with type 2 diabetes whose hypertension is tightly controlled reduce their risk of macrovascular complications to a greater extent than estimated. The data clearly show that there are no natural thresholds under which the risk of microvascular and macrovascular complications in diabetes are fully prevented but the risk increases steadily with rising levels of risk factors. The lower the level of blood glucose, HbAtcc, or BP, the lower the risk of complications.
           
    It is difficult to maintain reductions in glucose concentrations and BP even when using multiple drugs that in short term trials have produced excellent results. This was also confirmed in the UKPDS. Thus, the alternative possibility would be to start treatment at lower levels than those currently used as thresholds.
           
    A large European epidemiological study showed that postprandial glucose concentration is a better predictor of mortality than is fasting glucose. Perhaps impaired glucose tolerance should be an indication for treatment. There is a need to carry out controlled clinical trials to find out whether lowering glucose concentrations at the levels of impaired glucose tolerance will reduce microvascular and macrovascular complications.
          

  • M.N. Alp, Ali Ozgen, I.Can et al, (Department of Ophthalmology, Numune Hospital Turkey; Department of Radiology, Hacettepe University, Ankara, Turkey)
    Colour Doppler Imaging of the orbital vasculature in Grave’s disease with computed tomographic correlation.
    Br.J.Ophthalmol 2000; 84:1027-1030.
          
    In patients with Graves’ ophthalmopathy orbital blood flow velocities are altered. This alteration may be detected by colour Doppler imaging.
           
    Some of these changes correlate with enlargement of the extraocular muscles. Orbital inflammation may lead to increased blood flow velocities.
          

  • A Fagot-Campagna, K.M.Venkat Narayan et al
    Type 2 diabetes in children
    BMJ, Vol.322, Feb.17,2001, pg.37-378
       
    Type 2 diabetes in children is being reported from USA, Canada, Japan, Hong-Kong, Australia, New Zealand, Libya and Bangladesh. Prevalence ranges from 4.1 per 1000 in US to 50.9 per 1000 in Pima Indians of Arizona.
        
    At diagnosis, the affected child may present with weight loss, ketosis and acidosis. Insulin and C-peptide levels are often raised and antibodies absent, which may help differentiate type I from type 2 diabetes, but insulin secretion may be blunted at diagnosis. Patients may have hypertension, hypertriglyceridemia, albuminuria, sleep apnoea and depression. Treatment varies considerably and several drugs used for glycaemia, blood pressure and lipid control are not approved for use in children.
       
    To respond to this emerging problem, we need to develop case definitions in children. Safety and efficacy of therapies used in adults is known but same information is not available for children. Also needed are well co-ordinated, multi-centre trials testing the feasibility of multiple risk factor reduction in children and its benefits for practical health outcomes, such as the early stages of vascular disease.
       

  • John Pickup and Harry Keen
    Editorial – Continuous subcutaneous insulin infusion in type I diabetes.
    BMJ, May 26, 2001, pg.1262-1263.

    About 25 years ago BMJ published an account of a new technique for achieving long-term strict blood glucose control in type I diabetes.

    Continuous subcutaneous insulin infusion, or insulin pump therapy, mimics physiological delivery of insulin. It is now used by at least 130,000 people worldwide, more than 80,000 in USA alone.

    There are misunderstandings about its effectiveness, safety and clinical use. A meta-analysis of studies showed that glycaemic control is slightly but significantly better during insulin pump therapy with a glycated Hb percentage about 0.5% lower than on optimized injection regimens. As to safety, there were initial reports of hypoglycaemic coma but in 2 recent trials severe hypoglycaemia was nearly 50% less than on multiple insulin injection therapy. Some studies have found less hypoglycaemia with monomeric lispro analogue than with regular human insulin as the pump insulin.

    High rates of ketoacidosis reported earlier were probably due to lack of experience, unsuitable pump insulin, with aggregation causing cannula blockage, and the use of less reliable pumps without alarms.

    Insulin pump therapy is not indicated in most people with type I diabetes, who can achieve good control with intensified insulin therapy. Real benefits are obtained in perhaps 1-2% of those with type I diabetes. Establishing simple clinical guidelines for using continuous subcutaneous insulin infusion will promote its wider, but selective and more rational availability.  
          

  • Israel in stem cell breakthroughs
    Scrip No.2667, August 8, 2001, p.22
         
    Researchers in Israel have made advances in stem cell research which could have applications for heart attack and diabetes patients. They have succeeded in producing heart cells from stem cells (cardiomyocytes) and insulin producing islet cells both in the laboratory stage. If they succeed, there will be major changes in the treatment of heart disease and diabetes.
       

  • Vahab Fatourechi 
    Adverse Effects of Subclinical Hyperthyroidism 
    Lancet, Vol.358, September 15, 2001, Pg.856
         
    Sensitive thyrotropin (sTSH) assays can measure very low concentrations (as low as 0.001 mU/L) of thyrotropin. Introduction of these assays has allowed clinicians to diagnose “subclinical hyperthyroidism” as a distinct disorder of a very low or undetactable thyrotropin concentration associated with normal concentrations of peripheral thyroid hormones. 
         
    Possible causes of a low serum thyrotropin concentration, such as treatment with dopamine, dobutamine, high doses of glucocorticoids or recovery from hyperthyroidism should be ruled out.
         
    The most common cause is excess thyroid-hormone therapy. Thyroid autonomy due to autonomous adenoma or nodular goitre, early or mild Graves’ disease, silent or postpartum thyroiditis, subacute thyroiditis, and ingestion of pharmacological amounts of iodine are other causes.
         
    For patients receiving thyroxine-replacement therapy, the dose must be adjusted to obtain a normal serum thyrotropin concentration.
         

  • Brent E. Wisse, and Michael Schwartz 
    Role of Melanocortins in Control of Obesity 
    Lancet, Vol.358, September 15, 2001, Pg. 857
         
    The discovery in 1994 that deficiency of the adipocyte hormone, leptin, underlies genetic obesity in ob/ob mice, provided compelling support for the hypothesis that humoral signals generated in proportion to body-fat mass provide afferent input to critical brain areas that control energy intake and expenditure. 
        
    Melanocortins are neuropeptides such as a-MSH that are derived from pro-opiomelanocortin (POMC) – precursor polypeptide. When released from axon terminals in the hypothalamus, these peptides reduce food intake while increasing energy expenditure, mainly via activation of the neuronal Mc4r melanocortin receptor subtype, although Mc3r may also play a role. Opposing the neuronal action of a-MSH in this system is the endogenous Mc3/4r antagonist, agouti-related peptide (AgRP). 
        
    Both a-MSH and antagonist AgRP are synthesised within adjacent but distinct subgroups of hypothalamic neurons that are sensitive to input from adiposity-related signals such as leptin.
         
    Efforts to introduce leptin as a treatment for obesity have proved disappointing, largely because obesity is associated with leptin resistance. Since drugs acting “downstream” of leptin may effectively bypass this resistance, they are particularly appealing. 
         
    Melanocortin receptor agonists are an example of this new class of drug and seem to promote weight loss even in leptin-resistant forms of obesity. Melanocortin receptors are expressed widely in the body, and are involved in functions as diverse as skin pigmentation (Mc1r) and secretion of adrenal hormones (Mc2r), an important challenge is to target neuronal melanocortin receptors selectively.
         

  • M Keston Jones
    Management of Nodular Thyroid Disease 
    BMJ Vol. 7308, 11 August 2001; Pg. 293-94
          
    Diagnosis of nodules in the thyroid gland has remained uncertain in spite of new diagnostic techniques.
         
    Fine needle aspiration cytology (FNBC) is commonly used. It is far from satisfactory. There are 3 limitations.
         
    Firstly, 20% of samples are initially unsatisfactory. Secondly, follicular adenomas cannot be distinguished from carcinomas. 
         
    Finally, there are a number of false negatives – missed carcinomas. In spite of these difficulties FNBC remains the commonest diagnostic procedure. 
           

  • A. Gupta, R. Gupta, B. Lal 
    Effect of Trigonella foenum-graecum (Fenugreek) Seeds on Glycaemic Control and Insulin Resistance in Type 2 Diabetes Mellitus: A Double Blind Placebo Controlled Study 
    JAPI, Vol.49, November 2001, Pg. 1057-1061
          
    Summary : A double-blind placebo controlled study was performed in mild to moderate type 2 diabetes mellitus patients to evaluate the effects of Fenugreek seeds on glycaemic control and insulin resistance (determined by HOMA model).
          
    A hydro-alcoholic extract of fenugreek seeds was used in the form of capsules, and patients were asked to take 2 capsules twice a day before meals, for 2 months. Twenty five newly diagnosed patients with type 2 diabetes (fasting glucose < 200 mg/dl) were randomly divided into 2 groups. Group 1 (n=12) received 1 gm/day hydro-alcoholic extract of fenugreek seeds and group 2 (n=13) received usual care (dietary control, exercise and placebo capsules).
          
    Conclusions of the study were that adjunct use of fenugreek seeds improve glycaemic control and decrease insulin resistance in mild type 2 diabetic patients. The serum triglycerides decreased and HDL-cholesterol increased significantly in the group treated with fenugreek seeds.
          

  • V. Mohan and M. Balasubramanyam 
    Editorial: Fenugreek and Insulin Resistance 
    JAPI, Vol.49, November 2001, Pg. 1055-1056
          
    Summary : The seeds of fenugreek comprising mucilaginous fibre (about 50% by weight) and steroid saponins (12% by weight) have been claimed to account for many of the beneficial effects of fenugreek. The steroid saponins are thought to inhibit cholesterol absorption and synthesis while the fibre may help lower blood sugar levels.
          
    The available data suggests that it could be used as an adjunct therapy of type 2 diabetes, but most studies have been performed on small number of patients. Therefore, toxicity testing and large multicentre randomized clinical studies are necessary.
          
    Recently, 4-hydroxyisoleucine, an amino acid extracted from fenugreek seeds has been shown to potentiate insulin secretion. Its action is very specific on beta-cells. Multiple beneficial effects of fenugreek on glucose and lipid metabolism indicate that it can serve as an effective supportive therapy in the clinical management of diabetes.
          
    One should be cautioned that fenugreek may react adversely with a variety of medications including glipizide, heparin, insulin, ticlopidine and warfarin.
          

  • Jay S. Skyler, William T. Cefalu, et al 
    Efficacy of Inhaled Human Insulin in Type 1 Diabetes Mellitus: A Randomised Proof-of-Concept Study
    Lancet Vol.357, February 3, 2001, Pg. 331-335
         
    Summary : Effective glycaemic control in type 1 diabetes mellitus usually requires two or more insulin injections daily. Inhaled intrapulmonary delivery of insulin offers a potential new way to deliver meal-related insulin, eliminating the need for preprandial injections.
            
    73 patients with type 1 diabetes mellitus were studied in an open-label, proof-of-concept, parallel-group randomised trial. Patients in the experimental group received preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection. 
            
    Patients in the control group received their usual insulin regimen of two to three injections per day. Participants monitored their blood glucose four times daily, and adjusted insulin doses weekly to achieve preprandial glucose targets of 5.6-8.9 mmol/L.
           
    The primary outcome measure was change in glycosylated haemoglobin (HbA1c) after 12 weeks. Secondary outcomes were fasting and postprandial glucose response to a mixed meal; hypoglycaemia frequency and severity; pulmonary function; and patients’ satisfaction.
            
    Changes in HbA1c were indistinguishable between groups (difference 0.2% [95% Cl – 0.2 to 0.5]). Changes in fasting and postprandial glucose concentrations, and occurrence and severity of hypoglycaemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function (ie, spirometry, lung volumes, diffusion capacity, and oxygen saturation).
            
    This proof-of-concept study shows that preprandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional preprandial insulin injections.
            

  • Edwin A. M. Gale 
    Commentary: Two Cheers for Inhaled Insulin
    Lancet Vol.357, February 3, 2001, Pg. 324-325
            
    Summary : Jay Skyler and colleagues have shown by comparison between inhaled insulin and conventional therapy in patients with type 1 diabetes, that one daily injection of long-acting insulin plus 3 preprandial inhalations gives glucose control similar to that of 2 or 3 insulin injections a day.
            
    First paper on inhaled insulin came out in 1924 and other routes, such as transdermal, oral, nasal, intestinal, and rectal, were also extensively investigated, but only a small and erratic fraction of the amount administered reaches circulation.
            
    Inhalation has emerged as the most promising route for non-invasive administration of peptides or proteins. Insulin with a molecular weight of 5700, is absorbed well. Inhaled insulin peaks rapidly like a fast-acting analogue injected under the skin and has a longer duration of effect.
             
    Intra-individual variability of absorption is similar to injected insulin. Some of the inhaled insulins in development contain bile salts, which enhance absorption, but the Pfizer preparation consists of dry insulin dispersed by aerosol into particles sufficiently fine to drift into distal twigs of respiratory tree.
             
    Absence of an absorption enhancer reduces risk of adverse reactions but may also reduce bioavailability. Cigarette smoking is an effective means of increasing absorption of insulin but the finding is best ignored. On present evidence inhalation delivers a small and reproducible fraction of inhaled dose safely and rapidly in the blood stream.
            
    Skyler’s study is a ‘proof of concept’, and inhaled insulin does not abolish the need for insulin injections, although it may allow people to get by on only one a day. Long-acting insulins are necessary in type I diabetes and still have to be given by injection.
            
    It is too early to conclude that inhaled insulin is as good as conventional insulin, as the sample size has been too small.
             

  • Gene-Jack Wang, Nora D. Volkow, et al
    Brain Dopamine and Obesity
    Lancet Vol.357, February 3, 2001, Pg. 354-357
           
    Summary : The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity, authors measured the availability of dopamine D2 receptors in brain. 
          
    Brain dopamine D2 receptor availability was measured with positron emission tomography [PET] and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Striatal dopamine D2 receptor availability was significantly lower in the 10 obese individuals than in controls. The interpretation was that the availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI (body-mass index). 
          
    Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.
            

  • Paul T. C. Harrison
    Endocrine Disrupters and Human Health
    BMJ Vol.323, December 8, 2001, Pg. 1317-1318
          
    The term environmental oestrogen has given way to the more encompassing term “environmental endocrine disrupter” defined as an exogenous substance that causes adverse health effects in an intact organism, or its progeny, subsequent to changes in endocrine function.
           
    Endocrine disrupters are potentially present in food as natural ‘phytoestrogens’ and chemical contaminants. Among specific chemicals implicated as endocrine disrupters phthalates may be of particular importance because of their ubiquity. Similarly bisphenol A has been shown to have high potential for endocrine disruption through its use in can linings.
           
    This is of major interest because of possible exposure of infants to these chemicals at critical stages of development. Phthalate and similar compounds continue to cause concern for testicular development. 
           
    The debate about phytoestrogens and women’s health continues. There is concern that any hormonally active substance can induce or exacerbate breast and uterine cancer, and on the other is the knowledge that these substances can be used as alternatives to hormone replacement therapy in the treatment of post-menopausal symptoms and osteoporosis.
             

  • Judy Siegel-Itzkovich, Jerusalem
    Scientists develop a “vaccine” against diabetes
    BMJ, Vol.323, 1 Dec. 2001, pg. 1272
       
    Scientists have developed the world’s first drug that successfully halts the immune system’s destruction of pancreatic b-cells in humans called DiaPep277, the drug offers the possibility of preventing type I diabetes in healthy people with a genetic risk of the disease and halting its progression in people whose b-cells have already begun to die.
       
    This peptide has undergone Phase II clinical trial on 35 patients. Mechanism of action may be changes in patients’ T cells. In children the destruction of pancreatic cells is very rapid taking place even in a couple of months.     
                                                        

  • Richard Stanhope                      
    Commentary – Use of a specific aromatase inhibitor in delayed puberty                    
    Lancet, vol.357, June 2, 2001, pg.1723                     
                                                                                                          
    Constitutional delay of puberty and growth may be diagnosed in short adolescents who have delayed puberty, a delayed bone age, and no underlying illness. The diagnosis however, should be made on clinical and anthropometric criteria since biochemical assessment is often misleading in delayed puberty and such patients require practical help rather than intensive investigation.
                                                                     
    In Lancet, Sanna Wickman and colleagues report the results of a randomised double-blind placebo-controlled trial of letrozole, a specific fourth-generation aromatase inhibitor, along with testosterone treatment in boys with constitutional delay of puberty and growth. In boys the spontaneous growth spurt occurs late in puberty – about 2 years after the start of sexual development.
                                                                                      
    Recent knowledge from the study of inborn errors of metabolism has shown that oestrogen is the predominant hormone that causes epiphyseal closure in both sexes. Men with mutations of the genes for oestrogen receptor
    a8 or P-450 aromatase continue to grow after the age of 20 and attain tall stature. Non-specific aromatase inhibitors, such as testolactone, have been used in paediatric endocrine practice for many years to block the conversion of testosterone to oestrogen. Wickman and colleagues have refined this intervention by the use of a specific aromatase inhibitor to mimic the effect of these inborn errors. When testosterone therapy is combined with an aromatase inhibitor, the former provides virilisation and a growth spurt, while the latter delays epiphyseal closure thus allowing growth over a longer time. Indeed, the effect of this double-edged therapeutic approach is magnified because combined therapy produces a higher serum testosterone and lower serum oestrogen concentration than would be attained by either agent alone. The overall effect is to advance pubertal development and improve the final-height potential.        
                                                

  • Sanna Wickman, Ilkka Sipila, et al        
    A specific aromatase ihibitor and potential increase in adult height in boys with delayed puberty: a   randomised controlled trial.          
    Lancet , June 2, 2001, 357, pg.1743-48                                               
                                                                     
    The role of oestrogens in the closure of growth plates in both sexes is unequivocal. Inhibition of oestrogen synthesis in boys with delayed puberty would delay maturation of the growth plates and ultimately result in increased adult height.                
                                                 
    A randomised, double-blind, placebo controlled study was done, in which authors treated boys with constitutional delay of puberty with testosterone and placebo, or testosterone and letrozole. Boys who decided to wait for the spontaneous progression of puberty without medical intervention composed the untreated group.                               
                                  
    Letrozole effectively inhibited oestrogen synthesis and delayed bone maturation. Progression of bone maturation was slower in the letrozole group than in the placebo group.                                      
                                                   
    Interpretation of the study suggests that if oestrogen action is inhibited in growing adolescents, adult height will increase. This finding provides a rationale for studies that aim to delay bone maturation in several growth disorders.                     
                                          

  • Sheila A. Doggrell (Department of Physiology and Pharmacology, The University of Queensland, Brisbane, Queensland, Australia) 
    Targets to Trials in Diabetic Complications 
    Drugs of Today, Vol. 37(11), November 2001, Pg. 739-748
         
    Diabetes is now the leading cause of end-stage renal disease, blindness, lower-extremity amputations and impotence. 
         
    Targets with potential for therapeutic intervention in diabetic complications
                      

    Genetic studies: Aldose reductase inhibitors
                               
    A candidate gene near the transcription site of the aldose reductase gene has been identified. Aldose reductase inhibitors have not been shown to be beneficial in diabetic complications. A possible explanation for this is that aldose reductase is only one pathway that leads to stimulation of MAPKs (mitogen-activated protein kinases), which may be common mediators of diabetic complications and thus inhibition of aldose reductase alone is not effective. 
                                          
    MAPKs (Mitogen-activated protein kinases) 
                                         
    Professor David Tomlinson (University of Manchester, U. K.) presented evidence that the MAPKs trigger all of the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy. Professor Tomlinson suggested that the damaging effects of glucose, regardless of pathway (sorbitol, nonenzymatic glycation of proteins, oxidative stress) were finally mediated by the MAPKs (ERK, JNK and p38).                              
                                    
    To support his hypothesis Professor Tomlinson provided experimental evidence using selective inhibitors of p38 (SB202190 and SB238063) and ERK (U0126) but stated that selective antagonists of JNK were not presently available. Some suggested that the MAPKs are far too widespread and involved in too many functions to be therapeutic without serious side effects and that signaling upstream of MAPKs would make more selective targets.     
                                                     
    Others suggested that in low doses MAPKs may have some therapeutic potential in diabetic complications. 
                      
    PKC (Protein kinase C)

    PKC is upstream in the MAP-kinase pathway. Inhibition of glomerular PKC activity by a specific inhibitor of the ß isoform (LY333531) has been shown to prevent diabetes-related vascular dysfunction and increases in albuminuria in an animal model (12).

    Activation of a specific isoform of PKC may be involved in retinopathy and this isoform is a potential target. The identification of a specific isoform of PKC associated with retinopathy increases the likelihood of having beneficial effects in retinopathy without excessive side effects. 

    TGF-?ß(Transforming growth factor-ß)

    The important role of TGF-?ß in mesangial and macro- and microvascular dysfunction was considered by Professor Kumar Sharma (Thomas Jefferson University, Philadelphia, U.S.A.). In an animal model of type II diabetes, the diabetic glomerular hypertrophy could be prevented with anti-TGF-ß antibodies. 

    The reported beneficial effects of the ACE inhibitor captopril and the AT1-receptor antagonist losartan in diabetic kidney disease may be partly due to inhibiting angiotensin II stimulation of TGF-ß. As TGF-?ß has beneficial effects at other sites, it seems an unlikely target for therapeutic intervention in diabetic complications, as these beneficial effects may also be inhibited. 

    However, if there is excessive production of TGF-?ß in diabetic complications, it may be possible to reduce the excessive effects without modifying the beneficial functions. 

    Another possible target is the interrupting of various downstream effects of TGF-ß. Thus, USF-1 (upstream stimulatory factor-1), GRE (glucose response element), IP3R (the inositol 1,4,5-triphosphate receptor) may be important therapeutic targets to combat diabetic complications. 

    Nitric oxide/tetrahydrobiopterin

    Diabetics have reduced vasodilatation and inadequate angiogenesis. These disturbed vascular responses appear to be the result of impaired synthesis of nitric oxide (NO). The roles of NO and tetrahydrobiopterin, an essential cofactor for NO synthase, in vascular dysfunction in diabetes were discussed by Dr. Cynthia Meininger. 

    There are several possible ways to improve the endothelial dysfunction in diabetes. Tetrahydrobiopterin supplements could be used. The nitrates and the NO-donor drugs also have the potential to overcome this dysfunction. 

    Antioxidants/superoxide dismutase

    Oxidative stress with superoxide production also contributes to the vascular dysfunction in diabetes. However, when vitamin E, an antioxidant, was used in the HOPE study it was ineffective. 

    They assessed whether vitamin E supplementation for three months would improve conduit and resistance vessel vasodilator function in 41 subjects with type I diabetes, in a double-blind, placebo-controlled, randomized study. 

    Vitamin E improved endothelial function assessed by brachial flow-mediated dilatation and by intraarterial acetylcholine. This improvement was associated with a decrease in LDL cholesterol oxidation. 

    Wound healing: VEGF

    Delayed wound healing, or an inability to carry out tissue repair processes, is a major complication of diabetes leading to an increased incidence of chronic wounds such as leg ulcers. 

    There are a number of factors involved in the healing impairment in diabetes. These include the acute effects of hyperglycemia, the long-term effects of advanced glycosylation of extracellular matrix proteins and changes in expression levels and availability of growth factors or cytokines. 

    VEGF is very important in angiogenesis but it is reduced in diabetic wounds. VEGF is detrimental in retinopathy. Thus, the local administration of VEGF to diabetic wounds will need careful testing of whether it is beneficial to the wounds without being detrimental to the eye. 

    Inhibition of advanced glycation endproducts (AGE) formation.

    ACE inhibition with ramipril decreased AGE levels in experimental diabetes and this effect may have contributed to the benefit of ramipril in diabetic patients in the HOPE trial.

    Connective tissue growth factor (CTGF) 

    CTGF is a potent inducer of extracellular matrix and its gene expression is increased in rodent models of diabetes. AGE induces CTGF through a non-PKC-dependent pathway, and AGE and CTGF induce fibronectin through a PKC-dependent mechanism. 

    Thus, CTGF may be a new target for consideration in the treatment of complications of diabetes. 

    Glucose transformer isoform 1 (GLUT-1) transporter

    As the GLUT-1 transporter is overexpressed in mesangial cells subject to mechanical stress, this is a potential site for pharmacological intervention in diabetic complications. 

    Nephrin

    Nephrin is a cytoskeletal protein that localizes to the slit pore of podocytes. In some proteinuric models, deficiencies in nephrin have been associated with increases in albuminuria. Nephrin is a potential target for pharmacological intervention in diabetes associated with hypertension. 

 

 

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