Future Development Of Diabetes Research Articles

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

In their recent study, Utzschneider et al. (1) demonstrated that indexes of insulin secretion and insulin sensitivity derived from plasma glucose and insulin concentration during the oral glucose tolerance test (OGTT) display an inverse relationship similar to that observed with the frequently sampled intravenous glucose tolerance test. Further, the product of the change in insulin divided by change in glucose (ΔI/ΔG) × insulin sensitivity (the insulin secretion/insulin resistance [IS/IR] index or so-called disposition index), which provides an estimate of β-cell function relative to the prevailing level of insulin resistance, was shown to predict the future risk for type 2 diabetes independent of the glucose tolerance status in Japanese-American individuals. These observations are consistent with previous publications from our lab (2–5) and extend our …

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function.RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30).RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations.CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: A cohort and nested case–control analysis

To determine the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) compared with that in patients with noninflammatory rheumatic disorders and to determine risk factors for MI in RA, the relationship between cardiovascular risk factors and corticosteroid use, and the relationship between RA treatment and MI. We conducted a cohort study of MI in 17,738 patients with RA and 3,001 patients with noninflammatory rheumatic disorders who were assessed at 6-month intervals between 1999 and July 2006. We evaluated treatment effect in a nested case-control study of RA participants who were matched by age, sex, study duration, and date of study entry. The covariate-adjusted risk of first MI in RA versus that in noninflammatory rheumatic disorders was 1.9 (95% confidence interval 1.2-2.9) (P = 0.005). In RA, MI was predicted by age, sex, education level, hypertension, smoking, exercise, prior MI, diabetes, a comorbidity index, use of low-dose aspirin and antilipemic agents, RA severity and treatment variables, and corticosteroid use. Except for obesity, predictors were of equal strength in RA and noninflammatory rheumatic disorders. The increased risk for MI in RA compared with that in noninflammatory rheumatic disorders lessened when corticosteroid users were excluded. Use of corticosteroids was associated with future development of diabetes and hypertension. MI in RA is associated with demographic and cardiovascular risk factors and corticosteroid use. Study data support the hypothesis that RA activity causes MI and that corticosteroids are primarily a marker of RA activity. However, corticosteroids increase the risk of diabetes and hypertension and contribute to the overall risk of MI.

Obesity, Metabolic Syndrome, and Type 2 Diabetes: Inflammatory Basis of Glucose Metabolic Disorders

The latter half of the 20th century has witnessed rapid advances in medicine. Concurrently, secular trends in lifestyle practices in our increasingly sedentary society have led to burgeoning rates of obesity, metabolic syndrome, and type 2 diabetes. The number of Americans with type 2 diabetes more than doubled between 1980 and 2004 and the prevalence increases with age. Potential causes of this growing epidemic include changes in dietary patterns, physical inactivity, and obesity but may also include as yet unidentified genetic and environmental determinants. In this regard, experimental data provide evidence for a direct link between obesity and subclinical inflammation and support the concept that the metabolic syndrome and type 2 diabetes are, at least in part, inflammatory conditions. Furthermore, elevated levels of inflammatory biomarkers are not only associated with the development of future diabetes but cardiovascular disease as well. These findings suggest that subclinical inflammation may be a contributing factor not only to the etiology of these metabolic disorders but also their cardiovascular complications.

Beta-cell dysfunction is the primary contributor to the early postpartum diabetes among Chinese women with history of gestational diabetes mellitus

Women with a history of gestational diabetes mellitus (GDM) are at higher risk of future development of diabetes. This study investigated the risk factors associated with early postpartum abnormal glucose regulation (AGR) among Chinese women with a history of GDM. A total of 186 women with a history of GDM were screened for early postpartum AGR at 6-8 weeks after delivery. Those with AGR were given lifestyle intervention therapy and reevaluated in 6-12 months. The demographic, anthropometric, prenatal and delivery data were recorded. The plasma high-sensitivity C-reactive protein (HsCRP) and lipid concentration were measured, and insulin secretion were analyzed. Insulinogenic index Deltains30'/DeltaBG30', the homeostasis model assessment index (HOMA)-B, and HOMA-IR were calculated. Multiple regression analysis was performed to identify the risk factors. Of the GDM women 28.0% (52/186) had AGR at 6-8 weeks after delivery; 45.2% (17/40) of these AGR women reminded abnormal after 6-12 month lifestyle intervention. Compared to the women who reverted to normal, women with consistent AGR showed significantly lower fasting insulin concentration, lower Deltains30'/DeltaBG30' as well as lower HOMA-B. No significant differences in age, body mass index (BMI), waist circumference, blood pressure, lipid level, HsCRP and HOMA-IR were observed between the two groups. Pre-pregnancy BMI = 25 kg/m(2), fasting glucose level = 5.6 mmol/L and/or 75 g oral glucose tolerance test (OGTT) 2 hours glucose level = 11.1 mmol/L during pregnancy were predictors for the AGR at 6-8 weeks after delivery. Deltains30'/DeltaBG30 = 1.05 was a significant risk contributor to the consistent early postpartum AGR. There is a high incidence of early postpartum AGR among Chinese woman with prior GDM. Beta-cell dysfunction, rather than insulin resistance or inflammation, is the predominant contributor to the early onset and consistent AGR after delivery.

Prevalence of Undiagnosed Type-2-Diabetes Mellitus and Impaired Fasting Glucose in German Primary Care: Data from the German Metabolic and Cardiovascular Risk Project (GEMCAS)

Primary care physicians are gatekeepers of the healthcare system and thus responsible for screening, prevention and treatment of diabetes. Little is known about the prevalence of diabetes, impaired fasting glucose and factors that are associated with the risk of future development of diabetes and subsequent cardiovascular disease in unselected patients presenting to general practitioners. A nationwide sample of 35,869 primary care patients screened in 2005 was used to estimate the prevalence of detected and undetected diabetes as well as of impaired fasting glucose. Logistic regressions were used to assess the prevalence, cardiovascular morbidity and the factors associated with undetected diabetes and impaired fasting glucose. 1) Using a blood glucose screening algorithm the prevalence of known type 1 and type 2 diabetes mellitus was found to be 0.6 and 12.2%, respectively. Another 2.9% (23% of the diagnosed) had either undiagnosed diabetes (0.9%) or impaired fasting glucose (2.0%). 2) Undiagnosed patients had a more unfavourable cardiovascular risk profile compared to non-diabetic patients. 3) Moreover, higher age, male gender, low HDL-cholesterol and elevated triglycerides as well as a family history of diabetes were associated with unknown diabetes or impaired fasting glucose. Approximately 15.7% of individuals in Germany consulting a primary care physician are affected from either diabetes (known and unknown) or impaired fasting glucose and face a substantially elevated cardiovascular risk score. This study demonstrated that using a simplified blood glucose screening algorithm considering risk markers like higher age, male gender, low HDL-cholesterol, high triglycerides and a family history of diabetes may well serve as a suitable screening approach for undiagnosed diabetes and impaired fasting glucose in primary care practice.

Prevention of Type 2 Diabetes in Women With Previous Gestational Diabetes

The consequences of hyperglycemia appearing during pregnancy were well described in 1917, when Elliot P. Joslin described Case 309, which “showed sugar in 1897 during pregnancy, but following confinement, with resulting dead baby, it disappeared, but returned in 9 years in the form of moderate to severe diabetes… . [W]ith our present knowledge, it is quite possible that such an outcome could be prevented by active treatment of the glycosuria from the very start” (1). Subsequently, O'Sullivan and Mahan's definition of gestational diabetes mellitus (GDM) in 1964 was a formal recognition of the mother's increased risk of future development of diabetes (2). They defined GDM if a pregnant woman undergoing a 3-h 100-g oral glucose tolerance test had glucose values exceeding 2 SDs above the mean on two of the four values. This landmark study described a population of pregnant women with a lifetime risk of diabetes exceeding 70% (3). Multiple studies worldwide have demonstrated a broad ethnic and geographic distribution of GDM, but all studies share the increased risk of subsequent diabetes after delivery (4). Assessment of diabetes risk postpartum is influenced by the criteria used to define GDM, the testing undertaken postpartum, and the length of follow-up. Diagnosis of carbohydrate intolerance in the first trimester of pregnancy may reflect the ascertainment of previously undiagnosed and, presumably, asymptomatic diabetes. Alternatively, pregnancy creates a metabolic stress that may push a woman with compensated type 1 or type 2 diabetes into a decompensated hyperglycemic state. Under these circumstances, one would anticipate a high rate of persistent hyperglycemia in the postpartum state. In fact, the presence of GDM doubles the risk of diabetes within 4 months postpartum, whereas a fasting plasma glucose >121 mg/dl during the pregnancy increased the risk 21-fold (5). Differential criteria for diagnosis of GDM affects the …

Leptin predicts the development of diabetes in Mauritian men, but not women: a population–based study

To determine if levels of the adipocyte-derived hormone, leptin, predict the development of type 2 diabetes. Population-based surveys were undertaken in the multiethnic nation of Mauritius in 1987, 1992 and 1998. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. A cohort of 2330 participants who were free of diabetes, aged 25-79 years in 1987, and who were followed-up in 1992 and 1998 was studied. Serum leptin was measured in baseline samples. Glucose tolerance was classified according to WHO (World Health Organization) 1999 criteria. In total, 456 subjects developed diabetes over 11 years with similar incidences in all ethnic groups (P=0.2). Baseline leptin correlated positively with anthropometric measurements, fasting and postload insulin and homeostasis model assessment indices (all P<0.001), and inversely with subsequent weight increase. Participants with incident diabetes had higher serum levels of leptin at baseline than those remaining nondiabetic (P<0.001). After adjustment for confounders, high leptin levels and high leptin/body mass index ratio were independently associated with incident diabetes over 11 years in men (odds ratio for top versus bottom quartile of leptin 2.18; 95% CI: 1.09-4.35), but not in women. We conclude that high leptin levels are associated with the future development of diabetes, and the association is independent of other factors in men, but not in women.

The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer’s Disease

To verify the hypothesis that borderline diabetes may increase the risk of dementia and Alzheimer's disease, a community-based cohort of 1,173 dementia- and diabetes-free individuals aged >or=75 years was longitudinally examined three times to detect patients with dementia and Alzheimer's disease (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria). Borderline diabetes was defined as a random plasma glucose level of 7.8-11.0 mmol/l. Data were analyzed using Cox proportional hazards models. During the 9-year follow-up, 397 subjects developed dementia, including 307 Alzheimer's cases. At baseline, 47 subjects were identified with borderline diabetes. Borderline diabetes was associated with adjusted hazard ratios (95% CIs) of 1.67 (1.04-2.67) for dementia and 1.77 (1.06-2.97) for Alzheimer's disease; the significant associations were present after additional adjustment for future development of diabetes. Stratified analysis suggested a significant association between borderline diabetes and Alzheimer's disease only among noncarriers of APOE epsilon4 allele. There was an interaction between borderline diabetes and severe systolic hypertension on the risk of Alzheimer's disease (P = 0.04). We conclude that borderline diabetes is associated with increased risks of dementia and Alzheimer's disease; the risk effect is independent of the future development of diabetes. Borderline diabetes may interact with severe systolic hypertension to multiply the risk of Alzheimer's disease.

Thiazide Diuretics, Potassium, and the Development of Diabetes

National guidelines and a recent clinical trial have supported the use of thiazide diuretics as the preferred initial pharmacological treatment for hypertension. However, evidence from this and other clinical trials have also found an increased incidence of new onset diabetes among those patients receiving thiazide diuretics. The mechanisms responsible for the increased incidence of diabetes with thiazide diuretics have not been fully elucidated. This article provides a review of intervention studies that included data on the relation between thiazide-induced hypokalemia and glucose intolerance. We conducted a literature search from 1966 to June 2004 to identify clinical trials using thiazide diuretics where the metabolic effects on potassium and glucose are reported. A total of 59 clinical trials constituting 83 thiazide diuretic study arms were identified. Trial size, length, type of thiazide diuretic, and dose varied substantially among the studies. The association between average changes in potassium and glucose in the study arms is considered jointly in a weighted statistical model. The Pearson's correlation coefficient, weighted by study sample size, for the relationship between glucose and potassium was -0.54 (95% CI, -0.67 to -0.36; P < 0.01). A sensitivity analysis, which considered subset analyses and effect of covariates, as well as inverse-variance weighting, supported this finding. These data suggest that thiazide-induced hypokalemia is associated with increased blood glucose. Treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent the future development of diabetes.

Comparison of insulin resistance and serum high-sensitivity C-reactive protein levels according to the fasting blood glucose subgroups divided by the newly recommended criteria for fasting hyperglycemia in 10 059 healthy Koreans

The increment for the prevalence of diabetes mellitus and impaired glucose tolerance warrants lowering the cutoffs of normoglycemia to help predict the future development of diabetes. The aim of this study was to find out whether insulin resistance and high-sensitivity C-reactive protein (hsCRP), a nontraditional cardiovascular risk factor, were related to the fasting glucose level, even in normoglycemic range that was categorized by the newly recommended criteria by the American Diabetes Association. Among the participants undergoing medical checkup program at Kangbuk Samsung Hospital, 10 059 subjects (5535 men and 4524 women; mean age, 45 years) with normal fasting glucose levels, as defined by the newly recommended criteria (<5.6 mmol/L), were enrolled in this study. The blood pressures, body mass index (BMI), fasting blood glucose, fasting insulin, lipid batteries, and hsCRP levels were checked. The homeostatic model assessment–insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check indexes (QUICKI) were calculated. All subjects were subdivided into 4 groups according to the fasting glucose level. The HOMA-IR, QUICKI, and log-transformed (log) hsCRP, or log(hsCRP), level significantly increased according to the increment in fasting glucose, and these associations were consistent after adjustment for age and BMI, except for the log(hsCRP) ( P = .124 after adjustment). Log(hsCRP) increased as the HOMA-IR increased and as the QUICKI decreased, and when multiple regression analysis was done with log(hsCRP) as the dependent variable, age, high BMI, male sex, high HOMA-IR, hypertriglyceridemia, and low high-density lipoprotein cholesterol were the significant predictor for log(hsCRP). In conclusion, the insulin resistance indexes and hsCRP increased gradually even in the normal fasting glucose range, as categorized by the newly recommended criteria for abnormal fasting glucose levels, supporting the rationale for expanding the range of fasting hyperglycemia.

Gestational diabetes: The significance of persistent fasting hyperglycemia for the subsequent development of diabetes mellitus

There are little data regarding the temporal pattern of hyperglycaemia during gestational diabetes (GDM) and its significance for the development of future diabetes. The aim of this study was to examine the relationship between fasting and postprandial hyperglycemia in a GDM pregnancy, with the development of subsequent diabetes mellitus (DM). Participants with a history of GDM were identified by a medical records review and invited to be tested for diabetes. One hundred and two participants participated in the study, up to 8 years after their pregnancy. Diabetes had developed in 29%, and 16% had impaired glucose tolerance. Pregnancy factors predictive for the development of diabetes included BMI, the fasting and 2-h BGL on the GTT, and the use of insulin. We used the need for bedtime intermediate-acting insulin as an indicator of persistent fasting hyperglycemia and the need for prandial short-acting insulin as a marker of postprandial hyperglycemia. Compared with participants not treated with insulin, those requiring bedtime insulin had a relative risk of 6.2 (95% CI=2.7–14.1, P<.001) for the development of diabetes. However, participants who required prandial insulin only did not have a higher likelihood of diabetes, compared with those who did not require insulin (relative risk=1.5, 95% CI=0.5–3.8, NS). We conclude that the need for bedtime insulin, reflecting persistent fasting hyperglycemia in a GDM pregnancy, is highly predictive for the development of subsequent DM.

Point: Visceral Adiposity Is Causally Related to Insulin Resistance

The relationship between obesity and insulin resistance, while well recognized for many years, has nonetheless been confusing since not all obese individuals have insulin resistance (1) and because insulin resistance occurs in individuals who have BMIs that are within the normal or mildly overweight categories (2). Early attempts to understand the relationships between obesity, type 2 diabetes, and cardiovascular disease focused on the waist-to-hip ratio as a means of distinguishing those individuals who were at increased risk from those who were not (3,4). A high waist-to-hip ratio is a surrogate for masculine distribution of obesity (central obesity). Cross-sectional studies by Kissebah et al. (5) and Krotkiewski et al. (6) in the 1980s demonstrated that hypertension, hypertriglyceridemia, hyperinsulinemia, and glucose intolerance were increased in subjects with a high waist-to-hip ratio. Long-term longitudinal population-based studies of men (13.5 years) and women (12 years) in Gothenburg, Sweden, showed that the waist-to-hip ratio was a predictor of the future development of diabetes, myocardial infarction, angina pectoris, stroke, and death independent of BMI (3,4). Technology developed in the 1990s, including computer tomography scans and MRI, made it possible to precisely measure specific adipose tissue depots such as total body adipose tissue mass, abdominal subcutaneous adipose tissue mass, visceral adipose tissue mass, and hepatic and intramuscular triglyceride content (7,8). Utilizing those techniques, many studies have examined the relationship between total adipose tissue, abdominal subcutaneous adipose tissue, and visceral adipose tissue mass and insulin resistance, the components of the metabolic syndrome, and the development of type 2 diabetes or clinical cardiovascular events (9–21). Despite the much smaller size of the visceral adipose tissue depot compared with the total subcutaneous adipose tissue depot or total adiposity, many investigations demonstrated that the visceral adipose tissue mass and not …

Minimal Model Analysis in Nondiabetic Renal Transplant Recipients With Hepatitis C

Introduction Epidemiological data suggest that hepatitis C virus (HCV) infection may contribute to the development of posttransplantation diabetes mellitus (PTDM). Methods We investigated the glucose metabolism in 19 renal transplant recipients with antiHCV antibodies and without DM according to World Health Organization criteria before or after transplantation. We measured insulin sensitivity (SI), glucose effectiveness (SG), and pancreatic insulin response using the frequently sampled intravenous glucose tolerance test (FSIGTT). SI and SG were estimated using the Bergman minimal model method and pancreatic insulin response was expressed as the area under insulin curve (AUIC) between 0 and 19 minutes. Results Impaired glucose tolerance was shown in 42% of patients, some (31.5%) in the range of glucose intolerance (KG: 1–1.5) and others (10.5%) in the diabetes range (KG < 1). SI and SG were decreased in 39% and 63% of patients, respectively. Pancreatic insulin response revealed high variation among patients although showing a tendency to be enhanced. Conclusions A high number of HCV-positive renal transplant recipients without clinically manifest PTDM have impaired glucose tolerance, which suggests the future development of diabetes in these patients.

Fasting Plasma Glucose Cutoff Value for the Prediction of Future Diabetes Development: A Study of Middle-Aged Koreans in a Health Promotion Center

We determined optimal fasting plasma glucose (FPG) cutoff values predictive of future diabetes development in a group of middle-aged Koreans who visited a health promotion center. The medical records of 2,964 subjects, who attended the Health Promotion Center in 1998 and 2003, were examined. Subjects were classified into four groups according to their baseline FPG values (Group 1:FPG <5.0 mM/L; Group 2: 5.0≤FPG <5.6 mM/L; Group 3: 5.6≤FPG <6.1 mM/L; Group 4: 6.1≤FPG <7.0 mM/L). No significant difference was observed between Group 1 and Group 2 in terms of diabetes incidence. However, incidence in Group 3 was significantly higher than that in Group 1 [hazards ratio 4.88 (1.65-14.41), p=0.004] and the hazards ratio in Group 4 for diabetes was 36.91 (13.11-103.61), p<0.001, versus Group 1. Receiver operator characteristics curve analysis showed that an FPG of 5.97 mM/L represents the lower limit and gives the best combination of sensitivity and specificity. Our data shows that the risk of future diabetes development started to increase below an FPG of 6.1 mM/L and suggests the importance of efforts to modify diabetes development risk factors at lower impaired fasting glucose levels.

Postnatal glucocorticoid exposure alters the adult phenotype.

We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in alpha-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume).

Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians.

Adiponectin, secreted by fat cells, has regulatory functions on energy metabolism. Its low levels are predictive of future development of diabetes. Because no studies on the regulatory role of adiponectin in glucose homeostasis in Asian Indians exist, this analysis was performed to determine the prospective association of adiponectin and diabetes in subjects with impaired glucose tolerance (IGT). Baseline values of plasma adiponectin, results of anthropometry, fasting and 2-h plasma glucose levels, HbA(1c), results of lipid profile, and insulin resistance were analyzed in 91 subjects with IGT (53 men and 38 women) in a primary prevention study. Reassessment of glucose tolerance was performed during 1-year review. The predictive nature of adiponectin for development of diabetes was assessed using univariate and multiple logistic regression analyses. A control group comprising healthy, normoglycemic individuals was used for comparison. At follow-up, diabetes had developed in 25 of the 91 study subjects. The mean baseline adiponectin level was lower in the diabetic subjects than in the nondiabetic subjects (11.3 +/- 5.5 vs. 16.7 +/- 7.6 micro g/ml, P = 0.0017). Low adiponectin level was a strong predictor of future development of diabetes, and HbA(1c) also showed a positive predictive association. Women had higher adiponectin levels (16.4 +/- 6.1 micro g/ml) than men (13.9 +/- 7.6 micro g/ml) (P = 0.035). In Asian Indians, low plasma adiponectin level was predictive of future development of diabetes.

Measurement of insulin resistance in vivo.

Insulin sensitivity, which can be impaired in both glucose-intolerant and non-glucose-intolerant individuals, is a valuable parameter because of its potential as a marker for the future development of diabetes and increased cardiovascular risk. Techniques available for the determination of insulin sensitivity include the glucose clamp, insulin tolerance test, insulin suppression test, the frequently sampled intravenous glucose tolerance test and the regional artero-venous balance. Model assessment methods are also available for the measurement of insulin sensitivity at steady-state plasma glucose and insulin levels or after a standardised glucose infusion. Methods vary in their complexity, and the choice between them depends on the nature of the information required. There is also evidence for a strong genetic contribution to insulin sensitivity; although identification of the relevant gene(s) has not yet been successful, accurate phenotyping should still be carried out as part of the assessment of a patient's clinical status.

Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.

Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys.

The purpose of this study was to identify the relationship between basal hepatic glucose production (HGP) and peripheral insulin sensitivity as assessed by the hyperinsulinemic euglycemic clamp prior to and during the development of non-insulin-dependent (type 2) diabetes mellitus in rhesus monkeys. Twenty-six male monkeys (Macaca mulatta), including normal animals and monkeys in various phases of the development of spontaneous obesity-associated type 2 diabetes were studied. Fasting plasma glucose (FPG) and insulin (FIRI), basal HGP using a [3H]glucose infusion, and peripheral insulin sensitivity (as determined by the euglycemic clamp technique) were examined. The earliest change that could be detected was a significant reduction in peripheral insulin sensitivity accompanied by increased FIRI. These changes preceded a significant deterioration of glucose tolerance. Basal HGP changed in parallel with FPG (r = 0.90, P less than 0.001), becoming significantly elevated only when FPG rose to levels diagnostic of diabetes (greater than 140 mg/dl). Thus basal HGP and fasting glucose levels showed no significant changes early in the development of type 2 diabetes. We conclude that the early serial decreases in insulin sensitivity and progressive increases in FIRI, with or without decreased glucose tolerance, are prognostic of the future development of diabetes in obese monkeys, a longitudinal process that is also likely to be observed in most if not all obese humans progressing to diabetes.