No abstract

Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg·m Ϫ 2 ). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with BMI Յ 25 kg·m Ϫ 2 ), was present in 26% of the obese subgroup (538 subjects with a mean BMI of 29 kg·m Ϫ 2 ). Insulin sensitivity declined linearly with BMI at an age-and sex-adjusted rate of 1.2 mol·min Ϫ 1 ·kg FFM Ϫ 1 per BMI unit (95% confidence intervals ϭ 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly ( P Ͻ 0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waistto-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated ( P Ͻ 0.001) with insulin hypersecretion, particularly in women.In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity. ( J. Clin. Invest. 1997. 100:1166-1173.)

Patients with noninsulin-dependent diabetes mellitus (NIDDM) have both preprandial and postprandial hyperglycemia. To determine the mechanism responsible for the postprandial hyperglycemia insulin secretion, insulin action, and the pattern of carbohydrate metabolism after glucose ingestion were assessed in patients with NIDDM and in matched nondiabetic subjects using the dual isotope and forearm catheterization techniques. Prior to meal ingestion, hepatic glucose release was increased (P < 0.001) in the diabetic patients measured using [2-3Hj or 13-3HJ glucose. After meal ingestion, patients with NIDDM had excessive rates of systemic glucose entry (1,316±56 vs. 1,018±65 mg/kg 7 h, P < 0.01), primarily owing to a failure to suppress adequately endogenous glucose release (680±50 vs. 470±32 mg/kg-7 h, P < 0.01) from its high preprandial level. Despite impaired suppression of endogenous glucose production during a hyperinsulinemic glucose clamp (P < 0.001) and decreased postprandial C-peptide response (P <0.05) in NIDDM, percent suppression of hepatic glucose release after oral glucose was comparable in the diabetic and nondiabetic subjects (45±3 vs. 39±2%). Although new glucose formation from meal-derived three-carbon precursors (53±3 vs. 40±7 mg/kg 7 h, P < 0.05) was greater in the diabetic patients, it accounted for only a minor part of this excessive postprandial hepatic glucose release. Postprandial hyperglycemia was exacerbated by the lack of an appropriate increase in glucose uptake whether measured isotopically or by forearm glucose uptake. Thus as has been proposed for fasting hyperglycemia, excessive hepatic glucose release and impaired glucose uptake are involved in the pathogenesis of postprandial hyperglycemia in patients with NIDDM.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

SummarySex hormone binding globulin (SHBG) is a glycoprotein composed of two 373-amino-acid subunits. The SHBG gene and a promotor region have been identified. The SHBG receptor has yet to be cloned but is known to act through a G-protein-linked second-messenger system following plasma membrane binding. The principal function of SHBG has traditionally been considered to be that of a transport protein for sex steroids, regulating circulating concentrations of free (unbound) hormones and their transport to target tissues. Recent research suggests that SHBG has functions in addition to the binding and transport of sex steroids. Observational studies have associated a low SHBG concentration with an increased incidence of type 2 diabetes mellitus (DM) independent of sex hormone levels in men and women. Genetic studies using Mendelian randomization analysis linking three single nucleotide polymorphisms of the SHBG gene to risk of developing type 2 DM suggest SHBG may have a role in the pathogenesis of type 2 DM. The correlation between SHBG and insulin resistance that is evident in a number of cross-sectional studies is in keeping with the suggestion that the association between SHBG and incidence of type 2 DM is explained by insulin resistance. Several potential mechanisms may account for this association, including the identification of dietary factors that influence SHBG gene transcription. Further research to characterize the SHBG-receptor and the SHBG second messenger system is required. An interventional study examining the effects on insulin resistance of altering SHBG concentrations may help in determining whether this association is causal.