A b b re v i a t i o n s : AUC, area under the curve; 1st PH, first-phase insulin release; Gluc, plasma glucose concentration during the OGTT; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; Ins, plasma insulin concentration during the OGTT; IR, insulin resistance index; ISI, insulin sensitivity index; ISI(comp), composite insulin sensitivity index; MCR, metabolic clearance rate; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; 2nd PH, second-phase insulin release; Secr, insulin release index; SI, sensitivity index; S y x , residual error of re g ression; WHR, waist-to-hip ratio.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Use of the Oral Glucose Tolerance Test to Assess Insulin Release and Insulin S e n s i t i v ity O R I G I N A L A R T I C L E O B J E C T I V E -The oral glucose tolerance test (OGTT) has often been used to evaluate a p p a rent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be pre d i c t e d f rom an OGTT is unclear.RESEARCH DESIGN AND METHODS -We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear re g ression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. R E S U LT S -The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P 0 . 0 0 0 0 5 ) and ISI (r = 0.79, P 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P 0.00005) and 2nd PH (r = 0.79, P 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the 30-min insulin/ 30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. C O N C L U S I O N S E p i d e m i o l o g y / H e a l t h S e r v i c e s / P s y c h o s o c i a l R e s e a r c h 296DIABETES CARE, VOLUME 23, NUMBER 3, MARCH 2000Insulin release and insulin sensitivity 0.5 kg/m 2 (19.7-45.8), and waist-to-hip ratio (WHR) 0.84 ± 0.10 (0.67-1.03); 65 had normal glucose tolerance (NGT), and the remainder had impaired glucose tolerance (IGT) according to the World Health O rganization criteria (1). Within 2 months, all subjects underwent a 75-g OGTT, a h y p e rglycemic clamp study in which the a rterialized venous plasma glucose concentration was increas...

To explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin signaling in conscious fasted rats infused for 2-6 h with saline, insulin (18 mU x kg(-1) x min(-1)), or insulin and glucosamine (30 micromol x kg(-1) x min(-1)) under euglycemic conditions. Glucosamine infusion increased muscle UDP-N-acetylglucosamine concentrations 3.9- and 4.3-fold over saline- or insulin-infused animals, respectively (P < 0.001). Glucosamine induced significant insulin resistance to glucose uptake both at the level of the whole body and in rectus abdominis muscle, and it blunted the insulin-induced increase in muscle glycogen content. At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). These alterations in postreceptor insulin signaling were time-dependent and paralleled closely the progressive inhibition of systemic glucose disposal from 2 to 6 h of glucosamine infusion. We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. These data indicate that activation of the hexosamine pathway may directly modulate early postreceptor insulin signal transduction, perhaps via posttranslation modification of IRS proteins, and thus contribute to the insulin resistance induced by chronic hyperglycemia.

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In population surveys, blood pressure and plasma insulin concentration are related variables, but the association is confounded by age and obesity. Whether insulin resistance is independently associated with higher blood pressure in normal subjects is debated. We analyzed the database of the European Group for the Study of Insulin Resistance, made up of nondiabetic men and women from 20 centers, in whom insulin sensitivity was measured by the euglycemic insulin clamp. After excluding subjects aged > or =70 years, those with severe obesity (body mass index [BMI] >40 kg x m[-2]), and those with abnormal blood pressure values (> or =140/90 mm Hg), 333 cases (ages 18 to 70 years; BMI, 18.4 to 39.8 kg x m[-2]) were available for analysis. In univariate analysis, both systolic and diastolic blood pressures were inversely related to insulin sensitivity, with r values of 0.18 (P<.005) and 0.34 (P<.0001), respectively. In a multivariate model simultaneously accounting for sex, age, BMI, and fasting insulin, systolic and diastolic blood pressures were still inversely related to insulin sensitivity (partial r, 0.15 and 0.19; P<.01 for both). In this model, age was positively related to blood pressure levels independently of insulin sensitivity, whereas BMI was not. The predicted impact on blood pressure of a decrease in insulin sensitivity of 10 micromol x min(-1) x kg(-1) was +1.4 mm Hg, similar to that associated with a 10-year difference in age. Although insulin levels and insulin action were reciprocally interrelated, diastolic blood pressure varied as a simultaneous function of both. In normotensive, nondiabetic Europeans, insulin sensitivity and age are significant, mutually independent correlates of blood pressure, whereas body mass is not. The relation of blood pressure to both insulin action and circulating insulin levels is compatible with distinct influences on blood pressure by insulin resistance and compensatory hyperinsulinemia.