Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.

OBJECTIVE -To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS-A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18 -70 years, BMI 20 -65 kg/m 2 ) with normal glucose tolerance (n ϭ 100) or impaired glucose tolerance (n ϭ 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTTderived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis.RESULTS -The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose 0 -30 [AUC] ϫ insulin 0 -30 [AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin ϫ basal endogenous glucose production) (r ϭ 0.64, P Ͻ 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt Ϭ I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P ϭ 0.78, P Ͻ 0.0001).CONCLUSIONS -Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects. Diabetes Care 30:89 -94, 2007S keletal muscle and hepatic insulin resistance are characteristic features in type 2 diabetes (1). Insulin resistance is also commonly observed in nondiabetic subjects who are overweight and is associated with a cluster of metabolic and cardiovascular risk factors (dyslipidemia, hypertension, visceral obesity, and elevated inflammatory markers) known as the insulin resistance syndrome or dysmetabolic syndrome (2). Individuals with the insulin resistance syndrome have an approximate threefold increased risk for coronary heart disease and type 2 diabetes (3). Their risk for cardiovascular and allcause mortality is also increased compared with insulin-sensitive individuals (3). It is estimated that in the year 2000, more than one-third of the adult population (Ͼ20 years of age) in the U.S. had the insulin resistance syndrome and therefore are at high risk for the development of type 2 diabetes and cardiovascular disease (4).Improved insulin sensitivity with lifestyle intervention, e.g., weight reduction and increased physical activity, lowers the risk of future type 2 diabetes in insulinresistant individuals by more than onehalf (5,6), reduces the prevalence of cardiovascular risk factors (7), and decreases cardiovascular morbidity and mortality (8). Pharmacological intervention with agents that improve insulin sensitivity, including thiazolidinediones and metformin, also reduces the risk of conversion from impaired glucose tolerance (IGT) to type 2 diabetes (5,9) and decreases the risk of cardiovascular disease in individuals with established type 2 ...

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI]

OBJECTIVE -To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -A total of 23 diabetic patients (age 30 -70 years, BMI Ͻ 36 kg/m2 ) who were being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n ϭ 11) or pioglitazone (45 mg/day) (n ϭ 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT); and hepatic and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU ⅐ min Ϫ1 ⅐ m -2 ) clamp performed with 3-[ 3 H]glucose and indirect calorimetry. HbA 1c was measured monthly throughout the study period.RESULTS -After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 Ϯ 15 to 135 Ϯ 11 mg/dl, P Ͻ 0.01), mean plasma glucose during OGTT (293 Ϯ 12 to 225 Ϯ 14 mg/dl, P Ͻ 0.01), and HbA 1c (8.9 Ϯ 0.3 to 7.2 Ϯ 0.5%, P Ͻ 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 Ϯ 39 to 478 Ϯ 49 Eq/l, P Ͻ 0.01) and mean plasma FFA during OGTT (485 Ϯ 30 to 347 Ϯ 33 Eq/l, P Ͻ 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r ϭ 0.67, P Ͻ 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P Ͻ 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P Ͻ 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGTT was strongly related to the change in total body glucose disposal during the second insulin clamp step.CONCLUSIONS -These results suggest that pioglitazone therapy in type 2 diabetic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin. Diabetes Care 24:710 -719, 2001T ype 2 diabetes is characterized by defects in both insulin secretion and insulin sensitivity (1,2). The insulin resistance is established early in the natural history of type 2 diabetes (1-3), but with time there is a progressive failure of ␤-cell function (1,4,5). Based on the pathophysiology of type 2 diabetes, combination therapy with an insulin secretagogue and an insulin sensitizer provides a rational therapeutic approach to reduce blood glucose levels in poorly controlled type 2 diabetic patients (6). Such an approach has been used successfully with sulfonylureas and metformin (7).Recently, a new class of insulinsensitizing agents, the thiazolidinediones, was introduced for the treatment of type 2 diabetic patients (8). Troglitazone, the first thiazolidinedione introduced into the U.S. market, has been...

Aims/hypothesis. Both insulin resistance and beta-cell dysfunction play a role in the transition from normal glucose tolerance (NGT) to Type 2 diabetes (T2DM) through impaired glucose tolerance (IGT). The aim of the study was to define the level of glycaemia at which beta-cell dysfunction becomes evident in the context of existing insulin resistance. Methods. Insulin response (OGTT) and insulin sensitivity (euglycaemic insulin clamp) were evaluated in 388 subjects in the San Antonio Metabolism (SAM) study (138 NGT, 49 IGT and 201 T2DM). In all subjects the insulin secretion/insulin resistance index (DeltaI/DeltaGdivided byIR) was calculated as the ratio of the increment in plasma insulin to the increment in plasma glucose during the OGTT divided by insulin resistance, as measured during the clamp. Results. In lean NGTs with a 2-h plasma glucose concentration (2-h PG) between 5.6 and 6.6 and between 6.7 and 7.7 mmol/l, there was a progressive decline in DeltaI/AGdivided byIR compared with NGTs with a 2-h PG less than 5.6 mmol/l. There was a further decline in DeltaI/DeltaGdivided byIR in IGTs with a 2-h PG between 7.8 and 9.3 and between 9.4 and 11.0 mmol/l, and in Type 2 diabetic patients with a 2-h PG greater than It. I mmol/l. Lean and obese subjects showed coincident patterns of relation of 2-h PG to DeltaI/DeltaGdivided byIR. Conclusion/interpreation. When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in "normal" glucose tolerant individuals