Insulin Secretion and Action in Subjects With Impaired Fasting Glucose and Impaired Glucose Tolerance Results From the Veterans Administration Genetic Epidemiology Study

This study was conducted to observe changes in insulin secretion and insulin action in subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A total of 319 subjects were studied with an oral glucose tolerance test (OGTT). Fasting plasma glucose and insulin concentrations were measured at baseline and every 30 min during the OGTT. Fifty-eight subjects also received a euglycemic-hyperinsulinemic clamp. Insulin sensitivity was calculated as the total glucose disposal (TGD) during the last 30 min of the clamp. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin concentrations. Subjects with IFG had TGD similar to normal glucose-tolerant subjects, while subjects with IGT and combined IFG/IGT had significantly reduced TGD. HOMA-IR in subjects with IFG was similar to that in subjects with combined IFG/IGT and significantly higher than HOMA-IR in subjects with IGT or NGT. Insulin secretion, measured by the insulinogenic index ( I0–30/ G0–30) and by the ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose (0–120 min), was reduced to the same extent in all three glucoseintolerant groups. When both measurements of -cell function were adjusted for severity of insulin resistance, subjects with IGT and combined IFG/IGT had a significantly greater reduction in insulin secretion than subjects with IFG. Subjects with IGT and IFG have different metabolic characteristics. Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease. Diabetes 55:1430–1435, 2006 Impaired glucose intolerance (IGT) is an intermediate state in the transition from normal glucose tolerance (NGT) to type 2 diabetes (1). Subjects with IGT, although still normoglycemic, manifest the dual defects that are characteristic of type 2 diabetes: reduced insulin sensitivity and impaired -cell function (2). As a result, they are at high risk for progression to type 2 diabetes, with an annual conversion rate of 5–10%, depending upon the ethnic group that is studied (3–7). In 1997, the American Diabetes Association introduced another intermediate state, impaired fasting glucose (IFG) (8), in the transition of glucose homeostasis from NGT to type 2 diabetes. IFG was meant to be analogous to IGT, since subjects with IFG also are at high risk for progression to type 2 diabetes. In epidemiological studies (3–7), subjects with isolated IGT and isolated IFG had similar risk for progression to type 2 diabetes. However, only 45% of subjects with IFG had IGT; conversely, 25% of subjects with IGT had IFG (4,5,9–13). The partial overlap between IFG and IGT suggests that different pathophysiological mechanisms contribute to the disturbances in glucose homeostasis. In some studies, insulin resistance was reported to be the primary abnormality in subjects with IFG, while IGT was more associated with impaired -cell function (14–21). However, other investigators have reported completely opposite results (22–26). In part, the divergent results may be explained by the failure to utilize more sophisticated techniques to quantitate insulin sensitivity and insulin secretion. In this study, we used the oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp to examine the presence of impaired insulin secretion and insulin resistance in isolated IFG, isolated IGT, and combined IFG/IGT.