OBJECTIVE: To characterize in detail the association between insulin sensitivity and islet function in relation to glucose tolerance in nondiabetic subjects. RESEARCH DESIGN AND METHODS: The study included 108 postmenopausal women, aged 57-59 years, with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) and measured glucose tolerance (World Health Organization, 75 g glucose), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and islet function (the 2-5 min insulin responses [AIR] and glucagon [AGR] responses to 5 g intravenous arginine at fasting, 14 and >25 mmol/l glucose levels). The product of insulin sensitivity and secretion was calculated (disposition index [DI]) and used to study the relationship between the two parameters. RESULTS: Insulin sensitivity and insulin secretion were highly inversely correlated in a hyperbolic manner (r > 0.64, P < 0.001) in women with NGT (n = 71). Women with IGT (n = 37) had reduced insulin sensitivity compared with women with NGT (P = 0.011). The AIRs were not appropriately increased in relation to the reduced insulin sensitivity in the IGT women, demonstrated as reduced DI in IGT compared with NGT (P < 0.001). Further, women with IGT had an increased AGR (P < 0.001) and a reduced glucose inhibition of glucagon secretion (slopeAGR, P = 0.014) compared with women with NGT. In a multivariate regression model including all of the 108 women, 2-h glucose was independently determined by the DI, the AGR, and the slopeAGR (r = 0.63, P < 0.001). CONCLUSIONS: We have shown that both the individual ability to adapt insulin secretion to the ambient insulin sensitivity and the level of glucagon secretion are important parameters for maintenance of NGT. Therefore, islet dysfunction in IGT involves low insulin and high glucagon secretion, which present potential targets for correcting impaired glycemia.

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