Influence of Hyperinsulinemia and Insulin Resistance on In Vivo β-Cell Function Their Role in Human β-Cell Dysfunction

OBJECTIVE-Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the beta-cell could cause beta-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate beta-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR). RESEARCH DESIGN AND METHODS-Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at iso-glycemia (HSR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and beta-cell glucose sensitivity (beta-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study. RESULTS-In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to beta-GS (r = 0.16, P < 0.0001). Both IISR (-23 [39] vs. -9 [2]%, median [interquartile range], P < 0.03) and beta-GS (69 [47] vs. 118 [83] pmol . min(-1) . m(-2) . mmol(-1) . L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and beta-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by beta-GS (odds ratio 4.84 [95% CI 2.89-8.09]) and insulin sensitivity (3.06 [2.19-4.27]) but not by IISR (1.11 [0.77-1.611). CONCLUSIONS-Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on beta-cell dysfunction and dysglycemia. Diabetes 60:3141-3147, 2011