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

Lookup NU author(s): Professor Mark Walker

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Abstract

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

Publication metadata

Author(s): Mari A, Tura A, Natali A, Anderwald C, Balkau B, Lalic N, Walker M, Ferrannini E, RISC Investigators

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2011

Volume: 60

Issue: 12

Pages: 3141-3147

Print publication date: 25/10/2011

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/db11-0827

DOI: 10.2337/db11-0827

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