PANCREATIC BETA-CELL DYSFUNCTION AS THE PRIMARY GENETIC LESION IN NIDDM - EVIDENCE FROM STUDIES IN NORMAL GLUCOSE-TOLERANT INDIVIDUALS WITH A FIRST-DEGREE NIDDM RELATIVE

Objective.- To test the hypothesis that insulin resistance precedes impaired insulin secretion in individuals genetically predisposed to non-insulin-dependent diabetes mellitus (NIDDM). Design.- Case-control study. Setting.- Outpatient facility of clinical research center. Participants.- One hundred volunteers of European ancestry having normal glucose tolerance, 50 with and 50 without a first-degree NIDDM relative, matched for age, sex, and degree of obesity. Main Outcome Measures.- Insulin secretion and insulin sensitivity assessed by hyperglycemic (N=100) and euglycemic-hyperinsulinemic (N=62) clamp experiments. Results.- The individuals with a first-degree NIDDM relative had reduced first-and second-phase insulin responses (mean+/-SEM, 939+/-68 vs 1209+/-82 pmol/L, and 322+/-19 vs 407+/-24 pmol/L, respectively, P=.001 and .01), but their insulin sensitivity (148+/-6 and 92+/-6 nmol . kg(-1). min(-1)/pmol . L(-1) in hyperglycemic and euglycemic clamp studies) did not differ from that of the control group (126+/-5 and 81+/-7 nmol . kg(-1). min(-1)/pmol . L(-1), in hyperglycemic and euglycemic clamp studies, P=.07 and .24, respectively). In some individuals only first- or only second-phase insulin responses were reduced. Conclusion.- In this study population, heterogeneous defects in insulin secretion were demonstrated, while defects in insulin sensitivity were not evident. We therefore conclude that since the earliest defects identified in a group genetically at high risk to develop NIDDM are those related to insulin secretion, defects in insulin secretion rather than insulin sensitivity are likely the major genetic factor predisposing to development of NIDDM.