Different Pathophysiology of Impaired Glucose Tolerance in First Degree Relatives of Individuals with Type 2 Diabetes

摘要

To assess whether an increased genetic predisposition for type 2 diabetes (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an OGTT and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) that had normal glucose homeostasis and no first degree T2DM relative (NGH; N=133), IGT with a first degree T2DM relative (IGT/FH+; N=74) or IGT without a first degree T2DM relative (IGT/FH−; N=50). Compared to NGH, first and second phase plasma insulin responses were reduced ~45% and 30%, respectively (both P<0.001) in IGT/FH+, whereas insulin sensitivity was only ~20% reduced (P=0.011). In contrast, in IGT/FH−, first phase plasma insulin responses were only ~20% reduced (P=0.016), second phase plasma insulin responses were not reduced, but insulin sensitivity was ~40% reduced (P<0.001). IGT/FH+ differed significantly from IGT/FH− by having 25–30% lower first phase plasma insulin responses (P=0.026) and 25–30% greater insulin sensitivity (P=0.027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first phase plasma insulin responses were ~30% lower in IGT/FH+ with a BMI ≥27 kg/m² (P=0.018) but similar in IGT/FH+ with a BMI <27 kg/m² compared to the corresponding IGT/FH− subgroups. We conclude that in IGT an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.