Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time

We examined the relationship between insulin clearance, insulin sensitivity, and beta-cell function and the longitudinal effect of insulin clearance on beta-cell function in lean and obese insulin-sensitive and insulin-resistant adolescents. A hyperinsulinemic-euglycemic and a hyperglycemic clamp were performed in 110 youths to quantify hepatic and peripheral clearance, insulin sensitivity, and beta-cell function (disposition index, DIh-clamp). Participants underwent an oral glucose tolerance test at baseline and after 2 years to assess glucose tolerance and oral beta-cell function (oDI(cpep)) and were sorted into four groups (lean and obese normal glucose tolerance, insulin sensitive, insulin resistant, and impaired glucose tolerance). Insulin sensitivity was defined based on the median of insulin stimulated glucose disposal (M) measured during the hyperinsulinemic-euglycemic clamp. Lean and obese insulin-sensitive participants did not differ with respect to hepatic and peripheral clearance or for insulin sensitivity. Insulin sensitivity was linearly correlated with whole-body insulin clearance. Hepatic insulin extraction at baseline acted as an independent determinant of beta-cell function at follow-up. The decline in insulin sensitivity, even in the absence of an impairment of glucose tolerance, is associated with lowering of hepatic insulin clearance in obese youth, which in turn may contribute to the decline in beta-cell function over time.