Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response

Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. Howe ver, in normal individuals, central adiposity can be tolerated for many yea rs without development of impaired glucose tolerance or diabetes. Here we e xamine longitudinally the mechanisms by which glucose tolerance can be main tained in the face of substantial insulin resistance. Normal dogs mere fed a diet enriched with moderate amounts of fat (2 g . kg(-1) . day(-1)), simi lar to that seen in modern "cafeteria" diets, and the time course of metabo lic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (S-I) as determined by frequ ently sampled intravenous glucose tolerance tests was measured over a 12-we ek period. S-I, decreased 35% by week 1 and remained impaired for the entir e 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 wee k, recovered to baseline, and then again began to decline after 8 weeks. Fi rst-phase insulin response began to increase after week 2, peaked by meek 6 (190% of basal), and then declined. The increase in insulin response was d ue partially to enhanced beta -cell function (22%) but due also to an simil ar to 50% reduction in insulin clearance. This compensation by insulin clea rance was also confirmed with insulin clamps performed in fat-fed versus co ntrol dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin respo nse, such that the product of insulin sensitivity x secretion is little cha nged. However, the compensation is due as much to reduced insulin clearance as increased beta -cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the beta -cells during com pensation for the insulin-resistant state.