Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding

Reduced beta-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. The ability to increase beta-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces beta-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance (K-g), insulin sensitivity (S-I), and the acute insulin response to glucose (AIR,) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, S-I decreased by 57% (P = 0.003) but AIR(g) was unchanged. This absence of beta-cell compensation to insulin resistance contributed to a 41% reduction of K-g (P = 0.003) and abolished the normal hyperbolic relationship between AIR(g) and S-I observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level (P = 0.004) in association with an 8% reduction of glucose (P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat. feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.