The disposition index does not reflect ?-cell function in IGT subjects treated with pioglitazone

Aims and Hypothesis: The insulin secretion/insulin resistance (IR) (disposition) index (?I/?G ÷ IR, where ? is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of (3-cell function. This relationship is curvilinear and becomes linear when log transformed. ?I is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if ? plasma C-peptide(ACP) (instead of ? plasma insulin) was plotted against insulin sensitivity.,Methods: A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years.,Results: Pioglitazone reduced IGT conversion to diabetes by 72% (P<.0001). ?I/?G vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ?CP/?G or ?ISR/?G was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism where in the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia.,Conclusions: These results demonstrate the validity of the disposition index when relating the plasma insulin responseto insulin sensitivity but underscore the pitfall of this index when drawing conclusions about ?-cell function, because insulin secretion declined despite an increase in the plasma insulin response.