The Disposition Index Does Not Reflect β-Cell Function in IGT Subjects Treated With Pioglitazone

Aims and Hypothesis: The insulin secretion/insulin resistance (IR) (disposition) index (Delta I/Delta G divided by IR, where Delta is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of beta-cell function. This relationship is curvilinear and becomes linear when log transformed. Delta 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 Delta plasma C-peptide (Delta CP) (instead of Delta 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). Delta I/Delta G vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when Delta CP/Delta G or Delta ISR/Delta 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 wherein 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 response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about beta-cell function, because insulin secretion declined despite an increase in the plasma insulin response.