Effects of pioglitazone and metformin on β-cell function in nondiabetic subjects at high risk for type 2 diabetes

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved β-cell function is not clear. In vitro studies showed improved β-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on β-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect β-cell function. We evaluated β-cell function and insulin sensitivity (S_I) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S_I, glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S_G)]. Neither pioglitazone nor metformin significantly improved β-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S_I. Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR_max) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S _I, the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S_I and S _G. We did not find any evidence that either pioglitazone or metformin improved β-cell function. Improved β-cell compensation was observed primarily in the subgroup of subjects that had the lowest S_I at baseline.