The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator–activated receptor γ (PPAR-γ). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-γ gene knockout mouse model. Because homozygous PPAR-γ–null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-γ+/– mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-γ+/– groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance test, but insulin concentrations of the WT group were greater than those of the PPAR-γ+/– group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-γ+/– mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-γ+/– mice than in the WT mice. Taken together, these results indicate that — counterintuitively — although pharmacological activation of PPAR-γ improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.
Philip D.G. Miles, Yaacov Barak, Weiman He, Ronald M. Evans, Jerrold M. Olefsky
The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.