Improved insulin-sensitivity in mice heterozygous for PPAR-[gamma] deficiency.
Miles, Philip D.G. 1; Barak, Yaacov 2; He, Weiman 3; Evans, Ronald M. 2; Olefsky, Jerrold M. 3,4,5
[Miscellaneous Article] Journal of Clinical Investigation. 105(3):287-292, February 2000.

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The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator-activated receptor [gamma] (PPAR-[gamma]). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-[gamma] gene knockout mouse model. Because homozygous PPAR-[gamma]-null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-[gamma] /- mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-[gamma] /- 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-[gamma] /- group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-[gamma] /- mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-[gamma] /- mice than in the WT mice. Taken together, these results indicate that - counterintuitively - although pharmacological activation of PPAR-[gamma] improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.

Copyright (C) 2000 The American Society for Clinical Investigation, Inc.