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. 2000 Feb;105(3):287-92.
doi: 10.1172/JCI8538.

Improved Insulin-Sensitivity in Mice Heterozygous for PPAR-gamma Deficiency

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Free PMC article

Improved Insulin-Sensitivity in Mice Heterozygous for PPAR-gamma Deficiency

P D Miles et al. J Clin Invest. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Expression levels of PPAR-γ and Ob in white fat of WT and PPAR-γ+/– mice. RNA prepared from the epididymal fat pads of 5-month-old WT mice and PPAR-γ+/– littermates was subjected to Northern blot analysis with probes for PPAR-γ, Ob (leptin), and GAPDH.
Figure 2
Figure 2
Long-term glucose and insulin concentrations. Fasting glucose (a) and insulin (b) concentrations of PPAR-γ+/– and WT mice taken at 1-month intervals, from 2 months to 5 months of age.
Figure 3
Figure 3
OGTT. Glucose (a) and insulin (b) concentrations of PPAR-γ+/– mice and WT mice that underwent an OGTT (1.5 g/kg) at 8 months of age. *Significantly different from WT mice when values from timepoints of 0, 15, and 30 minutes were combined (P < 0.05).
Figure 4
Figure 4
Glucose turnover during glucose clamp experiments. Tracer-determined glucose disposal rate (a) and hepatic glucose production (b) during the steady-state portion of the hyperinsulinemic, euglycemic glucose clamp experiment for 8-month-old PPAR-γ+/– mice and WT mice. *Significantly different from WT mice (P < 0.05).

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