Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency

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


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Glucose / metabolism
  • Heterozygote
  • Homozygote
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Resistance / genetics
  • Mice
  • Mutation
  • Receptors, Cytoplasmic and Nuclear / deficiency*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • Insulin
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Glucose