Pioglitazone Reduces Islet Triglyceride Content and Restores Impaired Glucose-Stimulated Insulin Secretion in Heterozygous Peroxisome Proliferator–Activated Receptor-γ–Deficient Mice on a High-Fat Diet

Heterozygous peroxisome proliferator–activated receptor-γ (PPAR-γ)-deficient ( PPARγ +/−) mice were protected from high-fat diet–induced insulin resistance. To determine the impact of systemic reduction of PPAR-γ activity on β-cell function, we investigated insulin secretion in PPARγ +/− mice on a high-fat diet. Glucose-induced insulin secretion in PPARγ +/− mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARγ +/− mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-γ agonist, pioglitazone, reduced the islet TG content in PPARγ +/− mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-γ protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-γ agonist can restore impaired insulin secretion under conditions of islet fat accumulation.