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

Heterozygous peroxisome proliferator–activated receptor(PPAR)-deficient (PPAR / ) mice were protected from high-fat diet–induced insulin resistance. To determine the impact of systemic reduction of PPARactivity on -cell function, we investigated insulin secretion in PPAR / mice on a high-fat diet. Glucoseinduced insulin secretion in PPAR / mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPAR / 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 PPARagonist, pioglitazone, reduced the islet TG content in PPAR / mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPARprotects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPARagonist can restore impaired insulin secretion under conditions of islet fat accumulation. Diabetes 53:2844–2854, 2004