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

Author:

Matsui Junji1,Terauchi Yasuo2,Kubota Naoto12,Takamoto Iseki12,Eto Kazuhiro12,Yamashita Tokuyuki1,Komeda Kajuro3,Yamauchi Toshimasa12,Kamon Junji1,Kita Shunbun1,Noda Mitsuhiko24,Kadowaki Takashi12

Affiliation:

1. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, Japan

3. Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, Japan

4. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan

Abstract

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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