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
- Junji Matsui1,
- Yasuo Terauchi2,
- Naoto Kubota12,
- Iseki Takamoto12,
- Kazuhiro Eto12,
- Tokuyuki Yamashita1,
- Kajuro Komeda3,
- Toshimasa Yamauchi12,
- Junji Kamon1,
- Shunbun Kita1,
- Mitsuhiko Noda24 and
- Takashi Kadowaki12
- 1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 2Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, Japan
- 3Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, Japan
- 4Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
- Address correspondence and reprint requests to Takashi Kadowaki, MD, PhD, Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp
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.
- FFA, free fatty acid
- KRBB, Krebs-Ringer bicarbonate buffer
- PPAR, peroxisome proliferator–activated receptor
- TG, triglyceride
- WAT, white adipose tissue
Footnotes
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M.N. is currently affiliated with the Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
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- Accepted March 20, 2003.
- Received February 5, 2003.
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