Genetic Manipulations of Fatty Acid Metabolism in β-Cells Are Associated With Dysregulated Insulin Secretion
Genetic Manipulations of Fatty Acid Metabolism in β-Cells Are Associated With Dysregulated Insulin Secretion Kazuhiro Eto 1 , Tokuyuki Yamashita 1 , Junji Matsui 1 , Yasuo Terauchi 1 , Mitsuhiko Noda 2 and Takashi Kadowaki 1 1 Department of Metabolic Diseases, Graduate School of Medicine, University...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2002-12, Vol.51 (suppl 3), p.S414-S420 |
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Zusammenfassung: | Genetic Manipulations of Fatty Acid Metabolism in β-Cells Are Associated With Dysregulated Insulin Secretion
Kazuhiro Eto 1 ,
Tokuyuki Yamashita 1 ,
Junji Matsui 1 ,
Yasuo Terauchi 1 ,
Mitsuhiko Noda 2 and
Takashi Kadowaki 1
1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
Abstract
Triacylglyceride (TG) accumulation in pancreatic β-cells is associated with impaired insulin secretion, which is called lipotoxicity.
To gain a better understanding of the pathophysiology of lipotoxicity, we generated three models of dysregulated fatty acid
metabolism in β-cells. The overexpression of sterol regulatory element binding protein-1c induced lipogenic genes and TG accumulation.
Under these conditions, we observed a decrease in glucose oxidation and upregulation of uncoupling protein-2, which might
be causally related to the decreased glucose-stimulated insulin secretion. The overexpression of AMP-activated protein kinase
was accompanied by decreased lipogenesis, increased fatty acid oxidation, and decreased glucose oxidation; insulin secretions
to glucose and depolarization stimuli were decreased, probably because of the decrease in glucose oxidation and cellular insulin
content. It was notable that the secretory response to palmitate was blunted, which would suggest a role of the fatty acid
synthesis pathway, but not its oxidative pathway in palmitate-stimulated insulin secretion. Finally, we studied islets of
PPAR -γ +/− mice that had increased insulin sensitivity and low TG content in white adipose tissue, skeletal muscle, and liver. On a
high-fat diet, glucose-stimulated insulin secretion was decreased in association with increased TG content in the islets,
which might be mediated through the elevated serum free fatty acid levels and their passive transport into β-cells. These
results revealed some aspects about the mechanisms by which alterations of fatty acid metabolism affect β-cell functions.
Footnotes
Address correspondence and reprint requests to Takashi Kadowaki, Department of Metabolic Diseases, 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 .
Received for publication 23 March 2002 and accepted in revised form 3 April 2002.
ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside; AMPK, AMP-activated protei |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.51.2007.S414 |