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Diabetes. 2014 Nov;63(11):3805-14. doi: 10.2337/db13-1677. Epub 2014 Jun 26.

Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.

Author information

  • 1Department of Biochemistry, University of Wisconsin, Madison, WI.
  • 2Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ.
  • 3Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC.
  • 4Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA.
  • 5Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY.
  • 6Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC Departments of Medicine and Pharmacology and Cancer Biology, Duke University, Durham, NC.
  • 7Department of Biochemistry, University of Wisconsin, Madison, WI adattie@wisc.edu.

Abstract

We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including nonfuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT; Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. Small interfering RNA-mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from rat insulinoma β-cells (INS-1) as well as primary mouse islets. The effect on INS-1 cells was augmented in response to suppression of CACT. A nonhydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine-mediated regulation of IS.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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