We previously demonstrated that micro-RNAs 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 micro-RNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including non-fuel 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. SiRNA 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 INS-1 β-cells as well as primary mouse islets. The effect in INS-1 cells was augmented in response to suppression of CACT. A non-hydrolyzable 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.
- Received October 31, 2013.
- Accepted June 19, 2014.
- © 2014 by the American Diabetes Association.
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