| First Author | Martinez-Sanchez A | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 5 | Pages | 1268-82 |
| PubMed ID | 26861785 | Mgi Jnum | J:246783 |
| Mgi Id | MGI:5922380 | Doi | 10.2337/db15-1240 |
| Citation | Martinez-Sanchez A, et al. (2016) Disallowance of Acot7 in beta-Cells Is Required for Normal Glucose Tolerance and Insulin Secretion. Diabetes 65(5):1268-82 |
| abstractText | Encoding acyl-CoA thioesterase-7 (Acot7) is one of approximately 60 genes expressed ubiquitously across tissues but relatively silenced, or disallowed, in pancreatic beta-cells. The capacity of ACOT7 to hydrolyze long-chain acyl-CoA esters suggests potential roles in beta-oxidation, lipid biosynthesis, signal transduction, or insulin exocytosis. We explored the physiological relevance of beta-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) beta-cells impaired insulin secretion in response to glucose plus fatty acids. Furthermore, in a panel of transgenic mouse lines, we demonstrate that overexpression of mitochondrial ACOT7 selectively in the adult beta-cell reduces glucose tolerance dose dependently and impairs glucose-stimulated insulin secretion. By contrast, depolarization-induced secretion was unaffected, arguing against a direct action on the exocytotic machinery. Acyl-CoA levels, ATP/ADP increases, membrane depolarization, and Ca(2+) fluxes were all markedly reduced in transgenic mouse islets, whereas glucose-induced oxygen consumption was unchanged. Although glucose-induced increases in ATP/ADP ratio were similarly lowered after ACOT7 overexpression in INS1(832/13) cells, changes in mitochondrial membrane potential were unaffected, consistent with an action of Acot7 to increase cellular ATP consumption. Because Acot7 mRNA levels are increased in human islets in type 2 diabetes, inhibition of the enzyme might provide a novel therapeutic strategy. |
