Disallowance of Acot7 in ß-Cells Is Required for Normal Glucose Tolerance and Insulin Secretion.
Diabetes
; 65(5): 1268-82, 2016 05.
Article
em En
| MEDLINE
| ID: mdl-26861785
ABSTRACT
Encoding acyl-CoA thioesterase-7 (Acot7) is one of â¼60 genes expressed ubiquitously across tissues but relatively silenced, or disallowed, in pancreatic ß-cells. The capacity of ACOT7 to hydrolyze long-chain acyl-CoA esters suggests potential roles in ß-oxidation, lipid biosynthesis, signal transduction, or insulin exocytosis. We explored the physiological relevance of ß-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) ß-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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Palmitoil-CoA Hidrolase
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Regulação para Baixo
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Regulação Enzimológica da Expressão Gênica
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Células Secretoras de Insulina
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Ácidos Graxos não Esterificados
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Glucose
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Insulina
Limite:
Animals
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2016
Tipo de documento:
Article