Imperial College London
Alternate

DrTimothyPullen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Lecturer
 
 
 
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Contact

 

t.pullen Website

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Rutter:2016:10.2337/db15-1240,
author = {Rutter, GA},
doi = {10.2337/db15-1240},
journal = {Diabetes},
pages = {1268--1282},
title = {Disallowance of Acot7 in b-Cells is required for normal glucosetolerance and insulin secretion},
url = {http://dx.doi.org/10.2337/db15-1240},
volume = {65},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Acot7, encoding acyl-CoA thioesterase-7, is one of ∼60 genes expressed ubiquitously across tissues but relatively silenced, or “disallowed”, in pancreatic β-cells. The capacity of ACOT7 to hydrolyse long-chain acyl-CoA esters suggests potential roles in β-oxidation, lipid biosynthesis, signal transduction or insulin exocytosis. Here, we explored the physiological relevance of β-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) β-cells impaired insulin secretion in response to glucose plus fatty acids. Furthermore, examined in a panel of transgenic mouse lines, we demonstrate that overexpression of mitochondrial ACOT7 selectively in the adult β-cell reduced glucose tolerance dose-dependently and impaired glucose-stimulated insulin secretion. By contrast, depolarisation-induced secretion was unaffected, arguing against a direct action on the exocytotic machinery. Acyl-CoA levels, ATP/ADP increases, membrane depolarization and Ca2+ fluxes were all markedly reduced in transgenic mouse islets, whereas glucose-induced O2-consumption was unchanged. Whilst glucose-induced increases in ATP/ADP ratio were similarly lowered after ACOT7 over-expression in INS1(832/13) cells, changes in mitochondrial membrane potential (ΔΨ) were unaffected, consistent with an action of Acot7 to increase cellular ATP consumption. Since Acot7 mRNA levels are increased in human islets in type 2 diabetes, inhibition of the enzyme might provide a novel therapeutic strategy.
AU  - Rutter,GA
DO  - 10.2337/db15-1240
EP  - 1282
PY  - 2016///
SN  - 0012-1797
SP  - 1268
TI  - Disallowance of Acot7 in b-Cells is required for normal glucosetolerance and insulin secretion
T2  - Diabetes
UR  - http://dx.doi.org/10.2337/db15-1240
UR  - https://diabetes.diabetesjournals.org/content/65/5/1268
VL  - 65
ER  -
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