Sorcin links pancreatic β cell lipotoxicity to ER Ca2+ stores.

Details

Serval ID
serval:BIB_FD358A981FEB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Sorcin links pancreatic β cell lipotoxicity to ER Ca2+ stores.
Journal
Diabetes
Author(s)
Marmugi A., Parnis J., Chen X., Carmichael L., Hardy J., Mannan N., Marchetti P., Piemonti L., Bosco D., Johnson P., Shapiro A.M., Cruciani-Guglielmacci C., Magnan C., Ibberson M., Thorens B., Valdivia H.H., Rutter G.A., Leclerc I.
ISSN
1939-327X (Electronic)
ISSN-L
0012-1797
Publication state
Published
Issued date
2016
Volume
65
Number
4
Pages
1009-1021
Language
english
Abstract
Preserving β cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes (T2DM). Endoplasmic reticulum (ER) calcium (Ca(2+)) depletion induced by saturated free fatty acids and cytokines causes β cell ER stress and apoptosis, but the molecular mechanisms behind these phenomena are still poorly understood. Here, we demonstrate that palmitate-induced sorcin (SRI) down-regulation, and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. SRI is a calcium sensor protein involved in maintaining ER Ca(2+) by inhibiting ryanodine receptor activity and playing a role in terminating Ca(2+)-induced Ca(2+) release. G6PC2, a GWAS gene associated with fasting blood glucose, is a negative regulator of glucose-stimulated insulin secretion (GSIS). High fat feeding in mice and chronic exposure of human islets to palmitate decreases endogenous SRI expression while levels of G6PC2 mRNA increase. Sorcin null mice are glucose intolerant, with markedly impaired GSIS and increased expression of G6pc2. Under high fat diet, mice overexpressing SRI in the β cell display improved glucose tolerance, fasting blood glucose and GSIS, whereas G6PC2 levels are decreased and cytosolic and ER Ca(2+) are increased in transgenic islets. SRI may thus provide a target for intervention in T2DM.
Pubmed
Web of science
Open Access
Yes
Create date
17/02/2016 17:06
Last modification date
20/08/2019 17:28
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