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Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

Marmugi, Alice
Parnis, Julia
Chen, Xi
Carmichael, LeAnne
Hardy, Julie
Mannan, Naila
Marchetti, Piero
Piemonti, Lorenzo
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Published in Diabetes. 2016, vol. 65, no. 4, p. 1009-21
Abstract Preserving β-cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes. 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 downregulation and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. Sorcin 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 genome-wide association study 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 sorcin 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 sorcin 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. Sorcin may thus provide a target for intervention in type 2 diabetes.
Keywords AnimalsCalcium/metabolismCalcium Signaling/drug effectsCalcium-Binding Proteins/genetics/physiologyCellsCulturedDietHigh-Fat/adverse effectsDietary Fats/toxicityEndoplasmic Reticulum/drug effects/metabolismEndoplasmic Reticulum Stress/drug effectsInsulin-Secreting Cells/drug effects/metabolism/pathologyMiceMiceKnockoutMiceObeseObesity/metabolism/pathology
PMID: 26822088
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MARMUGI, Alice et al. Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores. In: Diabetes, 2016, vol. 65, n° 4, p. 1009-21. doi: 10.2337/db15-1334 https://archive-ouverte.unige.ch/unige:100303

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Deposited on : 2017-12-14

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