en
Scientific article
English

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

Published inDiabetes, vol. 65, no. 4, p. 1009-1021
Publication date2016
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
  • Animals
  • Calcium/metabolism
  • Calcium Signaling/drug effects
  • Calcium-Binding Proteins/genetics/physiology
  • Cells
  • Cultured
  • Diet
  • High-Fat/adverse effects
  • Dietary Fats/toxicity
  • Endoplasmic Reticulum/drug effects/metabolism
  • Endoplasmic Reticulum Stress/drug effects
  • Insulin-Secreting Cells/drug effects/metabolism/pathology
  • Mice
  • Mice
  • Knockout
  • Mice
  • Obese
  • Obesity/metabolism/pathology
Citation (ISO format)
MARMUGI, Alice et al. Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores. In: Diabetes, 2016, vol. 65, n° 4, p. 1009–1021. doi: 10.2337/db15-1334
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Article (Published version)
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Identifiers
ISSN of the journal0012-1797
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