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

Alice Marmugi, Julia Parnis, Xi Chen, LeAnne Carmichael, Julie Hardy, Naila Mannan, Piero Marchetti, Lorenzo Piemonti, Domenico Bosco, Paul Johnson, James A M Shapiro, Céline Cruciani-Guglielmacci, Christophe Magnan, Mark Ibberson, Bernard Thorens, Héctor H Valdivia, Guy A Rutter, Isabelle Leclerc

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1009-1021
Number of pages13
JournalDiabetes
Volume65
Issue number4
DOIs
Publication statusPublished - Apr 2016

Keywords

  • Animals
  • Calcium
  • Calcium Signaling
  • Calcium-Binding Proteins
  • Cells, Cultured
  • Diet, High-Fat
  • Dietary Fats
  • Endoplasmic Reticulum
  • Endoplasmic Reticulum Stress
  • Insulin-Secreting Cells
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Obesity
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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