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

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 (Ca2+) 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 Ca2+-induced Ca2+ by inhibiting ryanodine receptor activity and playing a role in terminating Ca2+ 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. Sorcinnull 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 Ca1 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 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Marmugi, A., Parnis, J., Chen, X., Carmichael, L., Hardy, J., Mannan, N., Marchetti, P., Piemonti, L., Bosco, D., Johnson, P., Shapiro, J. A. M., Cruciani-Guglielmacci, C., Magnan, C., Ibberson, M., Thorens, B., Valdivia, H. H., Rutter, G. A., & Leclerc, I. (2016). Sorcin links pancreatic β-cell lipotoxicity to ER Ca2+ stores. Diabetes, 65(4), 1009-1021. https://doi.org/10.2337/db15-1334