title: Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores.
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.
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Alice
authors.initials: A
authors.lastname: Marmugi
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Julia
authors.initials: J
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authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: LeAnne
authors.initials: L
authors.lastname: Carmichael
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Julie
authors.initials: J
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authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Naila
authors.initials: N
authors.lastname: Mannan
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.affiliation: Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: James A M
authors.initials: JA
authors.lastname: Shapiro
authors.affiliation: Unit of Functional and Adaptive Biology, Paris Diderot University-Paris 7, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cruciani-Guglielmacci
authors.affiliation: Unit of Functional and Adaptive Biology, Paris Diderot University-Paris 7, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI.
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K. i.leclerc@imperial.ac.uk g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, U.K. i.leclerc@imperial.ac.uk g.rutter@imperial.ac.uk.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclerc
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; D004041:Dietary Fats; C503114:Sri protein, mouse; D002118:Calcium
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