TY - JOUR
T1 - Sorcin links pancreatic β-cell lipotoxicity to ER Ca2+ stores
AU - Marmugi, Alice
AU - Parnis, Julia
AU - Chen, Xi
AU - Carmichael, Leanne
AU - Hardy, Julie
AU - Mannan, Naila
AU - Marchetti, Piero
AU - Piemonti, Lorenzo
AU - Bosco, Domenico
AU - Johnson, Paul
AU - Shapiro, James A M
AU - Cruciani-Guglielmacci, Céline
AU - Magnan, Christophe
AU - Ibberson, Mark
AU - Thorens, Bernard
AU - Valdivia, Héctor H.
AU - Rutter, Guy A.
AU - Leclerc, Isabelle
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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U2 - 10.2337/db15-1334
DO - 10.2337/db15-1334
M3 - Article
AN - SCOPUS:84962189527
VL - 65
SP - 1009
EP - 1021
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -