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- Title
Differential Effect of Glucose on ER-Mitochondria Ca<sup>2+</sup> Exchange Participates in Insulin Secretion and Glucotoxicity-Mediated Dysfunction of β-Cells.
- Authors
Dingreville, Florian; Panthu, Baptiste; Thivolet, Charles; Ducreux, Sylvie; Gouriou, Yves; Pesenti, Sandra; Chauvin, Marie-Agnès; Chikh, Karim; Errazuriz-Cerda, Elisabeth; Van Coppenolle, Fabien; Rieusset, Jennifer; Madec, Anne-Marie; Chick, Karim
- Abstract
Glucotoxicity-induced β-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in β-cells is still largely unknown, and their implication in glucotoxicity-associated β-cell dysfunction remains to be defined. Here, we report that acute glucose treatment stimulated ER-mitochondria interactions and calcium (Ca2+) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS and concomitantly reduced ER Ca2+ store, increased basal mitochondrial Ca2+, and reduced ATP-stimulated ER-mitochondria Ca2+ exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca2+ signaling are associated with ER stress, altered mitochondrial respiration, and mitochondria fragmentation, and these organelle stresses may participate in increased organelle tethering as a protective mechanism. Last, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca2+ exchange, induced mitochondrial fission, and altered GSIS. Therefore, dynamic organelle coupling participates in GSIS in β-cells, and over time, disruption of organelle Ca2+ exchange might be a novel mechanism contributing to glucotoxicity-induced β-cell dysfunction.
- Subjects
CATABOLITE repression; SECRETION; INSULIN; ISLANDS of Langerhans; TYPE 2 diabetes
- Publication
Diabetes, 2019, Vol 68, Issue 9, p1778
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db18-1112