Differential effect of glucose on ER-mitochondria Ca2+ exchange participates to insulin secretion and to glucotoxicity-mediated dysfunction of β cells.

Glucotoxicity-induced β cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and 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 stimulation stimulated ER-mitochondria interactions and calcium (Ca 2+ ) 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 Ca 2+ store, increased basal mitochondrial Ca 2+ and reduced ATP-stimulated ER-mitochondria Ca 2+ exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca 2+ signaling are associated with ER stress, altered mitochondrial respiration and mitochondria fragmentation, and these organelle stresses may participate to increased organelle tethering, as a protective mechanism. Lastly, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca 2+ exchange, induced mitochondrial fission and altered GSIS. Therefore, dynamic organelle coupling participates to GSIS in β cells and over-time disruption of organelle Ca 2+ exchange might be a novel mechanism contributing to glucotoxicity-induced β cell dysfunction.