In vivo Deletion of Beta Cell Drp1 Impairs Insulin Secretion without Affecting Islet Oxygen Consumption.

Mitochondria are dynamic organelles that undergo frequent fission and fusion events. Mitochondrial fission is required for ATP production, the tricarboxylic acid cycle, and processes beyond metabolism in a cell-type specific manner. Ex vivo and cell line studies have demonstrated that Drp1, a central regulator of mitochondrial fission, is required for glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells. Herein, we set out to interrogate the role of Drp1 in beta-cell insulin secretion in vivo. We generated beta-cell-specific Drp1 knockout (KO) mice (Drp1 beta-KO) by crossing a conditional allele of Drp1 to Ins1(cre) mice, in which Cre recombinase replaces the coding region of the Ins1 gene. Drp1 beta-KO mice were glucose intolerant due to impaired GSIS but did not progress to fasting hyperglycemia as adults. Despite markedly abnormal mitochondrial morphology, Drp1 beta-KO islets exhibited normal oxygen consumption rates and an unchanged glucose threshold for intracellular calcium mobilization. Instead, the most profound consequences of beta-cell Drp1 deletion were impaired second-phase insulin secretion and impaired glucose-stimulated amplification of insulin secretion. Our data establish Drp1 as an important regulator of insulin secretion in vivo and demonstrate a role for Drp1 in metabolic amplification and calcium handling without affecting oxygen consumption.