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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 β cells. Herein, we set out to interrogate the role of Drp1 in β-cell insulin secretion in vivo. We generated β-cell–specific Drp1 knockout (KO) mice (Drp1β-KO) by crossing a conditional allele of Drp1 to Ins1cre mice, in which Cre recombinase replaces the coding region of the Ins1 gene. Drp1β-KO mice were glucose intolerant due to impaired GSIS but did not progress to fasting hyperglycemia as adults. Despite markedly abnormal mitochondrial morphology, Drp1β-KO islets exhibited normal oxygen consumption rates and an unchanged glucose threshold for intracellular calcium mobilization. Instead, the most profound consequences of β-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.

In Vivo Deletion of β-Cell Drp1 Impairs Insulin Secretion Without Affecting Islet Oxygen Consumption