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Mitochondrial Fission in Pancreatic Beta Cell Insulin Secretion

  • Author(s): Hennings, Thomas George
  • Advisor(s): Ku, Gregory M
  • et al.

Insulin-producing pancreatic beta cells are central regulators of blood glucose homeostasis. In a process termed glucose-stimulated insulin secretion (GSIS) beta cells utilize mitochondrial glucose metabolism to precisely up- or down-regulate insulin vesicle exocytosis in response to changes in plasma glucose concentrations. As beta cells either die or become dysfunctional in both type 1 and type 2 diabetes, they are an attractive target for the generation of novel therapeutics. To discover new genetic regulators of beta cell biology, we conducted a genome- wide screen of beta cell insulin production and identified an important role for mitochondrial fission genes. Mitochondrial fission, the process by which one parental mitochondrion gives rise to multiple daughter mitochondria, regulates ATP production, the tricarboxylic acid (TCA) cycle, and processes beyond metabolism in a cell-type specific manner. Given the central role of mitochondrial metabolism in GSIS, we hypothesized that mitochondrial fission may play an important role in regulating beta cell insulin secretion. We thus generated mice lacking beta cell Drp1 (Drp1β-KO mice), a central regulator of mitochondrial fission. We found that 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 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 novel role for Drp1 in metabolic amplification and calcium handling without affecting oxygen consumption. Future studies will investigate the contribution of abnormal mitochondrial dynamics to the development of diabetes.

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