An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

Kyle S. McCommis, Wesley T. Hodges, Daniel K. Bricker, Dona R. Wisidagama, Vincent Compan, Maria S. Remedi, Carl S. Thummel, Brian N. Finck

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Objective Transport of pyruvate into the mitochondrial matrix by the Mitochondrial Pyruvate Carrier (MPC) is an important and rate-limiting step in its metabolism. In pancreatic β-cells, mitochondrial pyruvate metabolism is thought to be important for glucose sensing and glucose-stimulated insulin secretion. Methods To evaluate the role that the MPC plays in maintaining systemic glucose homeostasis, we used genetically-engineered Drosophila and mice with loss of MPC activity in insulin-producing cells. Results In both species, MPC deficiency results in elevated blood sugar concentrations and glucose intolerance accompanied by impaired glucose-stimulated insulin secretion. In mouse islets, β-cell MPC-deficiency resulted in decreased respiration with glucose, ATP-sensitive potassium (KATP) channel hyperactivity, and impaired insulin release. Moreover, treatment of pancreas-specific MPC knockout mice with glibenclamide, a sulfonylurea KATP channel inhibitor, improved defects in islet insulin secretion and abnormalities in glucose homeostasis in vivo. Finally, using a recently-developed biosensor for MPC activity, we show that the MPC is rapidly stimulated by glucose treatment in INS-1 insulinoma cells suggesting that glucose sensing is coupled to mitochondrial pyruvate carrier activity. Conclusions Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia.

Original languageEnglish
Pages (from-to)602-614
Number of pages13
JournalMolecular Metabolism
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2016

Keywords

  • Diabetes
  • Drosophila
  • Insulin
  • Mitochondria
  • Pyruvate
  • Stimulus-coupled secretion
  • β-Cell

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