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.
Keywords: DILP2, Drosophila insulin-like peptide 2; Diabetes; Drosophila; GSIS, glucose-stimulated insulin secretion; GTT, glucose tolerance test; IMM, inner mitochondrial membrane; IPCs, Insulin-producing Cells; ITT, insulin tolerance test; Insulin; MPC1 and MPC2, Mitochondrial Pyruvate Carrier 1 and 2; Mitochondria; OCR, oxygen consumption rates; Pdx1, pancreatic and duodenal homeobox 1; Pyruvate; RESPYR, REporter Sensitive to PYRuvate; Stimulus-coupled secretion; β-Cell.