1. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion
- Author
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Daniel K. Bricker, Kyle S. McCommis, Wesley T. Hodges, Vincent Compan, Carl S. Thummel, Dona R. Wisidagama, Brian N. Finck, Maria S. Remedi, Institut de Génomique Fonctionnelle (IGF), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,insulin tolerance test ,ITT ,[SDV]Life Sciences [q-bio] ,Stimulus-coupled secretion ,Pyruvate dehydrogenase phosphatase ,immune system diseases ,Insulin ,Insulin-producing Cells ,Inner mitochondrial membrane ,ComputingMilieux_MISCELLANEOUS ,glucose-stimulated insulin secretion ,Pdx1 ,IMM ,Diabetes ,MPC1 and MPC2 ,Pyruvate dehydrogenase complex ,OCR, oxygen consumption rates ,3. Good health ,Pyruvate carboxylase ,Mitochondria ,Biochemistry ,oxygen consumption rates ,GTT, glucose tolerance test ,beta-Cell ,Original Article ,Drosophila ,DILP2, Drosophila insulin-like peptide 2 ,IMM, inner mitochondrial membrane ,β-Cell ,IPCs, Insulin-producing Cells ,Pyruvate decarboxylation ,Pyruvate ,lcsh:Internal medicine ,Pyruvate dehydrogenase kinase ,RESPYR ,RESPYR, REporter Sensitive to PYRuvate ,glucose tolerance test ,PKM2 ,Biology ,Drosophila insulin-like peptide 2 ,GSIS, glucose-stimulated insulin secretion ,03 medical and health sciences ,Dihydrolipoyl transacetylase ,lcsh:RC31-1245 ,Molecular Biology ,inner mitochondrial membrane ,ITT, insulin tolerance test ,030102 biochemistry & molecular biology ,Cell Biology ,pancreatic and duodenal homeobox 1 ,REporter Sensitive to PYRuvate ,GSIS ,DILP2 ,MPC1 and MPC2, Mitochondrial Pyruvate Carrier 1 and 2 ,OCR ,030104 developmental biology ,IPCs ,GTT ,b-Cell ,Pdx1, pancreatic and duodenal homeobox 1 ,Mitochondrial Pyruvate Carrier 1 and 2 - 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., Highlights • Loss of MPC activity in Drosophila leads to hyperglycemia. • Glucose-stimulated insulin secretion is impaired in Drosophila lacking MPC. • β-cell-specific MPC deletion in mice also results in impaired insulin secretion. • The MPC may be a sensor for glucose concentration in β-cells and couple pyruvate production to insulin secretion.
- Published
- 2016
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