An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion.
An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion.
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DOI：
10.1016/j.molmet.2016.06.016
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发表时间：
2016-08
影响因子：
8.1
通讯作者：
Finck BN
中科院分区：
文献类型：
--
作者：
McCommis KS;Hodges WT;Bricker DK;Wisidagama DR;Compan V;Remedi MS;Thummel CS;Finck BN
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. 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. 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. 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. 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.
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DOI：
10.1073/pnas.1319116111
发表时间：
2014-04-15
影响因子：
11.1
作者：
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通讯作者：
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