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An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion
- Source :
- Molecular Metabolism, Molecular metabolism, Molecular metabolism, Elsevier, 2016, 5 (8), pp.602--614. ⟨10.1016/j.molmet.2016.06.016⟩, Molecular Metabolism, Vol 5, Iss 8, Pp 602-614 (2016)
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.<br />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.
- 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
Subjects
Details
- ISSN :
- 22128778
- Volume :
- 5
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular Metabolism
- Accession number :
- edsair.doi.dedup.....b019f56c56fe75579673e5231390deac
- Full Text :
- https://doi.org/10.1016/j.molmet.2016.06.016