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Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion

Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion
Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion
Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP(+)-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse beta-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.
0193-1849
E1354-E1362
Heart, Emma
f8b99fd2-026e-43cd-9db6-67edd6d18c98
Cline, Gary W.
46e297fd-92fe-4853-a5c9-b4bdb5ad5952
Collis, Leon P.
66f825a3-f4a7-4e85-a1ca-ee16497b8a81
Pongratz, Rebecca L.
bfb15be9-1648-434a-8a0b-4d6fd3d59ba2
Gray, Joshua P.
87bb062f-a135-4f9b-9b65-02ade9a7fece
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Heart, Emma
f8b99fd2-026e-43cd-9db6-67edd6d18c98
Cline, Gary W.
46e297fd-92fe-4853-a5c9-b4bdb5ad5952
Collis, Leon P.
66f825a3-f4a7-4e85-a1ca-ee16497b8a81
Pongratz, Rebecca L.
bfb15be9-1648-434a-8a0b-4d6fd3d59ba2
Gray, Joshua P.
87bb062f-a135-4f9b-9b65-02ade9a7fece
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c

Heart, Emma, Cline, Gary W., Collis, Leon P., Pongratz, Rebecca L., Gray, Joshua P. and Smith, Peter J.S. (2009) Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion. American Journal of Physiology: Endocrinology and Metabolism, 296 (6), E1354-E1362. (doi:10.1152/ajpendo.90836.2008). (PMID:19293334)

Record type: Article

Abstract

Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP(+)-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse beta-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.

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Published date: June 2009

Identifiers

Local EPrints ID: 190275
URI: http://eprints.soton.ac.uk/id/eprint/190275
ISSN: 0193-1849
PURE UUID: 4692cf47-0f9c-45f0-a5cc-877eca15ffc7
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 13 Jun 2011 08:47
Last modified: 21 Nov 2021 03:04

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Contributors

Author: Emma Heart
Author: Gary W. Cline
Author: Leon P. Collis
Author: Rebecca L. Pongratz
Author: Joshua P. Gray

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