Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion.

Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Research Abstract Details 

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Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Abstract Text:

Rebecca L Pongratz,Richard G Kibbey,Gerald I Shulman,Gary W Cline,

In islet beta-cells and INS-1 cells both the high activity of malic enzyme and the correlation of insulin secretion rates with pyruvate carboxylase (PC) flux suggest that a pyruvate-malate cycle is functionally relevant to insulin secretion. Expression of the malic enzyme isoforms in INS-1 cells and rat islets was measured, and small interfering RNA was used to selectively reduce isoform mRNA expression in INS-1 cells to evaluate its impact on insulin secretion. The cytosolic NADP(+)-specific isoform (ME1) was the most abundant, with the mitochondrial isoforms NAD(+)-preferred (ME2) expressed at approximately 50%, and the NADP(+)-specific (ME3) at approximately 10% compared with ME1. Selective reduction (89 +/- 2%) of cytosolic ME1 mRNA expression and enzyme activity significantly reduced glucose (15 mM:41 +/- 6%, p < 0.01) and amino acid (4 mM glutamine +/- 10 mM leucine: 39 +/- 6%, p < 0.01)-stimulated insulin secretion. Selective small interfering RNA reduction (51 +/- 6%) of mitochondrial ME2 mRNA expression did not impact glucose-induced insulin secretion, but decreased amino acid-stimulated insulin secretion by 25 +/- 4% (p < 0.01). Modeling of the metabolism of [U-(13)C]glucose by its isotopic distribution in glutamate indicates a second pool of pyruvate distinct from glycolytically derived pyruvate in INS-1 cells. ME1 knockdown decreased flux of both pools of pyruvate through PC. In contrast, ME2 knockdown affected only PC flux of the pyruvate derived from glutamate metabolism. These results suggest a physiological basis for two metabolically and functionally distinct pyruvate cycles. The cycling of pyruvate by ME1 generates cytosolic NADPH, whereas mitochondrial ME2 responds to elevated amino acids and serves to supply sufficient pyruvate for increased Krebs cycle flux when glucose is limiting.

Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Publishing Authors By Initials

RL Pongratz,RG Kibbey,GI Shulman,GW Cline,

For similar animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats research abstracts see: animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats research

PUBMED ID PMID:

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Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 200-7

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 13

MONTH: 11

YEAR: 2006

Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Keywords Mesh Terms:

KEYWORDS: Rats

MESH TERMS: metabolism

Chemical & Substance for Abstract: Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. Information

Substance Name: NADP

Registry Number: 53-59-8

Grant and Affiliation Information for Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion.

AFFILIATION: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: U24 DK-59635

ACRONYM: DK

MEDLINETA: J Biol Chem

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