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PMID: 17403370 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mitochondrial GTP regulates glucose-stimulated insulin secretion.

Cell metabolism ·Vol. 5 ·No. 4 ·2007-04-00 ·Pages 253-64

Kibbey RG, Pongratz RL, Romanelli AJ, Wollheim CB, Cline GW, Shulman GI

Abstract

Nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl-CoA synthetase (SCS) catalyze substrate-level synthesis of mitochondrial GTP (mtGTP) and ATP (mtATP). While mtATP yield from glucose metabolism is coupled with oxidative phosphorylation and can vary, each molecule of glucose metabolized within pancreatic beta cells produces approximately one mtGTP, making mtGTP a potentially important fuel signal. In INS-1 832/13 cells and cultured rat islets, siRNA suppression of the GTP-producing pathway (DeltaSCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, while suppression of the ATP-producing isoform (DeltaSCS-ATP) increased GSIS 2-fold. Insulin secretion correlated with increases in cytosolic calcium, but not with changes in NAD(P)H or the ATP/ADP ratio. These data suggest a role for mtGTP in controlling pancreatic GSIS through modulation of mitochondrial metabolism, possibly involving mitochondrial calcium. Furthermore, in light of its tight coupling to TCA oxidation rates, mtGTP production may serve as an important molecular signal of TCA-cycle activity.

MeSH Terms
Animals Calcium/metabolism Cells, Cultured Energy Metabolism/physiology Glucose/pharmacology Guanosine Triphosphate/analysis,physiology Insulin/metabolism Insulin Secretion Insulin-Secreting Cells/drug effects,metabolism Mitochondria/chemistry,drug effects Models, Biological Oxidation-Reduction RNA, Small Interfering/pharmacology Rats Rats, Sprague-Dawley Succinate-CoA Ligases/antagonists & inhibitors,genetics
Chemicals
Insulin RNA, Small Interfering Guanosine Triphosphate Succinate-CoA Ligases Glucose Calcium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kibbey Richard G
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Pongratz Rebecca L
Romanelli Anthony J
Wollheim Claes B
Cline Gary W
Shulman Gerald I
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1550-4131
DOI
10.1016/j.cmet.2007.02.008
Published
2007-04-00
Pages
253-64
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC1876711
Subset
IM
Grants
NIDDK NIH HHS · R01 DK049230 · United States
NIDDK NIH HHS · U24 DK076169 · United States
NIDDK NIH HHS · R01 DK-40936 · United States
NIDDK NIH HHS · P01 DK068229-030001 · United States
NIDDK NIH HHS · P30 DK045735-119001 · United States
NIDDK NIH HHS · U24 DK059635 · United States
NIDDK NIH HHS · U24 DK059635-05 · United States
NIDDK NIH HHS · P01 DK068229 · United States
NIDDK NIH HHS · P30 DK-45735 · United States
NIDDK NIH HHS · R01 DK040936 · United States
NIDDK NIH HHS · R01 DK040936-18 · United States
NIDDK NIH HHS · R24 DK085638 · United States
NIDDK NIH HHS · P30 DK045735 · United States
NIDDK NIH HHS · U24 DK-76169 · United States
NIDDK NIH HHS · R01 DK-71071 · United States
NIDDK NIH HHS · R01 DK071071 · United States
NIDDK NIH HHS · P01 DK-68229 · United States
NIDDK NIH HHS · K08 DK080142 · United States
External Links
PubMed source DOI: 10.1016/j.cmet.2007.02.008 PMC Full Text View journal details
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