| The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells. | |
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MedLine Citation:
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PMID: 20949348 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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AIMS/HYPOTHESIS: We have previously described a strong correlation between pyruvate cycling and insulin secretion. We have also demonstrated a particularly important role for a pyruvate-isocitrate cycling pathway involving the mitochondrial citrate/isocitrate carrier (CIC) and cytosolic NADP-dependent isocitrate dehydrogenase. CIC requires cytosolic malate as a counter-substrate during citrate and isocitrate export. Thus, considering that the mitochondrial dicarboxylate carrier (DIC) provides an important source of cytosolic malate, we investigated the potential role of DIC in control of glucose-stimulated insulin secretion (GSIS). METHODS: We used pharmacological and small interfering RNA (siRNA) tools to assess the role of DIC in insulin release in clonal insulin-secreting 832/13 cells and isolated rat islets. RESULTS: Butylmalonate, an inhibitor of malate transport, reduced cytosolic malate and citrate levels, and inhibited GSIS in a dose-dependent manner in 832/13 cells. Suppression of DIC expression resulted in inhibition of GSIS by 5% to 69%, the extent of inhibition of insulin secretion being proportional to the level of Dic (also known as Slc25a10) gene knockdown. The most effective siRNA duplex against Dic did not affect glucose utilisation, glucose oxidation or ATP/ADP ratio, but did suppress glucose-induced increments of the NADPH/NADP(+) ratio. Confirmation of our results in primary cultures of isolated rat islets showed that butylmalonate and an adenovirus expressing an siRNA against Dic-inhibited GSIS. CONCLUSIONS/INTERPRETATION: Malate transport by DIC may play an important role in GSIS, possibly by providing cytosolic malate as a counter-substrate for citrate and/or isocitrate export by CIC. These studies also suggest that malate transport by DIC is (1) a critical component of NADPH production mediated by pyruvate-cycling and (2) regulates GSIS. |
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Authors:
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P Huypens; R Pillai; T Sheinin; S Schaefer; M Huang; M L Odegaard; S M Ronnebaum; S D Wettig; J W Joseph |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-15 |
Journal Detail:
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Title: Diabetologia Volume: 54 ISSN: 1432-0428 ISO Abbreviation: Diabetologia Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-02 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0006777 Medline TA: Diabetologia Country: Germany |
Other Details:
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Languages: eng Pagination: 135-45 Citation Subset: IM |
Affiliation:
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University of Waterloo, Kitchener, ON, Canada. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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