Document Detail

Effect of mitochondrial and/or cytosolic glycerol 3-phosphate dehydrogenase overexpression on glucose-stimulated insulin secretion from MIN6 and HIT cells.
MedLine Citation:
PMID:  8772729     Owner:  NLM     Status:  MEDLINE    
The glycerol phosphate shuttle consists of FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) and its cytosolic NAD-linked isoform (cGPDH). Impaired mGPDH activity has recently been suggested to be one of the primary causes of insulin secretory defects in beta-cells. We found that mGPDH and cGPDH activities in MIN6 cells are comparable to those of isolated islets and higher than those in HIT cells by eightfold and threefold, respectively. Therefore, we selected the MIN6 cell line as a beta-cell model with normally regulated insulin secretion and normal shuttle enzyme activities and the HIT cell line as a beta-cell model with impaired insulin secretion and lower activities of these enzymes. The role of these dehydrogenases in glucose-stimulated insulin secretion was addressed by examining the effects of overexpression of mGPDH and/or cGPDH via recombinant adenoviruses in these cells. Infection with recombinant adenovirus with a cDNA encoding the Escherichia coli beta-galactosidase gene resulted in expression of its gene in 90% of MIN6 and HIT cells. Infection with a recombinant adenovirus with mGPDH cDNA (Adex1CAmGPDH) caused 2.1-fold and 5.7-fold increases in dehydrogenase activity as compared with those of control MIN6 and HIT cells, respectively. Infection with a recombinant adenovirus with cGPDH cDNA (Adex1CAcGPDH) caused a more than 50-fold increase in activity in both cell lines. Glycerol phosphate shuttle flux, as estimated by [2-3H]glycerol conversion to [3H]H2O, was increased to 120-130% by infection with Adex1CAmGPDH, but not with Adex1CAcGPDH infection, in both MIN6 and HIT cells. No further increase in flux through the glycerol phosphate shuttle was detected when the cells were infected with Adex1CAmGPDH together with Adex1CAcGPDH. Furthermore, neither [U-14C]glucose oxidation nor the insulin secretory response to glucose was affected in either cell line. Thus, mGPDH abundance in MIN6 and HIT cells is not directly related to their insulin secretory capacity in response to glucose, and reduced expression of mGPDH is not the primary cause of abnormal insulin secretory responses in HIT cells. The present data indicate that the emerging hypothesis pointing to mGPDH deficiency as a possible cause of NIDDM needs to be carefully evaluated.
H Ishihara; M Nakazaki; Y Kanegae; K Inukai; T Asano; H Katagiri; Y Yazaki; M Kikuchi; J Miyazaki; I Saito; Y Oka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes     Volume:  45     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  1996 Sep 
Date Detail:
Created Date:  1996-10-08     Completed Date:  1996-10-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1238-44     Citation Subset:  AIM; IM    
Institute for Adult Diseases, Asahi Life Foundation, Shinjuku-ku, Japan.
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MeSH Terms
Cytosol / enzymology
Glucose / metabolism*,  pharmacology
Glycerol / metabolism
Glycerolphosphate Dehydrogenase / biosynthesis*
Insulin / secretion*
Islets of Langerhans / drug effects,  physiology*
Isoenzymes / biosynthesis
Mitochondria / enzymology*
Molecular Sequence Data
Recombinant Proteins / biosynthesis
beta-Galactosidase / biosynthesis
Reg. No./Substance:
0/Isoenzymes; 0/Recombinant Proteins; 11061-68-0/Insulin; 50-99-7/Glucose; 56-81-5/Glycerol; EC 1.1.-/Glycerolphosphate Dehydrogenase; EC

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