title: Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets.
abstract: Glucose-stimulated insulin secretion is impaired in GK (Goto-Kakizaki) rats, perhaps because of abnormalities in glucose metabolism in pancreatic islet beta cells. The glycerol phosphate shuttle plays a major role in glucose metabolism by reoxidizing cytosolic NADH generated by glycolysis. In the pancreatic islets of GK rats, the activity of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase (mGPDH), the key enzyme of the glycerol phosphate shuttle, is decreased and this abnormality may be responsible, at least in part, for impaired glucose-stimulated insulin secretion. To investigate this possibility, we overexpressed mGPDH in islets isolated from GK rats via recombinant adenovirus-mediated gene transduction, and examined glucose-stimulated insulin secretion. In islets isolated from diabetic GK rats at 8 to 10 weeks of age, glucose-stimulated insulin secretion was severely impaired, and mGPDH activity was decreased to 79 % of that in non-diabetic Wistar rats. When mGPDH was overexpressed in islets from GK rats, enzyme activity and protein content increased 2- and 6-fold, respectively. Basal (3 mmol/l glucose) and glucose-stimulated (20 mmol/l) insulin secretion from the Adex1CAlacZ-infected GK rat islets were, respectively, 4.4 +/- 0.7 and 8.1 +/- 0.7 ng. x islet(-1) x 30 min(-1), and those from mGPDH-overexpressed GK rat islets 4.7 +/- 0.3 and 9.1 +/- 0.8 ng x islet(-1) x 30 min(-1), in contrast to those from the AdexlCAlacZ-infected non-diabetic Wistar rat islets (4.7 +/- 1.6 and 47.6 +/- 11.9 ng x islet(-1) x 30 min(-1)). Thus, glucose-stimulated insulin secretion is severely impaired in GK rats even in the stage when mGPDH activity is modestly decreased, and at this stage, overexpression of mGPDH cannot restore glucose-stimulated insulin secretion. We conclude that decreased mGPDH activity in GK rat islets is not the defect primarily responsible for impaired glucose-stimulated insulin secretion.
authors.affiliation: Third Department of Internal Medicine, Yamaguchi University, School of Medicine, Ube, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ueda
authors.forename: Y
authors.initials: Y
authors.lastname: Tanizawa
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
authors.forename: N
authors.initials: N
authors.lastname: Kizuki
authors.forename: Y
authors.initials: Y
authors.lastname: Ohta
authors.forename: A
authors.initials: A
authors.lastname: Matsutani
authors.forename: Y
authors.initials: Y
authors.lastname: Oka
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000494:pharmacology; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism*; D007763:Lac Operon / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection / Q000235:genetics
chemical_list: D007328:Insulin; D011993:Recombinant Fusion Proteins; D005182:Flavin-Adenine Dinucleotide; D005993:Glycerolphosphate Dehydrogenase; D005947:Glucose