Long term in vitro effects of streptozotocin, interleukin-1, and high glucose concentration on the activity of mitochondrial dehydrogenases and the secretion of insulin in pancreatic islets.
When cultured mouse pancreatic islets were exposed for 30 min to streptozotocin (STZ; 1.8 mM) and then maintained for 7 days in tissue culture, they displayed a decreased secretory response to D-glucose and an impairment of both FAD-linked glycerophosphate dehydrogenase and NAD-dependent 2-ketoglutarate dehydrogenase specific activities, with little change in either NAD-linked glycerophosphate dehydrogenase or glutamate dehydrogenase activity. The enzymatic defect was not reproduced by prolonged exposure of either rat islets to interleukin-1 (10 U/ml) or mouse islets to a high concentration of D-glucose (28 mM). In the former, but not latter, situation, the secretory response to D-glucose was again impaired. These findings reveal that STZ, but not all beta-cytotoxic agents, lowers the activity of selected islet mitochondrial dehydrogenases. Such enzymatic defects, especially the suppression of FAD-linked glycerophosphate dehydrogenase, may explain the preferential alteration of the B-cell metabolic and secretory responses to D-glucose, as previously observed in islets of adult rats injected with STZ during the neonatal period.
Rasschaert
J
J
Laboratory of Experimental Medicine, Brussels Free University, Belgium.
Eizirik
D L
DL
Malaisse
W J
WJ
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013311:Streptozocin / Q000494:pharmacology*
D007328:Insulin; D007375:Interleukin-1; D011506:Proteins; D011994:Recombinant Proteins; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D013311:Streptozocin; D004247:DNA; D005993:Glycerolphosphate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D005947:Glucose