Effects of two aldose reductase inhibitors upon sorbitol output, D-glucose metabolism and insulin release in islets from normal and hereditarily diabetic rats.
The effects of two aldose reductase inhibitors, ARI 509 (4.0 microM) and tolrestat (40.0 microM), upon sorbitol output, D-[5-3H]glucose and D-[U-14C]glucose metabolism and insulin release were investigated in pancreatic islets prepared from normal rats or hereditarily diabetic animals (Goto-Kakizaki rats) and incubated in the presence of 16.7 mM D-glucose. At this hexose concentration, the output of sorbitol, the utilization of D-[5-3H]glucose, the oxidation of D-[U-14C]glucose and its conversion to 14C-labelled acidic metabolites and amino acids and the secretion of insulin were all much higher than those found in islets exposed to only 2.8 mM D-glucose. In both normal and diabetic rats, the aldose reductase inhibitors suppressed glucose-stimulated sorbitol output, but failed to affect the metabolism of D-[5(-3H]glucose or D-[U-14C]glucose and the secretory response to the hexose. These findings document the efficiency and specificity of ARI 509 and tolrestat as inhibitors of aldose reductase in islet cells, whilst arguing against any major role of sorbitol formation in the stimulus-secretion coupling process for glucose-induced insulin release and any major perturbation of those factors regulating the generation and output of sorbitol in islets of Goto-Kakizaki rats.
Laboratory of Experimental Medicine, Brussels Free University, Belgium.
L E
LE
Flores
J J
JJ
Gagliardino
A
A
Sener
W J
WJ
Malaisse
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007328:Insulin; D009281:Naphthalenes; C091470:WAY 121-509; C040550:tolrestat; D013012:Sorbitol; D000449:Aldehyde Reductase; D005947:Glucose