Pharmacological Research, Vol. 37, No. 6, 1998 Article Number: fr980321 EFFECTS OF TWO ALDOSE REDUCTASE INHIBITORS UPON SORBITOL OUTPUT, D-GLUCOSE METABOLISM AND INSULIN RELEASE IN ISLETS FROM NORMAL AND HEREDITARILY DIABETIC RATS L.E. FLORES, J.J. GAGLIARDINO, A. SENER and W.J. MALAISSE  Laboratory of Experimental Medicine, Brussels Free Uni ersity, Brussels, Belgium and Centro de Endocrinologia Experimental y Aplicada, Faculda de Ciencias Medicas, Uni ersidad ´ Nacional de La Plata, La Plata, Argentina Accepted 19 March 1998 Ž . Ž . The effects of two aldose reductase inhibitors, ARI 509 4.0  M and tolrestat 40.0  M ,  3   14  upon sorbitol output, D- 5- H glucose and D- U- C glucose metabolism and insulin release were investigated in pancreatic islets prepared from normal rats or hereditarily diabetic Ž . animals Goto Kakizaki rats and incubated in the presence of 16.7 mMD-glucose. At this  3  hexose concentration, the output of sorbitol, the utilization of D- 5- H glucose, the oxida-  14  14 tion of D- U- C glucose and its conversion to C-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 mMD-glucose. In both normal and diabetic rats, the aldose reductase inhibitors suppressed glucose-stimulated sorbitol output, but failed to affect the metabolism of  3   14  D- 5- H glucose or D- U- C 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.  1998 The Italian Pharmacological Society KEY WORDS: aldose reductase inhibitors, pancreatic islets, sorbitol, insulin release. INTRODUCTION  A recent report 1 has revived interest in the view that aldose reductase inhibitors may inhibit glucose-stimulated insulin release, suggesting that the generation of sorbitol from D-glucose may play a role in the mechanism by which the hexose stimu- lates insulin secretion, as first suggested by Gabbay  and Tze 2 . Since this issue remains a matter of   debate 3, 4 , the present study was undertaken to evaluate the effect of two aldose reductase inhibi-   tors, tolrestat 5 and ARI 509 6 , upon the output of sorbitol, metabolism of D-glucose and secretory response to the hexose in pancreatic islets prepared Ž from either normal rats or Goto Kakizaki rats GK . rats with inherited non-insulin-dependent diabetes   mellitus 7, 8 .  Corresponding author. Laboratory of Experimental Medicine, Brussels Free University, 808 Route de Lennik, B-1070 Brussels, Belgium. MATERIALS AND METHODS Tolrestat and ARI 509 were kindly provided by John Ž . Wyeth-Ayerst Laboratories Inc. New Jersey, USA . Ž Female Wistar normal rats B and K Universal . Ltd., Hull, UK and male GK rats from our local Ž colony were given free access to food KM-04-k12; . Pavan Service, Oud Turnhout, Belgium and tap water up to the time of killing by decapitation. All experiments were conducted in freshly isolated  islets prepared by the collagenase procedure 9. They were incubated for 120 min either at a low, Ž non-insulinotropic concentration of D-glucose 2.8 . Ž . mM or at a higher concentration 16.7 mM yielding close-to-maximal metabolic and secretory responses. The aldose reductase inhibitors ARI 509 and tolre- stat were tested at respective concentrations of 4.0 and 40.0  M, taking into account the fact that ARI 509 is approximately one order of magnitude more potent than tolrestat to inhibit polyol accumulation  in lens, erythrocytes or sciatic nerve 6 . The concen- 104366189806049304$30.000 1998 The Italian Pharmacological Society