Improvement by aminoguanidine of insulin secretion from pancreatic islets grafted to syngeneic diabetic rats

Prolonged hyperglycemia inhibits B-cell function by mechanisms that are lar gely unclarified. We investigated the involvement of advanced glycation end products (AGEs), using aminoguanidine as well as the AGE-breaking compound ALT-711 in a transplantation model. Islets from Wistar-Furth rats were tra nsplanted under the kidney capsule of syngeneic streptozocin-diabetic recip ients. Aminoguanidine was administered as 1 g/L in the drinking water. Graf t-hearing kidneys were isolated and perfused to investigate insulin secreti on, and grafts were excised to measure preproinsulin mRNA contents. In all transplants to diabetic rats, insulin responses to 27.8 mM glucose were abo lished and aminoguanidine failed to correct this abnormality. However, amin oguanidine treatment for 8 weeks following transplantation increased prepro insulin mRNA contents of the grafts (P < 0.05). In addition, treatment with aminoguanidine enhanced the insulin secretory response to arginine (P < 0. 05). Arginine-induced insulin secretion was also enhanced when aminoguanidi ne treatment was started after an initial 2-week implantation period rather than immediately after transplantation. On the other hand, treatment with ALT-711 (0.1 mg/kg by gavage) for 8 weeks completely failed to affect B-cel l function of grafts, and ALT-711 was also ineffective under in vitro condi tions. Our findings indicate that aminoguanidine effects in vivo are to a m ajor extent not coupled to AGEs or nitric oxide synthetase inhibition, but possibly to oxidative modifications accomplished by the guanidine compound. (C) 2000 Elsevier Science Inc.