Improvement by aminoguanidine of insulin secretion from pancreatic islets grafted to syngeneic diabetic rats.
Prolonged hyperglycemia inhibits B-cell function by mechanisms that are largely 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 transplanted under the kidney capsule of syngeneic streptozocin-diabetic recipients. Aminoguanidine was administered as 1 g/L in the drinking water. Graft-bearing kidneys were isolated and perfused to investigate insulin secretion, and grafts were excised to measure preproinsulin mRNA contents. In all transplants to diabetic rats, insulin responses to 27.8 mM glucose were abolished and aminoguanidine failed to correct this abnormality. However, aminoguanidine treatment for 8 weeks following transplantation increased preproinsulin 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 aminoguanidine 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-cell function of grafts, and ALT-711 was also ineffective under in vitro conditions. Our findings indicate that aminoguanidine effects in vivo are to a major extent not coupled to AGEs or nitric oxide synthetase inhibition, but possibly to oxidative modifications accomplished by the guanidine compound.
Hiramatsu
S
S
Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Karolinska Institute, S-17176, Stockholm, Sweden.
Inoue
K
K
Tajirl
Y
Y
Grill
V
V
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000601:surgery; D006146:Guanidines / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology; D014185:Transplantation, Isogeneic
D006146:Guanidines; D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; D013844:Thiazoles; C013737:preproinsulin; D011384:Proinsulin; C406794:alagebrium; C004479:pimagedine