The Effects Of Insulin Plus ALT-711on Erectile Dysfunction Related To Metabolic Memory In Diabetic Rats

Objective: The aim of this study is to investigate the effects of metabolicmemory on erectile dysfunction (ED), and possible utility of ALT-711andinsulin on DM-associated ED.Methods: Fifty male8-week-old Sprague-Dawley rats were randomlydistributed into5groups: normal control group, diabetic group, insulin-treateddiabetic group, ALT-711-treated diabetic group and insulin plus ALT-711treated diabetic group. Diabetes was induced by a one-time intraperitonealinjection of streptozotocin(60mg/kg).8weeks after diabetes induction,ALT-711was administered by intraperitoneal(3mg/kg).2-6units of neutralprotamine Hagedorn was injected subcutaneously twice a day forinsulin-treated group and insulin plus ALT-711-treated group to achieve normallevels of glycemic control. After treatment for6weeks,erectile function viaintracavernous pressures(ICP) were determined by electrostimulation ofcavernous nerve. The deposition of advanced glycation end-products(AGEs),expression of receptors for AGEs(RAGE), SOD activity, lipid peroxidationwere measured. We also evaluated penile histologic changes such as smoothmuscle contents, endothelial cells contents, and apoptotic activity. Main Outcome Measures. The main outcome measures were the ratio of ICP/MAP,penile endothelial cells, smooth muscle cells, nNOS, AGE and RAGEexpression, MDA concentration, SOD activity and apoptosis index.Results：Diabetic rats demonstrated significantly reduced ICP/MAP ratio,penile endothelial cells, smooth muscles cells, increased AGEs and RAGEexpression, and increased apoptosis. Insulin and ALT-711monotherapypartially restored erectile function and histologic changes. However thecombination therapy group showed erectile parameters and components similarto those in normal control. ALT-711-treated group demonstrated less depositionof AGEs and lower expression of RAGE than those in insulin-treated group.Conclusions:These results suggested that although insulin could controlglycemic level effectively, it could not completely alter the pathologicalchanges in erectile tissues. Better efficacy could be expected with tightglycemic control plus ALT-711, an AGEs cross-link breaker. The combinationtherapy might have the potential to eliminate metabolic memory bydown-regulating the AGEs-RAGE-oxidative stress axis.