Experimental And Clinical Research On Diabetic Erectile Dysfunction

BACKGROND&OBJECTIVETraditional treatments have poor effects or even ineffective on diabetic erectile dysfunction(DED),suggesting that DED has its unique pathogenesis that is currently unknown.Studies have found that the level of nerve growth factor(NGF)in the testis of a diabetic model is significantly reduced.Leydig cells(LC)are neuroendocrine cells in nature,and express some known NGF receptors in adult testes.This study was going to apply bioinformatics to study DED,identify differentially expression genes(DEG)between diabetic penile tissues and normal tissues,and reveal the hub genes to further understand the pathogenesis of DED.In order to illustrate the role of NGF in the biosynthesis of testosterone,we planed to make a diabetic cellular model in LC,and then applied NGF intervention to clarify the possible role of NGF.Subsequently,a 2-arm randomized clinical trial of NGF's curative effect was carried out to establish a theoretical foundation and provided practical experience for effective treatment of DED.METHODS1.All the data were downloaded from Gene Expression Omnibus(GEO).Differential expression genes(DEG)were identified through the constructed volcano plot.The function enrichment of Gene Ontology(GO)and KEGG was analyzed with the DAVID online tool.The interaction between the DEG was revealed through constructing a protein-protein interaction network,and the hub genes were uncovered using the STRING and Cytoscape tool.Lastly,the data of diabetic ED patients were applied to verify the bioinformatics findings.2.Methylglyoxal(MGO)was used to establish the diabetic injury mouse LC model.Cell viability was measured using CCK-8,mitochondrial membrane potential(MMP)was examined by Rh123 staining followed by photofluorography,and Western blot was used to detect the expression of steroidogenic acute regulatory protein(StAR)and cytochrome P450 cholesterol side-chain cleavage enzyme(CYP11A1),with and without NGF.3.A randomized 2-arm open-label clinical trial was carried out to confirm the increase in serum testosterone levels and international erectile function index(IIEF-5)scores in male patients with type 2 diabetes(T2DM)induced ED and diabetic sensorimotor polyneuropathy(DSPN)in NGF treatment group and the control.RESULTS1.There are 172 DEGs in diabetic penile tissues compared to the normal,13 of which are hub genes.The impaired extracellular protein synthesis related to deficient insulin signaling is probably an important cause of the diabetic ED.There is a significant negative correlation between the insulin resistance homeostasis model assessment(HOMA-IR)and IIEF-5 score in DED patients(r=-0.51).2.The optimal concentration of MGO is 200 ?M to establish a diabetic injury mouse LC model.3.After exposure to MGO,the cell viability of LC significantly decreased in a dose-dependent manner.However,pretreated with NGF,the cell viability of LC impaired by MGO was attenuated,and the optimal concentration of NGF was 25 ng/ml.4.The MMP of LC was significantly impaired after the exposure to MGO.However,the pretreatment with NGF before the exposure to MGO significantly increased the MMP level as compared with that of the control.5.The expression of StAR was no obviously disturbed after exposed to MGO for 24 hours.Nonetheless,NGF was significantly able to enhance the expression of StAR.MGO exposure caused a significant decrease in CYP11A1 expression,but NGF pretreatment neutralized it.NGF alone was able to significantly up-regulate the expression of CYP11A1.6.Clinical observation found that after using NGF in male T2DM-induced ED and DSPN patients,the serum testosterone level and IIEF-5 score were significantly increased.CONCLUSIONInsulin resistance is one of the main causes of DED.NGF can prevent diabetes-induced injury,in terms of the restore of cell viability and MMP,as well as the facilitation of StAR and CYP11A1 expression.NGF enhanced serum testosterone level and IIEF-5 score in male T2DM-induced ED and DSPN patients.These findings suggest that NGF has a clinical potential in the management of T2DM-induced ED.