How Does Diabetes Impair Penile Tissues during Erectile Dysfunction?

Author(s): Yi-Xing Wu, Chun-Tao Yang, Na Li, Xue Zheng, Xiang Li, Hui Zhang, Jie Shen*

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 20 , Issue 9 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Erectile dysfunction (ED) is a significant but underestimated complication during diabetes mellitus (DM). Currently, few special treatments are available clinically due to the lack of specific therapeutic targets. Genomic analysis can be helpful to find potential targets. In this study, the gene expression under diabetic ED condition was analyzed using a gene array, and the significance of the outcomes was evaluated through clinical data.

Methods: The expressions of 15923 genes were analyzed using R software. Differential expression genes (DEGs) were identified through the constructed volcano plot. The function enrichment of Gene Ontology (GO) and KEGG was screened with the DAVID online tool. The interaction between these DEGs 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.

Results: The study showed that 75 genes in the rat penile tissues were upregulated, while 97 genes were downregulated on the diabetic ED condition. These genes were mainly involved in extracellular matrix composition, collagen fibril organization, as well as protein digestion & absorption. Additionally, insulin-related signaling pathways were affected. The clinical analysis indicated that insulin resistance was associated with the diabetic ED severity. Notably, the bioinformatics analysis also suggested that ferroptosis pathway was probably activated under the diabetic ED condition.

Conclusion: The impaired protein synthesis induced by deficient insulin signaling is an important cause of the diabetic ED. The improvement of protein synthesis through restoring insulin function may be potentially useful for diabetic ED therapy.

Keywords: Bioinformatics, diabetic erectile dysfunction, penile tissues, insulin resistance, PPI network, protein synthesis.

[1]
Al-Lawati, J.A. Diabetes Mellitus: a local and global public health emergency! Oman Med. J., 2017, 32(3), 177-179.
[http://dx.doi.org/10.5001/omj.2017.34] [PMID: 28584596]
[2]
Brown, J.S.; Wessells, H.; Chancellor, M.B.; Howards, S.S.; Stamm, W.E.; Stapleton, A.E.; Steers, W.D.; Van Den Eeden, S.K.; McVary, K.T. Urologic complications of diabetes. Diabetes Care, 2005, 28(1), 177-185.
[http://dx.doi.org/10.2337/diacare.28.1.177] [PMID: 15616253]
[3]
Zhang, H.; Zhuang, X.D.; Meng, F.H.; Chen, L.; Dong, X.B.; Liu, G.H.; Li, J.H.; Dong, Q.; Xu, J.D.; Yang, C.T. Calcitriol prevents peripheral RSC96 Schwann neural cells from high glucose & methylglyoxal-induced injury through restoration of CBS/H2S expression. Neurochem. Int., 2016, 92, 49-57.
[http://dx.doi.org/10.1016/j.neuint.2015.12.005] [PMID: 26707812]
[4]
Schalkwijk, C.G.; Stehouwer, C.D. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin. Sci. (Lond.), 2005, 109(2), 143-159.
[http://dx.doi.org/10.1042/CS20050025] [PMID: 16033329]
[5]
Yang, C.T.; Chen, L.; Chen, W.L.; Li, N.; Chen, M.J.; Li, X.; Zheng, X.; Zhao, Y.Z.; Wu, Y.X.; Xian, M.; Liu, J. Hydrogen sulfide primes diabetic wound to close through inhibition of NETosis. Mol. Cell. Endocrinol., 2019, 480, 74-82.
[http://dx.doi.org/10.1016/j.mce.2018.10.013] [PMID: 30339820]
[6]
Duan, Y.; Gao, H.; Su, H.; Liu, A.; Liu, Y.; Yuan, H.; Xie, C. Exploring the protective effect of shenqi compound on skeletal muscle in diabetic macrovasculopathy mice. Endocr. Metab. Immune Disord. Drug Targets, 2020, 20(6), 943-951.
[http://dx.doi.org/10.2174/1871530320666200225094756] [PMID: 32096754]
[7]
Wu, Y.; Yang, C.; Meng, F.; Que, F.; Xiao, W.; Rao, H.; Wan, Y.; Taylor, H.S.; Lu, L. Nerve growth factor improves the outcome of type 2 diabetes-induced hypotestosteronemia and erectile dysfunction. Reprod. Sci., 2019, 26(3), 386-393.
[http://dx.doi.org/10.1177/1933719118773421] [PMID: 29724155]
[8]
Abdulla, H.; Smith, K.; Atherton, P.J.; Idris, I. Role of insulin in the regulation of human skeletal muscle protein synthesis and breakdown: A systematic review and meta-analysis. Diabetologia, 2016, 59(1), 44-55.
[http://dx.doi.org/10.1007/s00125-015-3751-0] [PMID: 26404065]
[9]
Tuvdendorj, D.; Zhang, X.J.; Chinkes, D.L.; Aarsland, A.; Kulp, G.A.; Jeschke, M.G.; Herndon, D.N. Intensive insulin treatment increases donor site wound protein synthesis in burn patients. Surgery, 2011, 149(4), 512-518.
[http://dx.doi.org/10.1016/j.surg.2010.10.021] [PMID: 21236451]
[10]
Bassil, M.S.; Gougeon, R. Muscle protein anabolism in type 2 diabetes. Curr. Opin. Clin. Nutr. Metab. Care, 2013, 16(1), 83-88.
[http://dx.doi.org/10.1097/MCO.0b013e32835a88ee] [PMID: 23196814]
[11]
Lima, M.H.; Caricilli, A.M.; de Abreu, L.L.; Araújo, E.P.; Pelegrinelli, F.F.; Thirone, A.C.; Tsukumo, D.M.; Pessoa, A.F.; dos Santos, M.F.; de Moraes, M.A.; Carvalheira, J.B.; Velloso, L.A.; Saad, M.J. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo controlled clinical trial. PLoS One, 2012, 7(5)e36974
[http://dx.doi.org/10.1371/journal.pone.0036974] [PMID: 22662132]
[12]
Sullivan, C.J.; Teal, T.H.; Luttrell, I.P.; Tran, K.B.; Peters, M.A.; Wessells, H. Microarray analysis reveals novel gene expression changes associated with erectile dysfunction in diabetic rats. Physiol. Genomics, 2005, 23(2), 192-205.
[http://dx.doi.org/10.1152/physiolgenomics.00112.2005] [PMID: 16118269]
[13]
Nie, X.; Wei, J.; Hao, Y.; Tao, J.; Li, Y.; Liu, M.; Xu, B.; Li, B. Consistent biomarkers and related pathogenesis underlying asthma revealed by systems biology approach. Int. J. Mol. Sci., 2019, 20(16), 20.
[http://dx.doi.org/10.3390/ijms20164037] [PMID: 31430856]
[14]
Wallace, T.M.; Levy, J.C.; Matthews, D.R. Use and abuse of HOMA modeling. Diabetes Care, 2004, 27(6), 1487-1495.
[http://dx.doi.org/10.2337/diacare.27.6.1487] [PMID: 15161807]
[15]
Rosen, R.C.; Cappelleri, J.C.; Smith, M.D.; Lipsky, J.; Peña, B.M. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int. J. Impot. Res., 1999, 11(6), 319-326.
[http://dx.doi.org/10.1038/sj.ijir.3900472] [PMID: 10637462]
[16]
Shamloul, R.; Ghanem, H. Erectile dysfunction. Lancet, 2013, 381(9861), 153-165.
[http://dx.doi.org/10.1016/S0140-6736(12)60520-0] [PMID: 23040455]
[17]
Simonsen, U.; García-Sacristán, A.; Prieto, D. Penile arteries and erection. J. Vasc. Res., 2002, 39(4), 283-303.
[http://dx.doi.org/10.1159/000065541] [PMID: 12187119]
[18]
Dean, R.C.; Lue, T.F. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol. Clin. North Am., 2005, 32(4), 379-395,v.
[http://dx.doi.org/10.1016/j.ucl.2005.08.007] [PMID: 16291031]
[19]
Melman, A.; Gingell, J.C. The epidemiology and pathophysiology of erectile dysfunction. J. Urol., 1999, 161(1), 5-11.
[http://dx.doi.org/10.1016/S0022-5347(01)62045-7] [PMID: 10037356]
[20]
Yang, C.T.; Meng, F.H.; Chen, L.; Li, X.; Cen, L.J.; Wen, Y.H.; Li, C.C.; Zhang, H. Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine. Cell. Physiol. Biochem., 2017, 41(2), 742-754.
[http://dx.doi.org/10.1159/000458734] [PMID: 28214842]
[21]
Navarro-Flores, E.; Cauli, O. Quality of life in individuals with diabetic foot syndrome. Endocr. Metab. Immune Disord. Drug Targets, 2020.
[http://dx.doi.org/10.2174/1871530320666200128154036] [PMID: 32003676]
[22]
Boudina, S.; Abel, E.D. Diabetic cardiomyopathy revisited. Circulation, 2007, 115(25), 3213-3223.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.679597] [PMID: 17592090]
[23]
Fong, D.S.; Aiello, L.; Gardner, T.W.; King, G.L.; Blankenship, G.; Cavallerano, J.D.; Ferris, F.L., III; Klein, R. American Diabetes Association. Retinopathy in diabetes. Diabetes Care, 2004, 27(Suppl. 1), S84-S87.
[http://dx.doi.org/10.2337/diacare.27.2007.S84] [PMID: 14693935]
[24]
Yamanaka, M.; Shirai, M.; Shiina, H.; Tanaka, Y.; Tsujimura, A.; Matsumiya, K.; Okuyama, A.; Dahiya, R. Diabetes induced erectile dysfunction and apoptosis in penile crura are recovered by insulin treatment in rats. J. Urol., 2003, 170(1), 291-297.
[http://dx.doi.org/10.1097/01.ju.0000060564.31122.2a] [PMID: 12796708]
[25]
Pu, X.Y.; Hu, L.Q.; Wang, H.P.; Luo, Y.X.; Wang, X.H. Improvement in erectile dysfunction after insulin-like growth factor-1 gene therapy in diabetic rats. Asian J. Androl., 2007, 9(1), 83-91.
[http://dx.doi.org/10.1111/j.1745-7262.2007.00215.x] [PMID: 16855763]
[26]
Aversa, A.; Basciani, S.; Visca, P.; Arizzi, M.; Gnessi, L.; Frajese, G.; Fabbri, A. Platelet-derived growth factor (PDGF) and PDGF receptors in rat corpus cavernosum: changes in expression after transient in vivo hypoxia. J. Endocrinol., 2001, 170(2), 395-402.
[http://dx.doi.org/10.1677/joe.0.1700395] [PMID: 11479135]
[27]
Huang, X.; Liu, G.; Guo, J.; Su, Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int. J. Biol. Sci., 2018, 14(11), 1483-1496.
[http://dx.doi.org/10.7150/ijbs.27173] [PMID: 30263000]
[28]
Molinaro, A.; Becattini, B.; Mazzoli, A.; Bleve, A.; Radici, L.; Maxvall, I.; Sopasakis, V.R.; Molinaro, A.; Backhed, F.; Solinas, G. Insulin-driven PI3K-AKT signaling in the hepatocyte is mediated by redundant PI3K alpha and PI3K beta activities and is promoted by RAS. Cell Metab, 2019, 29, 1400-1409. e1405.
[29]
Li, R.; Cui, K.; Liu, K.; Li, H.; Zhang, Y.; Liu, X.; Chen, R.; Li, M.; Wang, T.; Wang, S.; Liu, J.; Rao, K. Metabolic syndrome in rats is associated with erectile dysfunction by impairing PI3K/Akt/eNOS activity. Sci. Rep., 2017, 7(1), 13464.
[http://dx.doi.org/10.1038/s41598-017-12907-1] [PMID: 29044143]
[30]
Olefsky, J.M.; Saltiel, A.R. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol. Metab., 2000, 11(9), 362-368.
[http://dx.doi.org/10.1016/S1043-2760(00)00306-4] [PMID: 11042466]
[31]
Haluzík, M.M.; Haluzík, M. PPAR-alpha and insulin sensitivity. Physiol. Res., 2006, 55(2), 115-122.
[PMID: 15910175]
[32]
Leonardini, A.; Laviola, L.; Perrini, S.; Natalicchio, A.; Giorgino, F. Cross-talk between PPAR gamma and insulin signaling and modulation of insulin sensitivity. PPAR Res., 2009.2009818945
[http://dx.doi.org/10.1155/2009/818945] [PMID: 20182551]
[33]
Hu, L.L.; Zhang, K.Q.; Tian, T.; Zhang, H.; Fu, Q. Probucol improves erectile function via Activation of Nrf2 and coordinates the HO-1/DDAH/PPAR-γ/eNOS pathways in streptozotocin-induced diabetic rats. Biochem. Biophys. Res. Commun., 2018, 507(1-4), 9-14.
[http://dx.doi.org/10.1016/j.bbrc.2018.10.036] [PMID: 30454888]
[34]
Zhang, Z.; Zhang, H.Y.; Zhang, Y.; Li, H. Inactivation of the Ras/MAPK/PPARγ signaling axis alleviates diabetic mellitus-induced erectile dysfunction through suppression of corpus cavernosal endothelial cell apoptosis by inhibiting HMGCS2 expression. Endocrine, 2019, 63(3), 615-631.
[http://dx.doi.org/10.1007/s12020-018-1810-2] [PMID: 30460485]
[35]
Yang, W.S.; Stockwell, B.R. Ferroptosis: death by lipid peroxidation. Trends Cell Biol., 2016, 26(3), 165-176.
[http://dx.doi.org/10.1016/j.tcb.2015.10.014] [PMID: 26653790]
[36]
Xie, Y.; Hou, W.; Song, X.; Yu, Y.; Huang, J.; Sun, X.; Kang, R.; Tang, D. Ferroptosis: process and function. Cell Death Differ., 2016, 23(3), 369-379.
[http://dx.doi.org/10.1038/cdd.2015.158] [PMID: 26794443]
[37]
Bromfield, E.G.; Walters, J.L.H.; Cafe, S.L.; Bernstein, I.R.; Stanger, S.J.; Anderson, A.L.; Aitken, R.J.; McLaughlin, E.A.; Dun, M.D.; Gadella, B.M.; Nixon, B. Differential cell death decisions in the testis: evidence for an exclusive window of ferroptosis in round spermatids. Mol. Hum. Reprod., 2019, 25(5), 241-256.
[http://dx.doi.org/10.1093/molehr/gaz015] [PMID: 30865280]
[38]
Hinman, A.; Holst, C.R.; Latham, J.C.; Bruegger, J.J.; Ulas, G.; McCusker, K.P.; Amagata, A.; Davis, D.; Hoff, K.G.; Kahn-Kirby, A.H.; Kim, V.; Kosaka, Y.; Lee, E.; Malone, S.A.; Mei, J.J.; Richards, S.J.; Rivera, V.; Miller, G.; Trimmer, J.K.; Shrader, W.D. Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One, 2018, 13(8)e0201369
[http://dx.doi.org/10.1371/journal.pone.0201369] [PMID: 30110365]
[39]
Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: A regulated cell death Nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285.
[http://dx.doi.org/10.1016/j.cell.2017.09.021] [PMID: 28985560]
[40]
De Young, L.; Yu, D.; Bateman, R.M.; Brock, G.B. Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction. J. Androl., 2004, 25(5), 830-836.
[http://dx.doi.org/10.1002/j.1939-4640.2004.tb02862.x] [PMID: 15292117]
[41]
Helmy, M.M.; Senbel, A.M. Evaluation of vitamin E in the treatment of erectile dysfunction in aged rats. Life Sci., 2012, 90(13-14), 489-494.
[http://dx.doi.org/10.1016/j.lfs.2011.12.019] [PMID: 22280834]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 9
Year: 2020
Published on: 05 November, 2020
Page: [1535 - 1542]
Pages: 8
DOI: 10.2174/1871530320666200531140735
Price: $65

Article Metrics

PDF: 27
HTML: 2