Diabetes mellitus-induced disruptions of male reproductive functions: A comprehensive review

Abstract

Diabetes mellitus has emerged as a widespread global health concern, contributing significantly to morbidity and mortality rates. The metabolic disturbances associated with diabetes can adversely impact the male reproductive system, leading to reduced fertility. This review offers an in-depth evaluation of recent global research exploring the impact of diabetes on male reproductive health. Relevant experimental and clinical studies were identified, with a focus on diabetes-related effects on reproductive organs, hormones, and sexual function. The review highlights that insulin deficiency and resistance in diabetic conditions disrupt the hypothalamic-pituitary-gonadal axis, reducing levels of key reproductive hormones such as gonadotropin releasing hormone, luteinizing hormone, follicle stimulating hormone, and testosterone. These hormonal disruptions lead to structural and functional damage in reproductive organs including the testes, Sertoli cells, epididymis, sperm, and accessory glands. Moreover, diabetes contributes to erectile and ejaculatory dysfunctions. Various pathophysiological mechanisms such as oxidative stress, hormonal imbalances, germ cell apoptosis, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress are identified as underlying contributors to diabetes-induced male infertility. The findings of this review provide valuable insights into the complex mechanisms by which diabetes affects the male reproductive function. By integrating current research, it highlights the critical need for further studies and the development of targeted therapies to effectively address diabetes-induced infertility.

Keywords

Diabetes mellitus / Male reproductive function / Insulin / Sperm parameters / Infertility / Oxidative stress

Conflict of interest statement

The authors declare no conflicts of interest to disclose.

Funding

The study receives no extramural funding.

Authors’ contributions

Tanvi Jangid contributed to the original draft preparation and was involved in review and editing. Aditya Jain was responsible for conceptualization and also contributed to review and editing. Gauri Shankar Bhardwaj contributed to the review process and figure editing. Ram Niwas Jangir was involved in editing, original draft writing, and visualization. Gyan Chand Jain contributed to the review and editing of the manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Publisher’s Note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] American Diabetes Association Professional Practice Committee. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2022. Diabetes Care 2022; 45(Suppl 1):S1-S38.

[2] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14(2):88-98.

[3] Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas. Diabetes Res Clin Pract 2019; 157:107843. doi: 10.1016/j.diabres.2019.107843.

[4] Temidayo SO, Du Plessis SS. Diabetes mellitus and male infertility. Asian Pac J Reprod 2018; 7(1):6-14.

[5] Arthur CG, Hall J. Guyton and hall textbook of medical physiology. 12th ed. Philadalphia PA, USA: Elsevier; 2017

[6] Ma RC, Tong PC. Epidemiology of type 2 diabetes. In: Textbook of diabetes. 5th ed. Hoboken NJ, Unites States: John Wiley & Sons, Ltd, 2017, p. 43-64.

[7] DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, pregnancy risk assessment monitoring system (PRAMS), 2007-2010. Prev Chronic Dis 2010; 11:130415. doi: 10.5888/pcd11.130415.

[8] Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, et al. Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev 2022; 38(2):e3494.

[9] Jangir RN, Jain GC. Diabetes mellitus induced impairment of male reproductive functions: A review. Curr Diabetes Rev 2014; 10(3):147-157.

[10] He Z, Yin G, Li QQ, Zeng Q, Duan J. Diabetes mellitus causes male reproductive dysfunction: A review of the evidence and mechanisms. In Vivo 2021; 35(5):2503-2511.

[11] Shi GJ, Li ZM, Zheng J, Chen J, Han XX, Wu J, et al. Diabetes associated with male reproductive system damages: Onset of presentation, pathophysiological mechanisms and drug intervention. Biomed Pharmacother 2017; 90:562-574.

[12] Tsounapi P, Honda M, Dimitriadis F, Kawamoto B, Hikita K, Muraoka K, et al. Impact of antioxidants on seminal vesicles function and fertilizing potential in diabetic rats. Asian J Androl 2017; 19:639-646.

[13] Ayuob NN, Murad HA, Ali SS. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochem Cytobiol 2015; 53:35-48.

[14] Kolahian S, Sadri H, Larijani A, Hamidian G, Davasaz A. Supplementation of diabetic rats with leucine, zinc, and chromium: Effects on function and histological structure of testes. Int J Vitam Nutr Res 2015; 85:311-321.

[15] Long L, Wang J, Lu X, Xu Y, Zheng S, Luo C, et al. Protective effects of scutellarin on type II diabetes mellitus-induced testicular damages related to reactive oxygen species/Bcl-2/Bax and reactive oxygen species/microcirculation/staving pathway in diabetic rat. J Diabetes Res 2015; 2015:252530. doi: 10.1155/2015/252530.

[16] Jangir RN, Jain GC. Ameliorative effect of Moringa oleifera Lam. leaves extract on the sex hormone profile and testicular dysfunctions in streptozotocin-induced diabetic Wistar rats. Pharmacognosy Res 2022; 14(2):225-232.

[17] Zhao W, Hu Y, Long LL, Cai B, Li YB. Protective effects of scutellarin on testicular vessels of rats with type II diabetes mellitus-induced testicular damages. J Sun Yat-sen Univ Med Sci 2020; 2020:260-267.

[18] Sisman AR, Kiray M, Camsari UM, Evren M, Ates M, Baykara B, et al. Potential novel biomarkers for diabetic testicular damage in streptozotocin-induced diabetic rats: Nerve growth factor beta and vascular endothelial growth factor. Dis Markers 2014; 2014:108106. doi: 10.1155/2014/108106.

[19] Silva AAN, Oliveira JS, Oliveira RR, Moraes SRA, Junior VAS, Simas JN, et al. Resveratrol attenuates reproductive alterations in type 1 diabetes-induced rats. Int J Exp Pathol 2017; 98:312-328.

[20] Bhandari K, Mukherjee A, Ray I, Acharya S. Effect on the pituitarytesticular axis in streptozotocin-induced diabetic rats. World J Pharm Res 2015; 4:2096-2106.

[21] Kong WY, Tong LQ, Zhang HJ, Cao YG, Wang GC, Zhu JZ, et al. The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats. Asian J Androl 2016; 18:803-808.

[22] Oliveira PF, Alves MG, Rato L, Laurentino S, Silva J, Sa R, et al. Effect of insulin deprivation on metabolism and metabolism-associated gene transcript levels of in vitro cultured human Sertoli cells. Biochim Biophys Acta Gen Subj 2012; 1820:84-89.

[23] Rato L, Alves MG, Dias TR, Cavaco JE, Oliveira PF. Testicular metabolic reprogramming in neonatal streptozotocin-induced type 2 diabetic rats impairs glycolytic flux and promotes glycogen synthesis. J Diabetes Res 2015; 2015:973142. doi: 10.1155/2015/973142.

[24] Xu Y, Lei H, Guan R, Gao Z, Li H, Wang L, et al. Studies on the mechanism of testicular dysfunction in the early stage of a streptozotocin-induced diabetic rat model. Biochem Biophys Res Commun 2014; 450(1):87-92. doi: 10.1016/j.bbrc.2014.05.067.

[25] Brodjonegoro SR, Ghinorawa T, Wonatorey NKR, Zulfiqqar A, Heriyanto DS. Effect of hyperglycemia on fertility in streptozotocininduced diabetic male Wistar rats: Focus on glucose transporters and oxidative stress. Med J Indones 2021; 30(3):177-181.

[26] Kamani M, Nikzad H, Atlasi MA, Taherian A, Mahabadi JA, Ganji R. Histological changes of epididymis of STZ-induced diabetic rats. Glob J Med Res Res Stud 2014; 1:122-124.

[27] Jangir RN, Jain GC. Assessment of ameliorative effects of Moringa oleifera Lam. on epididymal dysfunctions and fertility in streptozotocininduced diabetic rats. Asian Pac J Reprod 2024; 13(6):271-280.

[28] Li J, Lin F, Zhu X, Lv Z. Impact of diabetic hyperglycaemia and insulin therapy on autophagy and impairment in rat epididymis. Andrologia 2020; 52(11):e13889. doi: 10.1111/and.13889.

[29] Kotian S, Kumar A, Mallik S, Bhat N, Souza A, Pandey A. Effect of diabetes on the male reproductive system-A histomorphological study. J Morphol Sci 2019; 36(01):17-23.

[30] Maresch CC, Stute DC, Alves MG, Oliveira PF, de Kretser DM, Linn T. Diabetes-induced hyperglycemia impairs male reproductive function: A systematic review. Hum Reprod Update 2018; 24(1):86-105.

[31] An T, Wang YF, Liu JX, Pan YY, Liu YF, He ZC, et al. Comparative analysis of proteomes between diabetic and normal human sperm: Insights into the effects of diabetes on male reproduction based on the regulation of mitochondria-related proteins. Mol Reprod Dev 2018; 85:7-16.

[32] Wei Y, Yang C, Wei Y, Zhao Z, Hou Y, Schatten H, et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci 2014; 111(5):1873-1878.

[33] Chen X, Lin Q, Wen J, Lin W, Liang J, Huang H, et al. Whole genome bisulfite sequencing of human spermatozoa reveals differentially methylated patterns from type 2 diabetic patients. J Diabetes Investig 2020; 11(4):856-864.

[34] Jiang GJ, Zhang T, An T, Zhao DD, Yang XY, Zhang DW, et al. Differential expression of long noncoding RNAs between sperm samples from diabetic and non-diabetic mice. PLoS One 2016; 11(4):e0154028. doi: 10.1371/journal.pone.0154028.

[35] Bhattacharya SM, Ghosh M, Nandi N. Diabetes mellitus and abnormalities in semen analysis. J Obstet Gynaecol Res 2013; 40(1):167-171.

[36] Lu X, Huang Y, Zhang H, Zhao J. Effect of diabetes mellitus on the quality and cytokine content of human semen. J Reprod Immunol 2017; 123:1-2.

[37] Porto EM, Santos SADA, Ribeiro LM, Lacorte LM, Rinaldi JC, Justulin LA Jr, et al. Lobe variation effects of experimental diabetes and insulin replacement on rat prostate. Microsc Res Tech 2011; 74(11):1040-1048.

[38] Dong B, Shi Z, Dong Y, Chen J, Wu ZX, Wu W, et al. Quercetin ameliorates oxidative stress-induced cell apoptosis of seminal vesicles via activating Nrf2 in type 1 diabetic rats. Biomed Pharmacother 2022; 151: 113108. doi: 10.1016/j.biopha.2022.113108.

[39] Yin Z, Yang JR, Rao JM, Song W, Zhou KQ. Association between benign prostatic hyperplasia, body mass index, and metabolic syndrome in Chinese men. Asian J Androl 2015; 17(5):826-830.

[40] Bahey NG, Soliman GM, El-Deeb TA, El-Drieny EA. Influence of insulin and testosterone on diabetic rat ventral prostate: Histological, morphometric and immunohistochemical study. J Microsc Ultrastruct 2014; 2(3):151-160.

[41] Corona G, Giorda CB, Cucinotta D, Guida P, Nada E. Sexual dysfunction at the onset of type 2 diabetes: The interplay of depression, hormonal and cardiovascular factors. J Sex Med 2014; 11(8):20652073.

[42] Kouidrat Y, Pizzol D, Cosco T, Thompson T, Carnaghi M, Bertoldo A, et al. High prevalence of erectile dysfunction in diabetes: A systematic review and meta-analysis of 145 studies. Diabet Med 2017; 34(9):11851192.

[43] Leite R, Giachini FR, Carneiro FS, Nunes KP, Tostes RC, Webb RC. Targets for the treatment of erectile dysfunction: Is NO/cGMP still the answer? Recent Pat Cardiovasc Drug Discov 2007; 2(2):119-132.

[44] Burnett AL, Musicki B. The nitric oxide signaling pathway in the penis. Curr Pharm Des 2005; 11(31):3987-3994.

[45] Hylmarova S, Stechova K, Pavlinkova G, Peknicova J, Macek M, Kvapil M. The impact of type 1 diabetes mellitus on male sexual functions and sex hormone levels. Endocr J 2019; 67(1):59-71.

[46] Ugwu T, Ezeani I, Onung S, Kolawole B, Ikem R. Predictors of erectile dysfunction in men with type 2 diabetes mellitus referred to a tertiary healthcare centre. Adv Endocrinol 2016; 2016:1-8. doi: 10.1155/2016/9753154.

[47] Zheng R, Cao L, Cao W, Chu W, Hu Y, Zhang H, et al. Risk factors for hypogonadism in male patients with type 2 diabetes. J Diabetes Res 2016; 2016:1-8. doi: 10.1155/2016/5162167.

[48] Shi MD, Chao JK, Ma MC, Chiang SK, Chao IC. The connection between type 2 diabetes and erectile dysfunction in Taiwanese aboriginal males. Int J Impot Res 2014; 26:235-240. doi: 10.1038/ijir.2014.26.

[49] El-Sakka AI. Premature ejaculation in non-insulin-dependent diabetic patients. Int J Androl 2003; 26(6):329-334.

[50] Fedder J, Kaspersen MD, Brandslund I, Højgaard A. Retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: A prospective, controlled study. Andrology 2013; 1(4):602-606.

[51] Kilarkaje N, Al-Hussaini H, Al-Bader MM. Diabetes-induced DNA damage and apoptosis are associated with poly (ADP ribose) polymerase 1 inhibition in the rat testis. Eur J Pharmacol 2014; 737:29-40.

[52] Pan F, You J, Liu Y, Qiu X, Yu W, Ma J, et al. Differentially expressed microRNAs in the corpus cavernosum from a murine model with type 2 diabetes mellitus-associated erectile dysfunction. Mol Genet Genomics 2016; 291:2215-2224.

[53] Bhandari K, Mukherjee A, Ray I, Acharya S. Study of morphometrical changes in the testis of diabetic rats. Glob J Res Anal 2015; 4(7):72-73.

[54] Sookhthezari A, Alirezaei M, Kheradmand A, Dezfoulian O. Streptozotocin-induced diabetic effects on the sperm fertility parameters, glycated hemoglobin, and total cholesterol in mice. J Shahid Sadoughi Univ Med Sci 2016; 23:980-988.

[55] Liu B, Zhang X, Qin M, Song A, Cui T, Wang C. Malfunction of Sertoli cell secretion leads to testicular damage in diabetic rats. Int J Clin Exp Med 2016; 9:9316-9321.

[56] Simas JN, Mendes TB, Paccola CC, Vendramini V, Miraglia SM. Resveratrol attenuates reproductive alterations in type 1 diabetes‐induced rats. Int J Exp Pathol 2017; 98(6):312-328.

[57] Omolaoye TS, Skosana BT, du Plessis SS. Diabetes mellitus-induction: Effect of different streptozotocin doses on male reproductive parameters. Acta Histochem 2018; 120(2):103-109.

[58] Türk G, Rişvanlı A, Çeribaşı AO, Sönmez M, Yüce A, Güvenç M, et al. Effect of gestational diabetes mellitus on testis and pancreatic tissues of male offspring. Andrologia 2018; 50(4). doi: 10.1111/and.12976.

[59] Long L, Qiu H, Cai B, Chen N, Lu X, Zheng S, et al. Hyperglycemia induced testicular damage in type 2 diabetes mellitus rats exhibiting microcirculation impairments associated with vascular endothelial growth factor decreased via PI3K/Akt pathway. Oncotarget 2018; 9(4):5321. doi: 10.18632/oncotarget.23915.

[60] Maresch CC, Stute DC, Fleming T, Lin J, Hammes HP, Linn T. Hyperglycemia induces spermatogenic disruption via major pathways of diabetes pathogenesis. Sci Rep 2019; 9(1):13074. doi: 10.1038/s41598-019-49600-4.

[61] Minaz N, Razdan R, Hammock BD, Mujwar S, Goswami SK. Impact of diabetes on male sexual function in streptozotocin-induced diabetic rats: Protective role of soluble epoxide hydrolase inhibitor. Biomed Pharmacother 2019; 115: 108897. doi: 10.1016/j.biopha.2019.108897.

[62] Nakane Y, Kemmochi Y, Ogawa N, Sasase T, Ohta T, Higami Y, et al. Hyperglycemia contributes to the development of Leydig cell hyperplasia in male spontaneously diabetic Torii rats. J Toxicol Pathol 2020; 33(2):121-129.

[63] Bégbin KE, Abizi G, Kouakou K. Effects of diabetes mellitus on the reproductive system of adult male mice after one cycle of spermatogenesis. Eur Sci J 2021; 17:149.

[64] Omolaoye TS, du Plessis SS. The effect of streptozotocin-induced diabetes on sperm function: A closer look at AGEs, RAGEs, MAPKs and activation of the apoptotic pathway. Toxicol Res 2021; 37:35-46.

[65] Baghel K, Azam Z, Srivastava R, Gupta N, Kango N. Withaferin-A attenuates diabetes mellitus induced male reproductive dysfunction mediated by ERα in brain and testes of Swiss albino mice. Sci Rep 2023; 13(1):17625. doi: 10.1038/s41598-023-44904-y.

[66] Rutte A, van Splunter MM, van der Heijden AA, Welschen LM, Elders PJ, Dekker JM, et al. Prevalence and correlates of sexual dysfunction in men and women with type 2 diabetes. J Sex Marital Ther 2015; 41(6):680-690.

[67] Salminen M, Vahlberg T, Räihä I, Niskanen L, Kivelä SL, Irjala K. Sex hormones and the risk of type 2 diabetes mellitus: A 9‐year follow up among elderly men in Finland. Geriatr Gerontol Int 2015; 15(5):559-564.

[68] Verit A, Verit FF, Oncel H, Ciftci H. Is there any effect of insulin resistance on male reproductive system? Arch Ital Urol Androl 2014; 86:5-8.

[69] Farias JM, Tinetti M, Khoury M, Umpierrez GE. Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes. J Clin Endocrinol Metab 2014; 99(12):4698-4703.

[70] AlMogbel TA. Erectile dysfunction and other sexual activity dysfunctions among Saudi type 2 diabetic patients. Int J Health Sci (Qassim) 2014; 8:347-359.

[71] Chakraborty PP, Ray S, Bhattacharjee R, Ghosh S, Mukhopadhyay P, Mukhopadhyay S, et al. Diabetes and primary infertility in young males: Do not forget cystic fibrosis. Clin Diabetes 2015; 33:80-83.

[72] La Vignera S, Condorelli RA, Di Mauro M, Lo Presti D, Mongioì LM, Russo G, et al. Reproductive function in male patients with type 1 diabetes mellitus. Andrology 2015; 3:1082-1087.

[73] Ho CH, Jaw FS, Wu CC, Chen KC, Wang CY, Hsieh JT, et al. The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men. J Sex Med 2015; 12:389-397.

[74] Portela JMD, Tavares RS, Mota PC, Ramalho-Santos J, Amaral S. High glucose concentrations per se do not adversely affect human sperm function in vitro. Reproduction 2015; 150:77-84.

[75] Sarma AV, Hotaling J, Dunn RL, Cleary PA, Braffett BH, Kim C, et al. Poor glycemic control is associated with reduced prostate specific antigen concentrations in men with type 1 diabetes. J Urol 2015; 193:786-793.

[76] Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 2016; 39(1):82-91.

[77] Majzoub A, Arafa M, Al-Said S, Dabbous Z, Aboulsoud S, Khalafalla K, et al. Premature ejaculation in type II diabetes mellitus patients: Association with glycemic control. Transl Androl Urol 2016; 5:248-254.

[78] Singh K, Devi S, Pankaj PP. Diabetes associated male reproductive dysfunctions: Prevalence, diagnosis and risk factors. Int J Drug Dev Res 2016; 8:7-10.

[79] Holmboe SA, Jensen TK, Linneberg A, Scheike T, Thuesen BH, Skakkebaek NE, et al. Low testosterone: A risk marker rather than a risk factor for type 2 diabetes. J Clin Endocrinol Metab 2016; 101:31803190.

[80] Maiorino MI, Bellastella G, Della Volpe E, Casciano O, Scappaticcio L, Cirillo P, et al. Erectile dysfunction in young men with type 1 diabetes. Int J Impot Res 2017; 29:17-22.

[81] Ghasemi M, Talebi A, Rahmanyan M, Nahangi H, Ghanizadeh T. Effects of diabetes mellitus type 2 on semen parameters. J Shahid Sadoughi Univ Med Sci 2017; 25:621-628.

[82] Najim SA, Khalil SAH, Majid AY. Evaluation of some inorganic elements in the serum and seminal plasma of male patients with type 2 diabetes mellitus and its relation to male infertility status. Int J Adv Biol Res 2006; 6:153-158.

[83] Chowdhary S, Ahmad M. Comparative study of serum testosterone levels in male patients of type 2 diabetes mellitus and non-diabetics presenting with complaints of sexual dysfunction. J Med Sci Clin Res 2017; 5:18910-18916.

[84] Kam J, Tsang VH, Chalasani V. Retrograde ejaculation: A rare presenting symptom of type 1 diabetes mellitus. Urol Case Rep 2017; 10:9-10.

[85] Condorelli RA, La Vignera S, Mongioì LM, Alamo A, Calogero AE. Diabetes mellitus and infertility: Different pathophysiological effects in type 1 and type 2 on sperm function. Front Endocrinol (Lausanne) 2018; 9:268.

[86] Teka S, Kinde S, Dedefo G, Mudi K, Tarekegn G. Hypogonadism and associated risk factors in male patients with type 2 diabetes mellitus attending the diabetic clinic of Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia. J Endocrinol Metab Diabetes South Afr 2019; 24:6-22.

[87] Liu X, Gao M, Sun J, Sun Z, Song J, Xue X, et al. Effects of testicular sperm aspiration upon first cycle ICSI-ET for type 2 diabetic male patients. Syst Biol Reprod Med 2020; 66:355-363.

[88] Jiang Q, Maresch CC, Petry SF, Paradowska-Dogan A, Bhushan S, Chang Y, et al. Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome. JCI Insight 2020; 5: e134882. doi: 10.1172/jci.insight.134882.

[89] Raheem OA, Hehemann MC, Rogers MJ, Fustok JN, Hirsch IB, Walsh TJ. Does type 1 diabetes affect male infertility: Type 1 diabetes exchange registry-based analysis. Soc Int Urol J 2021; 2:139-143.

[90] Caruso P, Cirillo P, Carbone C, Sarnataro A, Maiorino MI, Bellastella G, et al. Sexual dysfunctions and short-term glucose variability in young men with type 1 diabetes. Hormones (Athens) 2021; 20:475-482.

[91] Facondo P, Di Lodovico E, Delbarba A, Anelli V, Pezzaioli LC, Filippini E, et al. The impact of diabetes mellitus type 1 on male fertility: Systematic review and meta‐analysis. Andrology 2022; 10:426-440.

[92] Ali BR, Alameri AN, Rumaidh SA, Ethaib S. Correlation between reproductive hormones levels and semen quality in patients with diabetes. J Med Life 2022; 15:1507-1510.

[93] Dai M, Guo W, Zhu S, Gong G, Chen M, Zhong Z, et al. Type 2 diabetes mellitus and the risk of abnormal spermatozoa: A Mendelian randomization study. Front Endocrinol (Lausanne) 2022; 13: 1035338. doi: 10.3389/fendo.2022.1035338.

[94] Kalaiselvi S, Syed Ali M, Anuradha V, Subhashini A. A study on the association of diabetes and semen quality in and around Chennai, Tamil Nadu, India. Int J Reprod Contracept Obstet Gynecol 2023; 12(4):910-917.

[95] Longo M, Caruso P, Varro C, Tomasuolo M, Cirillo P, Scappaticcio L, et al. Semen quality and metabolic profile in people with type 1 diabetes with and without erectile dysfunction: A cross-sectional study. J Endocrinol Invest 2024;1-9. doi: 10.1007/s40618-023-02285-z.

[96] Fan C, Zhang J, Qiu D. Causal relationship between genetically predicted type 2 diabetes mellitus and male infertility. Front Endocrinol (Lausanne) 2024; 15: 1357279. doi: 10.3389/fendo.2024.1357279.

[97] Huang R, Chen J, Guo B, Jiang C, Sun W. Diabetes-induced male infertility: Potential mechanisms and treatment options. Mol Med 2024; 30(1):1-15.

[98] Schoeller EL, Albanna G, Frolova AI, Moley KH. Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes 2012; 61:1869-1878.

[99] Natah TM, Wtwt MA, Al-Saadi HK, Al-Saadi AH, Farhood HF. Study the levels of adiponectin, FSH, LH and sex hormones in type 2 diabetes (NIDDM). J Biol Agric Healthcare 2013; 3:172-181.

[100] Ahn SW, Gang GT, Kim YD, Ahn RS, Harris RA, Lee CH, et al. Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. J Biol Chem 2013; 288:15937-15946.

[101] Grosu C, Oprescu AC, Nita O, Bild W. Insulin and the brain. Rom J Diabetes Nutr Metab Dis 2017; 24:377-384.

[102] Aitken RJ, Shokri S, Pujianto DA, Curry BJ, Whiting SJ, Salamonsen L. Insulin as an important prosurvival factor for human spermatozoa. Andrology 2013; 1:626-635.

[103] Evans MC, Rizwan MZ, Anderson GM. Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice. Endocrinology 2014; 155:4368-4379.

[104] Alves MG, Martins AD, Rato L, Moreira PI, Socorro S, Oliveira PF. Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta 2013; 1832:626-635.

[105] Oghbaei H, Hamidian G, Alipour MR, Alipour S, Keyhanmanesh R. The effect of prolonged dietary sodium nitrate treatment on the hypothalamus-pituitary-gonadal axis and testicular structure and function in streptozotocin-induced diabetic male rats. Food Funct 2020; 11:2451-2465.

[106] Oghbaei H, Alipour MR, Hamidian G, Ahmadi M, Ghorbanzadeh V, Keyhanmanesh R. Two months sodium nitrate supplementation alleviates testicular injury in streptozotocin‐induced diabetic male rats. Exp Physiol 2018; 103:1603-1617.

[107] Escott GM, Jacobus AP, Loss ES. PI3K-dependent actions of insulin and IGF-I on seminiferous tubules from immature rats. Pflugers Arch 2013; 465:1497-1505.

[108] Kaur G, Thompson LA, Babcock RL, Mueller K, Dufour JM. Sertoli cells engineered to express insulin to lower blood glucose in diabetic mice. DNA Cell Biol 2018; 37:680-690.

[109] Lorigo M, Mariana M, Oliveira N, Lemos MC, Cairrao E. Vascular pathways of testosterone: Clinical implications. J Cardiovasc Transl Res 2020; 13:55-72.

[110] Zhang J, Huang X, Liao M, Gao Y, Tan A, Yang X, et al. Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: Results from Fangchenggang area male health and examination survey in China. Diabetes Metab Res Rev 2013; 29:391-397.

[111] Cree-Green M, Newcomer BR, Coe G, Newnes L, Baumgartner A, Brown MS, et al. Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids. Am J Physiol Endocrinol Metab 2015; 308(9):E726-E733. doi: 10.1152/ajpendo.00619.2014.

[112] Wang Y, Zhang Z, Guo W, Sun W, Miao X, Wu H, et al. Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. Am J Physiol Endocrinol Metab 2014; 307(1):E14-E23. doi: 10.1152/ajpendo.00702.2013.

[113] Kumar TR, Doreswamy K, Shrilatha B. Oxidative stress associated DNA damage in testis of mice: Induction of abnormal sperms and effects on fertility. Mutat Res 2002; 513(1-2):103-111.

[114] Kannan A, Ramatchandirin B, Sadasivam M, Balakrishnan S. Role of oxidative stress on testicular aquaporins expression in hyperglycemic rats. World Congr Diabetes India 2015; 4:1-5.

[115] Kovac S, Angelova PR, Holmström KM, Zhang Y, Dinkova-Kostova AT, Abramov AY. Nrf 2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta Gen Subj 2015; 1850(4):794-801.

[116] Lin CJ, Chen TL, Tseng YY, Wu GJ, Hsieh MH, Lin YW, et al. Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. Toxicol Appl Pharmacol 2016; 304:59-69.

[117] Sato S, Kataoka S, Kimura A, Mukai Y. Azuki bean (Vigna angularis) extract reduces oxidative stress and stimulates autophagy in the kidneys of streptozotocin-induced early diabetic rats. Can J Physiol Pharmacol 2016; 94(12):1298-1303.

[118] Tian Y, Song W, Xu D, Chen X, Li X, Zhao Y. Autophagy induced by ROS aggravates testis oxidative damage in diabetes via breaking the feedforward loop linking p62 and Nrf2. Oxid Med Cell Longev 2020; 2020:7156579. doi: 10.1155/2020/7156579.

[119] Sahu SK, Cockrem JF, Parkinson TJ, Laven RA. Effects of GnRH, a progesterone-releasing device, and energy balance on an oestrus synchronisation program in anoestrous dairy cows. Aust Vet J 2017; 95(8):281-288.

[120] Brown RJ, Joseph J, Cochran E, Gewert C, Semple R, Gorden P. Type B insulin resistance masquerading as ovarian hyperthecosis. J Clin Endocrinol Metab 2017; 102(6):1789-1791.

[121] Hannan MA, Kawate N, Fukami Y, Weerakoon WWPN, Büllesbach EE, Inaba T, et al. Effects of long-acting GnRH antagonist, degarelix acetate, on plasma insulin-like peptide 3, testosterone, and luteinizing hormone concentrations, and scrotal circumference in male goats. Theriogenology 2017; 88:228-235.

[122] Kanter M, Aktas C, Erboga M. Curcumin attenuates testicular damage, apoptotic germ cell death, and oxidative stress in streptozotocininduced diabetic rats. Mol Nutr Food Res 2013; 57(9):1578-1585.

[123] Adedara IA, Awogbindin IO, Anamelechi JP, Farombi EO. Garcinia kola seed ameliorates renal, hepatic, and testicular oxidative damage in streptozotocin-induced diabetic rats. Pharm Biol 2015; 53:695-704.

[124] Zhao P, Zhou RU, Zhu XY, Hao YJ, Li N, Wang J, et al. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice. Int J Mol Med 2015; 36:633-644.

[125] Zhao P, Zhou R, Li HN, Yao WX, Qiao HQ, Wang SJ, et al. Oxymatrine attenuated hypoxic-ischemic brain damage in neonatal rats via improving antioxidant enzyme activities and inhibiting cell death. Neurochem Int 2015; 89:17-27.

[126] Moghaddami Z, Sheikhzadeh HF, Banan Khojasteh SM, Hemmati AR, Dastranj A. The effect of long-term exercise via TNF-a level on the type-1 diabetic rats in testis tissues. Yazd Int Congr Stud Award Reprod Med Reprod Genet Congr 2015; 719:728.

[127] Pentikäinen V, Erkkilä K, Suomalainen L, Otala M, Pentikäinen MO, Parvinen M, et al. TNFalpha down-regulates the Fas ligand and inhibits germ cell apoptosis in the human testis. J Clin Endocrinol Metab 2001; 86:4480-4488.

[128] Oghbaei H, Fattahi A, Hamidian G, Sadigh-Eteghad S, Ziaee M, Mahmoudi J. A closer look at the role of insulin for the regulation of male reproductive function. Gen Comp Endocrinol 2021; 300:113643.

[129] Incalza MA, D’Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vasc Pharmacol 2018; 100:1-19.

[130] Karna KK, Shin YS, Choi BR, Kim HK, Park JK. The role of endoplasmic reticulum stress response in male reproductive physiology and pathology: A review. World J Mens Health 2020; 38:484-494.

[131] Chow CY, Avila FW, Clark AG, Wolfner MF. Induction of excessive endoplasmic reticulum stress in the drosophila male accessory gland results in infertility. PLoS One 2015; 10: e0119386. doi: 10.1371/journal.pone.0119386.

[132] Williams B, Verchot J, Dickman MB. When supply does not meet demand-ER stress and plant programmed cell death. Front Plant Sci 2014; 5:211.

[133] Liu X, Jin X, Su R, Li Z. The reproductive toxicology of male SD rats after PM2.5 exposure mediated by the stimulation of endoplasmic reticulum stress. Chemosphere 2017; 189:547-555.

[134] Cao SS, Kaufman RJ. Unfolded protein response. Curr Biol 2012; 22: R622-R626. doi: 10.1016/j.cub.2012.07.004.

[135] Vertika S, Singh KK, Rajender S. Mitochondria, spermatogenesis, and male infertility-An update. Mitochondrion 2020; 54:26-40.

[136] Pelliccione F, Micillo A, Cordeschi G, D’Angeli A, Necozione S, Gandini L, et al. Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia. Fertil Steril 2011; 95:641-646.

[137] Condorelli RA, La Vignera S, Bellanca S, Vicari E, Calogero AE. Myoinositol: Does it improve sperm mitochondrial function and sperm motility? Urology 2012; 79:1290-1295.

[138] Bejarano I, Rodríguez AB, Pariente JA. Apoptosis is a demanding selective tool during the development of fetal male germ cells. Front Cell Dev Biol 2018; 6:65.

[139] Talebi E, Karimian M, Nikzad H. Association of sperm mitochondrial DNA deletions with male infertility in an Iranian population. Mitochondrial DNA Part A 2018; 29:615-623.

[140] Agarwal A, Bertolla RP, Samanta L. Sperm proteomics: Potential impact on male infertility treatment. Expert Rev Proteomics 2016; 13:285-296.

[141] Wen X, Klionsky DJ. At a glance: A history of autophagy and cancer. Semin Cancer Biol 2020; 66:3-11.

[142] Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: Oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014; 2014:102158. doi: 10.1155/2014/102158.

[143] Xiao T, Luo J, Wu Z, Li F, Zeng O, Yang J. Effects of hydrogen sulfide on myocardial fibrosis and PI3K/AKT1-regulated autophagy in diabetic rats. Mol Med Rep 2016; 13:1765-1773.

[144] Huang C, Lin MZ, Cheng D, Braet F, Pollock CA, Chen XM. KCa3.1 mediates dysfunction of tubular autophagy in diabetic kidneys via PI3k/Akt/mTOR signaling pathways. Sci Rep 2016; 6:23884. doi: 10.1038/srep23884.

[145] Jiang Q, Linn T, Drlica K, Shi L. Diabetes as a potential compounding factor in COVID-19-mediated male subfertility. Cell Biosci 2022; 12:35.

[146] Fraczek M, Kurpisz M. Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa. J Androl 2007; 28:325-333.