Diabetes Mellitus is a chronic disease that affects important body organs in a very serious manner. The consequences of this disease turn out to be a significant problem for the patient, who tries to cope with the new condition his organism has been placed in. The most common effect of the disease, hyperglycaemia, leads over time to serious damage to various body systems, such as nerves and blood vessels. What is not widely known among the population is that diabetes may have harmful effects on the reproductive system of the men suffering from diabetes type 1 and 2 and that such a parameter could lead to or might be the reason for infertility problems for couples, for example, miscarriage or embryonic failure. AGEs is a number of products which are believed to play an important role, because their presence has been detected in increased level in diabetic men. This implies that those glycation products might play a key role in diabetic complications. Their receptor, RAGE, member of the immunoglobulin superfamily has been detected in the reproductive tract of diabetic men. Reactive oxygen species (ROS), a possible product of AGEs appear in high levels in seminal plasma and are believed to be the cause of DNA fragmentation. The objective of this review was to gather all the available material i.e. studies on diabetes mellitus in one article, to study the research which has already been conducted and the conclusions that have been drawn, in order to offer, if possible, new pathways and perspectives to the scientists, who focus on fertility problems, sometimes intractable.
Agbaje, I.M., Rogers, D.A., McVicar, C.M., McClure, N., Atkinson, A.B., Mallidis, C. and Lewis, S.E. (2007) Insulin Dependent Diabetes Mellitus: Implications for Male Reproductive Function. Human Reproduction, 22, 1871-1877. https://doi.org/10.1093/humrep/dem077
Wild, S., Roglic, G., Green, A., Sicree, R. and King, H. (2004) Global Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030. Diabetes Care, 27, 1047-1053. https://doi.org/10.2337/diacare.27.5.1047
Carlsen, E., Giwercman, A., Keiding, N. and Skakkebaek, N.E. (1992) Evidence for Decreasing Quality of Semen during Past 50 Years. British Medical Journal, 305, 609-613. https://doi.org/10.1136/bmj.305.6854.609
Morgan, S.P. (2003) Is Low Fertility a Twenty-First-Century Demographic Crisis? Demography, 40, 589-603. https://doi.org/10.1353/dem.2003.0037
Jensen, T.K., Carlsen, E., Jorgensen, N., Berthelsen, J.G., Keiding, N., Christensen, K., Petersen, J.H., Knudsen, L.B. and Skakkebaek, N.E. (2002) Poor Semen Quality May Contribute to Recent Decline in Fertility Rates. Human Reproduction, 17, 1437-1440. https://doi.org/10.1093/humrep/17.6.1437
Singh, R., Barden, A., Mori, T. and Beilin, L. (2001) Advanced Glycation End-Products: A Review. Diabetologia, 44, 129-146. https://doi.org/10.1007/s001250051591
Unoki, H., Bujo, H., Yamagishi, S., Takeuchi, M., Imaizumi, T. and Saito, Y. (2007) Advanced Glycation End Products Attenuate Cellular Insulin Sensitivity by Increasing the Generation of Intracellular Reactive Oxygen Species in Adipocytes. Diabetes Research and Clinical Practice, 76, 236-244. https://doi.org/10.1016/j.diabres.2006.09.016
Mallidis, C., Agbaje, I.M., Rogers, D.A., Glenn, J.V., Pringle, R., Atkinson, A.B., Steger, K., Stitt, A.W. and McClure, N. (2009) Advanced Glycation End Products Accumulate in the Reproductive Tract of Men with Diabetes. International Journal of Andrology, 32, 295-305. https://doi.org/10.1111/j.1365-2605.2007.00849.x
Karimi, J., Goodarzi, M.T., Tavilani, H., Khodadadi, I. and Amiri, I. (2011) Relationship between Advanced Glycation End Products and Increased Lipid Peroxidation in Semen of Diabetic Men. Diabetes Research and Clinical Practice, 91, 61-66. https://doi.org/10.1016/j.diabres.2010.09.024
Bierhaus, A. and Nawroth, P.P. (2009) Multiple Levels of Regulation Determine the Role of the Receptor for AGE (RAGE) as Common Soil in Inflammation, Immune Responses and Diabetes Mellitus and Its Complications. Diabetologia, 52, 2251-2263. https://doi.org/10.1007/s00125-009-1458-9
Bierhaus, A., Humpert, P.M., Morcos, M., Wendt, T., Chavakis, T., Arnold, B., Stern, D.M. and Nawroth, P.P. (2005) Understanding RAGE, the Receptor for Advanced Glycation End Products. Journal of Molecular Medicine, 83, 876-886. https://doi.org/10.1007/s00109-005-0688-7
Schmidt, A.M., Yan, S.D., Yan, S.F. and Stern, D.M. (2000) The Biology of the Receptor for Advanced Glycation End Products and Its Ligands. Biochimica et Biophysica Acta, 1498, 99-111. https://doi.org/10.1016/S0167-4889(00)00087-2
Chavakis, T., Bierhaus, A. and Nawroth, P.P. (2004) RAGE (Receptor for Advanced Glycation End Products): A Central Player in the Inflammatory Response. Microbes and Infection, 6, 1219-1225. https://doi.org/10.1016/j.micinf.2004.08.004
Ramasamy, R., Vannucci, S.J., Yan, S.S., Herold, K., Yan, S.F. and Schmidt, A.M. (2005) Advanced Glycation End Products and RAGE: A Common Thread in Aging, Diabetes, Neurodegeneration, and Inflammation. Glycobiology, 15, 16R-28R. https://doi.org/10.1093/glycob/cwi053
Mallidis, C., Agbaje, I., Rogers, D., Glenn, J., McCullough, S., Atkinson, A.B., Steger, K., Stitt, A. and McClure, N. (2007) Distribution of the Receptor for Advanced Glycation End Products in the Human Male Reproductive Tract: Prevalence in Men with Diabetes Mellitus. Human Reproduction, 22, 2169-2177. https://doi.org/10.1093/humrep/dem156
Karimi, J., Goodarzi, M.T., Tavilani, H., Khodadadi, I. and Amiri, I. (2011) Increased Receptor for Advanced Glycation End Products in Spermatozoa of Diabetic Men and Its Association with Sperm Nuclear DNA Fragmentation. Andrologia, 44, 280-286. https://doi.org/10.1111/j.1439-0272.2011.01178.x
Saleh, R.A., Agarwal, A., Nelson, D.R., Nada, E.A., El-Tonsy, M.H., Alvarez, J.G., Thomas, A.J. and Sharma, R.K. (2002) Increased Sperm Nuclear DNA Damage in Normozoospermic Infertile Men: A Prospective Study. Fertility and Sterility, 78, 313-318. https://doi.org/10.1016/S0015-0282(02)03219-3
Mahfouz, R., Sharma, R., Sharma, D., Sabanegh, E. and Agarwal, A. (2009) Diagnostic Value of the Total Antioxidant Capacity (TAC) in Human Seminal Plasma. Fertility and Sterility, 91, 805-811. https://doi.org/10.1016/j.fertnstert.2008.01.022
Nakamura, H., Kimura, T., Nakajima, A., Shimoya, K., Takemura, M., Hashimoto, K., et al. (2002) Detection of Oxidative Stress in Seminal Plasma and Fractionated Sperm from Subfertile Male Patients. European Journal of Obstetrics & Gynecology and Reproductive Biology, 105, 155-160. https://doi.org/10.1016/S0301-2115(02)00194-X
Aitken, R.J. and Sawyer, D. (2003) The Human Spermatozoon—Not Waving but Drowning. In: Robaire, B. and Hales, B.F., Eds., Advances in Experimental Medicine and Biology, Springer, Boston, 85-98. https://doi.org/10.1007/978-1-4419-9190-4_8
Wautier, J.L. and Schmidt, A.M. (2004) Protein Glycation: A Firm Link to Endothelial Cell Dysfunction. Circulation Research, 95, 233-238. https://doi.org/10.1161/01.RES.0000137876.28454.64
Chekir, C., Nakatsuka, M., Noguchi, S., Konishi, H., Kamada, Y., Sasaki, A., Hao, L. and Hiramatsu, Y. (2006) Accumulation of Advanced Glycation End Products in Women with Preeclampsia: Possible Involvement of Placental Oxidative and Nitrative Stress. Placenta, 27, 225-233. https://doi.org/10.1016/j.placenta.2005.02.016
Roessner, C., Paasch, U., Kratzsch, J., Glander, H.J. and Grunewald, S. (2012) Sperm Apoptosis Signalling in Diabetic Men. Reproductive Biomedicine Online, 25, 292-299. https://doi.org/10.1016/j.rbmo.2012.06.004
Yan, S.F., Barile, G.R., D’Agati, V., Du Yan, S., Ramasamy, R. and Schmidt, A.M. (2007) The Biology of RAGE and Its Ligands: Uncovering Mechanisms at the Heart of Diabetes and Its Complications. Current Diabetes Reports, 7, 146-153. https://doi.org/10.1007/s11892-007-0024-4
Chohan, K.R., Griffin, J.T., Lafromboise, M., De Jonge, C.J. and Carrell, D.T. (2006) Comparison of Chromatin Assays for DNA Fragmentation Evaluation in Human Sperm. Journal of Andrology, 27, 53-59. https://doi.org/10.2164/jandrol.05068
Evenson, D.P. and Wixon, R. (2006) Clinical Aspects of Sperm DNA Fragmentation Detection and Male Infertility. Theriogenology, 65, 979-991. https://doi.org/10.1016/j.theriogenology.2005.09.011
Dominguez-Fandos, D., Camejo, M.I., Ballesca, J.L. and Oliva, R. (2007) Human Sperm DNA Fragmentation: Correlation of TUNEL Results as Assessed by Flow Cytometry and Optical Microscopy. Cytometry Part A, 71A, 1011-1018. https://doi.org/10.1002/cyto.a.20484
Bungum, M., Humaidan, P., Spano, M., Jepson, K., Bungum, L. and Giwercman, A. (2004) The Predictive Value of Sperm Chromatin Structure Assay (SCSA) Parameters for the Outcome of Intrauterine Insemination, IVF and ICSI. Human Reproduction, 19, 1401-1408. https://doi.org/10.1093/humrep/deh280
Sergerie, M., Laforest, G., Bujan, L., Bissonnette, F. and Bleau, G. (2005) Sperm DNA Fragmentation: Threshold Value in Male Fertility. Human Reproduction, 20, 3446-3451. https://doi.org/10.1093/humrep/dei231
Baccetti, B., La Marca, A., Piomboni, P., Capitani, S., Bruni, E., Petraglia, F. and De Leo, V. (2002) Insulin-Dependent Diabetes in Men Is Associated with Hypothalamo-Pituitary Derangement and with Impairment in Semen Quality. Human Reproduction, 17, 2673-2677. https://doi.org/10.1093/humrep/17.10.2673
Jutte, N.H., Grootegoed, J.A., Rommerts, F.F. and van der Molen, H.J. (1981) Exogenous Lactate Is Essential for Metabolic Activities in Isolated Rat Spermatocytes and Spermatids. Journal of Reproduction and Fertility, 62, 399-405. https://doi.org/10.1530/jrf.0.0620399
Mita, M., Price, J.M. and Hall, P.F. (1982) Stimulation by Follicle-Stimulating Hormone of Synthesis of Lactate by Sertoli Cells from Rat Testis. Endocrinology, 110, 1535-1541. https://doi.org/10.1210/endo-110-5-1535
Boussouar, F. and Benahmed, M. (2004) Lactate and Energy Metabolism in Male Germ Cells. Trends in Endocrinology & Metabolism, 15, 345-350. https://doi.org/10.1016/j.tem.2004.07.003
Rato, L., Alves, M.G., Socorro, S., Duarte, A.I., Cavaco, J.E. and Oliveira, P.F. (2012) Metabolic Regulation is Important for Spermatogenesis. Nature Reviews Urology, 9, 330-228. https://doi.org/10.1038/nrurol.2012.77
Alves, M.G., Socorro, S., Silva, J., Barros, A., Sousa, M., Cavaco, J.E. and Oliveira, P.F. (2012) In Vitro Cultured Human Sertoli Cells Secrete High Amounts of Acetate that Is Stimulated by 17β-Estradiol and Suppressed by Insulin Deprivation. Biochimica et Biophysica Acta, 1823, 1389-1394. https://doi.org/10.1016/j.bbamcr.2012.06.002
Oliveira, P.F., Alves, M.G., Rato, L., Laurentino, S., Silva, J., Sá, R., Barros, A., Sousa, M., Carvalho, R.A., Cavaco, J.E. and Socorro, S. (2012) Effect of Insulin Deprivation on Metabolism and Metabolism-Associated Gene Transcript Levels of in Vitro Cultured Human Sertoli Cells. Biochimica et Biophysica Acta, 1820, 84-89. https://doi.org/10.1016/j.bbagen.2011.11.006
Hall, P.F. and Mita, M. (1984) Influence of Follicle-Stimulating Hormone on Glucose Transport by Cultured Sertoli Cells. Biology of Reproduction, 31, 863-869. https://doi.org/10.1095/biolreprod31.5.863
Angulo, C., Rauch, M.C., Droppelmann, A., Reyes, A.M., Slebe, J.C., Delgado-Lopez, F., Guaiquil, V.H. and Vera, J.C. (1998) Concha, II, Hexose Transporter Expression and Function in Mammalian Spermatozoa: Cellular Localization and Transport of Hexoses and Vitamin C. Journal of Cellular Biochemistry, 71, 189-203. https://doi.org/10.1002/(SICI)1097-4644(19981101)71:2%3C189::AID-JCB5%3E3.0.CO;2-R
Seethalakshmi, L., Menon, M. and Diamond, D. (1987) The Effect of Streptozotocin-Induced Diabetes on the Neuroendocrine-Male Reproductive Tract Axis of the Adult Rat. The Journal of Urology, 138, 190-194. https://doi.org/10.1016/S0022-5347(17)43042-4
Muralidhara, S.B. (2007) Early Oxidative Stress in Testis and Epididymal Sperm in Streptozotocin-Induced Diabetic Mice: Its Progression and Genotoxic Consequences. Reproductive Toxicology, 23, 578-587. https://doi.org/10.1016/j.reprotox.2007.02.001
Cummins, J.M., Jequier, A.M. and Kan, R. (1994) Molecular Biology of Human Male Infertility: Links with Aging, Mitochondrial Genetics, and Oxidative Stress? Molecular Reproduction and Development, 37, 345-362. https://doi.org/10.1002/mrd.1080370314
St John, J.C., Jokhi, R.P. and Barratt, C.L. (2005) The Impact of Mitochondrial Genetics on Male Infertility. International Journal of Andrology, 28, 65-73. https://doi.org/10.1111/j.1365-2605.2005.00515.x
Lestienne, P., Reynier, P., Chretien, M.F., et al. (1997) Oligoasthenospermia Associated with Multiple Mitochondrial DNA Rearrangements. Molecular Human Reproduction, 3, 811-814. https://doi.org/10.1093/molehr/3.9.811
Kao, S.H., Chao, H.T. and Wei, Y.H. (1998) Multiple Deletions of Mitochondrial DNA Are Associated with the Decline of Motility and Fertility of Human Spermatozoa. Molecular Human Reproduction, 4, 657-666. https://doi.org/10.1093/molehr/4.7.657
Spiropoulos, J., Turnbull, D.M. and Chinnery, P.F. (2002) Can Mitochondrial DNA Mutations Cause Sperm Dysfunction? Molecular Human Reproduction, 8, 719-721. https://doi.org/10.1093/molehr/8.8.719
Miller, D., Briggs, D., Snowden, H., Hamlington, J., Rollinson, S., Lilford, R., et al. (1999) A Complex Population of RNAs Exists in Human Ejaculate Spermatozoa: Implications for Understanding Molecular Aspects of Spermatogenesis. Gene, 237, 385-392. https://doi.org/10.1016/S0378-1119(99)00324-8
Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA Profiles of Normal Fertile Men. The Lancet, 360, 772-777. https://doi.org/10.1016/S0140-6736(02)09899-9
Ostermeier, G.C., Goodrich, R.J., Diamond, M.P., Dix, D.J. and Krawetz, S.A. (2005) Toward Using Stable Spermatozoal RNAs for Prognostic Assessment of Male Factor Fertility. Fertility and Sterility, 83, 1687-1694. https://doi.org/10.1016/j.fertnstert.2004.12.046
Platts, A.E., Dix, D.J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J.C., et al. (2007) Success and Failure in Human Spermatogenesis as Revealed by Teratozoospermic RNAs. Human Molecular Genetics, 16, 763-773. https://doi.org/10.1093/hmg/ddm012
Van Houten, B., Woshner, V. and Santos, J.H. (2006) Role of Mitochondrial DNA in Toxic Responses to Oxidative Stress. DNA Repair, 5, 145-152. https://doi.org/10.1016/j.dnarep.2005.03.002
Shoffner, J.M. and Wallace, D.C. (1994) Oxidative Phosphorylation Diseases and Mitochondrial DNA Mutations: Diagnosis and Treatment. Annual Review of Nutrition, 14, 535-568. https://doi.org/10.1146/annurev.nu.14.070194.002535
Bennetts, L.E. and Aitken, R.J. (2005) A Comparative Study of Oxidative DNA Damage in Mammalian Spermatozoa. Molecular Reproduction and Development, 71, 77-87. https://doi.org/10.1002/mrd.20285
Lewis, S.E., O’Connell, M., Stevenson, M., et al. (2004) An Algorithm to Predict Pregnancy in Assisted Reproduction. Human Reproduction, 19, 1385-1394. https://doi.org/10.1093/humrep/deh227