Men with Diabetes Might be Liable to Increased Infertility Risk

Glucose Metabolism Affects Reproductive Mechanism in Men

Mankind is inching towards worsening quality of life with the proliferation of disruptive diseases and health problems. Diabetes and infertility are two of the common obstacles faced by many individuals in today’s life. Juvenile diabetes is extremely common these days and a greater number of middle-aged people are victims of type 2 diabetes mellitus (T2DM) owing to inappropriate lifestyle practises and social factors. Fertility rates don’t seem to be positive either-plenty of couples prefer ART methods for conception failing natural conception and there are others who don’t succeed in either. This again, is due to diminishing sperm quality, delayed pregnancies due to career/financial demands and likewise. Statistics show that almost 17% couples seek medical help for fertility treatment indicating deterioration in human reproductive health. This has elicited the attention of researchers and people worldwide on the reasons behind decreasing sperm quality and male fertility rates.

There has been ample discussion on obesity, sedentariness and lifestyle as the key reasons behind decreasing fertility rates in men but the impact of diabetes mellitus (DM) on male reproductive health remains arguable. Worldwide, there are more than 400 million people who suffer from diabetes, both type 1 and type 2. Each of the types has a different history behind its prevalence and brings about different effects on the human body. DM has the ability to garner long-term damage, dysfunction and failure of various organs including loss of vision, renal failure, foot amputation, foot ulcers, cardiovascular symptoms and sexual dysfunction. Diabetes causes substantial effect on the male reproductive system and glucose metabolism is an important event in spermatogenesis. There exists a number of studies, both in animals and humans, that confirm the deleterious effect of diabetes on sexual functions such as semen parameters, nuclear DNA fragments and chromatin quality. Animal models present us with better perspectives in this regard-all of them show decreased fecundity (potential to reproduce). We also have a study which shows that DM is linked to important changes in the metabolomic profile of the testis and a higher percentage of both sperm nuclear and mitochondrial DNA damage.

Diabetes Effect on Epigenetic Regulation of Spermatogenesis
Sperms primarily focus on transferring male haploid DNA to female DNA via a series of mechanisms. Sperm cells are used to trigger fertilization with the female egg and need energy to maintain motion competence after epididymal maturation as they are immobile in the testis. Much adenosine triphosphate (ATP) in sperms is consumed for maintaining this motility. They seek energy mainly in the form of sugar including glucose, fructose and mannose via two metabolic pathways namely anaerobic glycolysis and oxidative phosphorylation. Glucides are polar molecules rich I -OH groups capable of passing the lipidic bilayer in a very slow and inefficient way. An important role of supplying cells with energy is realized by different membrane proteins that can actively (sodium-dependent glucose transporters [SGLT]) or passively (glucose transporters [GLUT]) transport hexose through lipid bilayer. Proteins belonging to SGLT are primary transporters of sugars, especially glucose; proteins of GLUT too transport sugar besides other hexoses such as fructose and mannitol, vitamins and amino sugars. GLUTs mainly function to help the sperm adapt to changes in the environment, metabolic requirements etc but the presence of an abnormal environment such as diabetes can cause dysfunction in nutrient transport leading to decreased fertility rates and adverse foetal outcomes. A study examining GLUT expression of GLUT8 and GLUT9 in sperm and testes in 2 genetically modified diabetic rats showed that rats lacking GLUT9 protein had low sperm motility and decreased fertilization rates. Absence of insulin or hyperglycaemia was the reason behind impaired GLUT9 transcription which shows that insulin and glucose are important to sperm maturation. Treating these mice with insulin showed that sperm motility and concentration improved significantly proving that insulin played a dominant role in sperm quality. The study also showed that it was glucose and not fructose that was needed for fertilization-for sperm oocyte binding and embryo viability in the mouse.

Diabetes Impact on Male Fertility
Type 1 and type 2 diabetes, both affect testicular function and spermatogenesis. Type 1 diabetes brings about structural defects with nuclear and mitochondrial DNA fragmentation, reduced motility and decreased zona pellucida binding in sperm cells. Polyamines in sperms have antioxidant capability, are antiglycating agents and offer protection against structural/functional advanced glycation end products (AGE) modifications. Changes in antioxidant expression could be a triggering factor for oxidative stress (OS) and the number of sperms displaying the receptor for advanced glycation end product (RAGE). The protein content in sperms is normally higher than what is found in the sperm of type 1 diabetic men. Increase in AGE in seminal plasma of type 1 and type 2 diabetic subjects shows that glycation and increased OS play eminent roles in reproductive system dysfunction. Diabetic people suffer from increased levels of RAGE protein and DNA fragmentation in sperms which suggests clearly that RAGE plays a pivotal role in disturbing sexual functionality in diabetic men. Motility rates of these sperms too change owing to alterations in mitochondrial DNA in diabetes.

Researchers have proved that seminal plasma nitrate/nitrite levels and 8-hydroxydeoxyguanosine (8-OHdG) levels are observed to be drastically high in the diabetic group-such high nitrate/nitrite levels must be the work of ROS-induced DNA damage that’s related to 8-OHdG levels but not sperm parameters. But this does not affect sperm motility in any way. On the other hand, malondialdehyde, one of the final products of lipid peroxidation and well-known markers of OS is present in abundance in the semen of infertile men with T2DM and has also been negatively linked to sperm density, total sperm count, progressive motility and normal forms. Controlling glycemic levels in such patients helps in preventing sperm damage. A research by Paasch et al. showed that type 1 diabetes, type 2 diabetes and obesity are accompanied by multiple changes in the sperm proteome.

Absence of normal insulin levels decreases testosterone and Leydig cell function and also FSH, which in turn affects LH levels. Such FSH decrease affects sperm output and fertility. Streptozotocin (STZ) injected in mice for a month showed metabolic adaptations such as increase in efficiency of mitochondrial ATP production. Research shows that fertility rates in the STZ-injected mice were much below than that in the normal group. Even in the fertilized zygotes, embryo development rates to the blastocyst stage in two diabetic models were lower than that in controls. STZ-injected rats also displayed defective sperm maturation and insulin replacement prevented these changes partially or completely.  

Impact of Diabetes on Assisted Reproduction Treatment (ART)
A research set forth to analyse whether presence of diabetes in men affected ART outcomes. Men who reported as diabetic the first time they visited the centre for fertility treatment were considered for the study. Information fetched was split into three data stream which included male, female and assisted reproduction treatment. Information regarding date of birth, diabetes type and duration, smoking status and nature of the treatment was recorded for men. Sperm data regarding volume of ejaculate, sperm concentration and extent of liquefaction were also noted. In the case of female, information on number of cycles, number of eggs harvested, number fertilized, whether embryos were frozen and other clinical outcomes were measured. There were 80 couples among whom 18 diabetic men (aged 28-51 years) and their partner (aged 24-41 years) had undergone assisted reproductive treatment between 2004 and 2007.

Reasons for infertility was attributed to idiopathic male factor for 4 couples, polycystic ovary syndrome for 2 couples, unexplained causes for 10 couples, hyperprolactinaemia for one couple and endometriosis for one couple. While it was the first child for all female participants one subject had three previous miscarriages and another one had suffered from one miscarriage. On an average, men had suffered from diabetes for around 17 years. 38% reported that their levels were well-controlled, 27% told that it was poorly controlled and the other 35% reported that they were unaware of the status. Of the 18 diabetic males, 2 (11%) of them had retrograde ejaculation and two were azoospermic, none of them tested positive for antibody presence, liquification was normal for 13 subjects, reduced motility was present in 80% subjects and 60% showed decrease in percentage of normal forms.
Of the 18 couples who opted for ART 5 of them underwent 10 circles of IVF, 12 underwent 19 cycles of intracytoplasmic sperm injection (ICSI) and one couple underwent two cycles of IVF and one cycle of ICSI. 5 couples who started with ICSI opted for frozen embryo transfer (FET) (seven cycles). For IVF, a 68% fertilization rate was possible for 66 harvested eggs. In spite of 12 embryo transfers there was no signs of pregnancy. In the case of ICSI a fertilization rate of 62% was achieved for 198 harvested eggs. Here, despite 18 embryonic transfers there was only one clinical pregnancy represented and a combined IVF/ICSI clinical pregnancy rate per embryo transfer of 3.3% for fresh cycles occurred. FET showed better outcomes with 29% clinical pregnancy rate and no miscarriage or complications were present in any of the deliveries.

Type 1 & Type 2 Diabetes Effects on Sperm Quality
Here, study participants were divided into three groups-38 patients with DM1, 55 with DM2 and 100 healthy fertile subjects as controls. DM1 patients were further divided into three groups depending on the duration of the disease- <5 years, between 5 and 10 years and >10 years. All the participants underwent a sperm analysis, a flow cytometric sperm analysis, assessment of the presence of urogenital infection, oxidative stress evaluation and an andrological evaluation. Sperm parameters showed considerable difference between the three groups. Individuals with DM1 and DM2 showed decreased sperm concentration compared to controls while DM2 participants showed slightly lower sperm quality compared to DM1 individuals. Motility rates were lower in DM1 and DM2 individuals compared to controls, much lower in DM1 compared to DM2. Semen fluid volume was comparatively lower in patients with DM1 though not much significant in DM2 participants when compared to controls. Sperms having normal forms were in lower percentage compared to controls. Sperm vitality decreased in DM2 participants and one patient had higher degree of DNA fragmentation spermatozoa compared to DM1 patients and controls.

This study showed that type 1 diabetes patients have low ejaculate volume due to increased oxidative stress which can also alter other conventional sperm parameters. Type 2 diabetes patients suffer from increased concentration of seminal fluid leukocytes that raise OS levels damaging sperm parameters, sperm DNA and vitality.

All these show that glucose metabolism plays a pivotal role in sperm cells and any type of diabetes could have detrimental effects on male fertility, specifically sperm quality.

References
Diabetes Mellitus & Infertility: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980990/pdf/fendo-09-00268.pdf

Male Diabetes Mellitus & Assisted Reproduction Treatment Outcome: https://www.rbmojournal.com/article/S1472-6483(10)00652-8/pdf

The Effects of Diabetes on Male Fertility & Epigenetic Regulation During Spermatogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814953/pdf/AJA-17-948.pdf