Hyperglycaemia is Associated with Male Infertility and Activin Dysregulation in Type 1 Diabetes

Type 1 diabetes mellitus is a chronic, lifelong condition with worldwide increasing incidence. Furthermore, it affects a growing number of men of reproductive age since 90 % of these patients are diagnosed before the age of 30. Numerous studies have indicated that diabetes mellitus disrupts fertility at various levels including altered spermatogenesis, degenerative and apoptotic changes in testes, and altered glucose metabolism in Sertoli cells, but little is known about the underlying mechanisms. In the present work, the mev-1 mutant of the nematode Caenorhabditis elegans, the Ins2Akita+/- mouse model, as well as cultured Sertoli cells were used to investigate whether hyperglycaemia alters the secretory patterns and actions of the activin family of proteins.

It was found that glucose at a concentration of 100 mM significantly reduced brood size in mev-1 nematodes. Most interestingly, diabetic Ins2Akita+/- mice showed progressive testicular disturbance, with a 30 % reduction in testis weight at 24 weeks of age, which correlated with blood glucose and HbA1c values. Diabetic mice showed significantly reduced seminiferous tubule diameters and increased spermatogenic disruption, although testes morphology appeared grossly normal. Serum LH and testosterone were similar in all groups. All Ins2Akita+/- mice showed elevation of the testicular inflammatory cytokines activin A and IL-6 at 12 and 24 weeks of age, while other key inflammatory cytokines were unaffected. Conversely, intratesticular activin B was downregulated at both time-points, while the activin regulatory proteins, follistatin and inhibin, were unchanged. At 24 weeks, activin type 2 receptor subunit expression was reduced in the diabetic mice, but Smad signalling was enhanced. Finally, investigations on in vitro cultured Sertoli cells did not show an effect of hyperglycaemia on activin A regulation or the formation of tight junctions.

In conclusion the present work demonstrates that hyperglycaemia disrupts fertility in both mev-1 nematodes and the Ins2Akita+/- mouse model. Moreover, it was shown that prolonged exposure to elevated blood glucose in the Ins2Akita+/- mice leads to progressive testicular disruption, which may be exacerbated by dysregulation of testicular activin activity rather than by dysregulation of the hypogonadal pituitary
gonadal-axis.