Hyperglycemia is associated with reduced testicular function and activin dysregulation in the Ins2Akita+/− mouse model of type 1 diabetes

- Type 1 diabetic Ins2Akita+/− mice show progressive disruption within the testis and sperm.
- Type 1 diabetes leads to a dysregulation of the activin family of proteins.
- Type 1 diabetes activates the Smad signalling pathway due to an increased phosphorylation of Smad3.
- IL-6 might be involved in the promotion of activin A signalling via suppression of activin B.

Type 1 diabetes (T1D) is associated with subfertility in men. We hypothesised that this results from inhibitory effects of chronic hyperglycemia on testicular function and used the Ins2 Akita+/− mouse model to investigate this. Diabetic mice exhibited progressive testicular dysfunction, with a 30% reduction in testis weight at 24 weeks of age. Diabetic mice showed significantly reduced seminiferous tubule diameters and increased spermatogenic disruption, although testes morphology appeared grossly normal. Unexpectedly, serum LH and intra-testicular testosterone were similar in all groups. Ins2Akita+/− mice displayed elevation of the testicular inflammatory cytokines activin A and IL-6. Intratesticular activin B was downregulated, while the activin regulatory proteins, follistatin and inhibin, were unchanged. Activin signalling, measured by pSmad3 and Smad4 production, was enhanced in diabetic mice only. These results suggest that prolonged exposure to hyperglycemia in the Ins2Akita+/− mice leads to progressive testicular disruption mediated by testicular activin activity, rather than hormonal dysregulation.