Type I diabetes is associated with male infertility, and has features of a chronic inflammatory condition. Male fertility is inhibited by inflammation, and activin A is an inflammatory protein that regulates testicular function. Our aim was to evaluate the role of activin A and its binding protein, follistatin, in the Ins2(Akita) mouse, which has an inactivating mutation of the insulin gene (Ins2). Mice that are heterozygous for the Ins2(Akita) mutation may or may not develop progressive diabetes.
Diabetes was determined by increased blood glucose and HbA1c. Body and testis weight were measured in diabetic and non-diabetic heterozygous Ins2(Akita) mice and wild-type mice at 12 and 24 weeks of age. qPCR was used to evaluate expression of the Inhba gene, encoding the activin A subunit, as well as follistatin, activin receptor subunits and key inflammatory cytokines (TNF, IL-1α, IL-1β, IL-8, INF-γ), in the testis. Activin A protein was detected by immunohistochemistry.
Compared with mice that did not develop diabetes, diabetic mice showed a reduction of body weight at 12 and 24 weeks and a 30% reduction in testis weight at 24 weeks, indicating progressive testicular failure; however, testes morphology appeared normal. Testicular Inhba mRNA was significantly up-regulated (400-fold) only in diabetic mice at 12 weeks and returned to baseline at 24 weeks; however, immunolocalisation of activin A in Sertoli cells, interstitial macrophages and peritubular cells showed no changes at either time-point. Testicular follistatin, activin receptor subunits and inflammatory cytokine mRNA expression were not significantly altered by diabetes.
These data indicate that reduced insulin, leading to the development of diabetes in Ins2(Akita) mice, results in reduced testicular function, without evidence of inflammation. Activin A is implicated in this loss of function, because of the direct correlation between elevated activin A at 12 weeks, the development of diabetes and testicular damage.