Evidence that extrapancreatic insulin production is involved in the mediation of sperm survival

Evidence is presented for expression of the insulin receptor on the surface of mammalian spermatozoa as well as transcripts for the receptor substrate adaptor proteins (IRS1-4) needed to mediate insulin action. Exposure to this hormone resulted in insulin receptor phosphorylation (pTyr972), activation of AKT (pSer473) and the stimulation of sperm motility. Intriguingly, the male germ line is also shown to be capable of generating insulin, possessing the relevant mRNA transcript and expressing strong immunocytochemical signals for both insulin and C-peptide. Insulin could be released from the spermatozoa by sonication in a concentration-dependent manner but was not secreted in response to glucose, fructose or stimulation with progesterone. However, insulin release could be induced by factors present in human uterine lavages. Furthermore, the endometrium was also shown to possess the machinery for insulin production and action (mRNA, insulin, C-peptide, proprotein convertase and insulin receptor), releasing insulin into the uterine lumen prior to ovulation. These studies emphasize the fundamental importance of extra-pancreatic insulin in regulating the reproductive process, particularly in the support of spermatozoa on their perilous voyage to the site of fertilization.