Date of Award
Doctor of Philosophy (PhD)
Glucose regulation is important in both spermatogenesis as well as mature sperm function. The impact of diabetes on sperm function is becoming increasingly clear, though much work is still needed to elucidate the mechanism by which diabetes impairs spermatogenesis. Diabetes causes disruptions in the hypothalamic pituitary gonadal (HPG) axis, the regulatory system that controls reproduction. The HPG axis functions by secreting GnRH pulses from the hypothalamus, which bind to receptors on the pituitary and cause secretion of follicle stimulating hormone and luteinizing hormone, which then bind to receptors in the testes and facilitate spermatogenesis. Type 1 diabetes can severely impact function of the HPG axis, leading to fertility defects. Using the Akita mouse model, a genetic model of type 1 diabetes, we show that in the absence of sufficient insulin, spermatogenesis is arrested and the mice are infertile. These mice have lower levels of luteinizing hormone, follicle stimulating hormone, and testosterone. Upon treatment with either insulin or leptin, spermatogenesis is restored, despite persistent levels of high blood glucose. We conclude that the lack of insulin and leptin during the pathogenesis of type 1 diabetes causes an arrest in spermatogenesis by abrogating function of the HPG axis. It is possible that insulin and leptin have redundant roles regulating reproductive function within the hypothalamus, and a mechanism for the precise molecular targets of both insulin and leptin that restore HPG axis function remains to be determined.
We additionally found that insulin secretion occurs within the testes in addition to that secreted by the pancreas. Insulin protein was localized to the Sertoli, or "nurse", cell of the testes, which is the cell responsible for providing hormones and nutrients for sperm cells as they develop from spermatogonia to spermatozoa. Additionally, we determined the presence of glucose transporter 4 (GLUT4) on the mature sperm cell. As this is an insulin responsive transporter, this provides the potential for insulin regulation of sperm cells. We show the critical nature of both GLUT4 and the basal glucose transporter, GLUT1, in glucose uptake and fertilization capacity of sperm cells. These findings demonstrate the importance of hexose utilization to sperm cell competence, and further identification and characterization of glucose transporters in sperm cells will clarify the role of hexose metabolism during sperm cell maturation and fertilization reactions.
Chair and Committee
Kelle H. Moley
Sanjay Jain, Liang Ma, Joan Riley, Tim Schedl, David Wilson
Schoeller, Erica, "Type 1 Diabetes and the Male Reproductive Axis" (2013). Arts & Sciences Electronic Theses and Dissertations. 1038.