Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet beta-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates G alpha s via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate G alpha i to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes. Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic beta-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.