Background: Follicle-stimulating hormone (FSH) plays a key role in reproduction. The G-protein coupled FSH receptor (FSHR), is expressed primarily in gonads, and specifically binds FSH. FSHR is also expressed in vascular endothelium, osteoclasts, adipose tissue, monocytes and rodent pancreatic islets. Elevated FSH levels are associated with development of obesity, insulin resistance, osteoporosis, and cardiovascular disease. In a recent study, we showed that high FSH levels in prepubertal children with obesity are associated with increased risk of metabolic syndrome development during puberty. FSH levels correlated positively with plasma insulin levels, in this study. It is not known if the FSHR is expressed in human pancreatic islets and if so, whether binding of FSH to the receptor directly affects insulin secretion.
Hypotheses: FSHR is expressed in human islets and FSH acts via islet FSHR to potentiate glucose-stimulated insulin secretion.
Objective: To investigate FSHR expression in human pancreatic islets and effects of FSH on insulin secretion.
Methods: Human pancreatic islets were obtained from brain-dead donors without known metabolic disease from the Uppsala University Islet Transplantation Unit and from Prodo Lab Inc (CA). FSHR gene expression was assessed by quantitative polymerase chain reaction (qPCR). FSHR protein expression was evaluated by confocal immunofluorescence microscopy. Intracellular cAMP concentration changes were recorded from intact human islets transduced with an adenoviral vector encoding the FRET-based sensor Epac-SH187. Islets were perfused and insulin secretion was measured dynamically at 5.5 and 11 mM glucose and in the presence (10 IU/l, pubertal level) or absence of human FSH (Sigma-Aldrich, St. Louis, MO). Insulin was measured by ELISA (Mercodia AB, Uppsala, Sweden) and normalized to total protein content (DC protein assay, Bio-Rad Laboratories, Hercules, CA, USA).
Results: FSHR gene and protein expression were detected in human pancreatic islets primarily localized to insulin-producing pancreatic beta-cells. Insulin secretion at 5.5 mM glucose from isolated human islets was not affected by FSH. In contrast, when the glucose concentration was increased to 11 mM in the continued presence of 10 IU/l FSH, approximately 2-fold accentuated insulin secretion was observed. The addition of FSH (10 IU/l) in the presence of 11 mM glucose was also associated with increased intracellular cAMP concentration.
Conclusion: The follicle-stimulating hormone receptor is expressed in human pancreatic islet beta-cells and its activation increases glucose stimulated insulin secretion, likely via increased cAMP production.
15 Sep 2022 - 17 Sep 2022