Incedal Nilsson, C. | Search bioRxiv

bioRxiv2024

Follicle stimulating hormone receptor expression in human pancreas and effects on insulin secretion: A translational study

Follicle-stimulating hormone (FSH) is traditionally known for its role in reproduction, but recent studies suggest it may also influence metabolic processes. This study aimed to examine FSH receptor (FSHR) expression in human pancreatic islets and the direct effects of FSH on insulin secretion, as well as explore FSHs metabolic role during puberty, focusing on enhanced insulin secretion during this critical period. FSHR gene and protein expression were detected in isolated human pancreatic islets and co-localized with insulin-producing beta-cells. Additionally, FSH at prepubertal (0.1 IU/L) and pubertal concentrations (10 IU/L) significantly enhanced glucose-stimulated insulin secretion (GSIS) and increased intracellular cAMP concentrations in intact human pancreatic islets. In children with obesity from the Beta-JUDO cohort (n=608), plasma FSH levels were positively associated with several insulin secretion indices, particularly in pubertal children. These findings suggest that FSH has significant metabolic roles beyond reproduction, involving insulin secretion and potentially contributing to puberty-related hyperinsulinemia and insulin resistance.

cell biology↗

bioRxiv2024

Locally released somatostatin triggers cAMP and Ca2+ signaling in primary cilia to modulate pancreatic β-cell function

Somatostatin is produced and released from {delta}-cells within pancreatic islets of Langerhans and constitutes one of the most important negative regulators of islet hormone secretion. Somatostatin receptors (SSTR) are abundantly expressed in the islet cells and coupled to Gi and lowering of intracellular cAMP. We find that both SSTR3 and SSTR5 localize to primary cilia of {beta}-cells, and that activation of these receptors lowers the ciliary cAMP concentration. cAMP produced in the cytosol can enter the cilium through diffusion, but activation of ciliary SSTR3 specifically counteracts the rise of cAMP in the cilium. Moreover, we find that islet {delta}-cells are positioned near primary cilia of the other islet cell types and that somatostatin secretion is directed towards primary cilia. While acute exposure to somatostatin caused a rapid lowering of ciliary cAMP, sustained exposure promoted nuclear entry of the cilia-dependent transcription factor GLI2 through a mechanism that operated in parallel with the canonical Hedgehog pathway and depended on ciliary Ca2+ signaling. We also find that primary cilia length is reduced in islets from human donors with type-2 diabetes, which is associated with a reduction in cilia-{delta}-cell interactions. Our findings show that islet cell primary cilia constitute an important target of somatostatin action that endows it with the ability to regulate islet cell function beyond the acute suppression of hormone release.

cell biology↗