Abnormal CFTR Affects Glucagon Production by Islet α Cells in Cystic Fibrosis and Polycystic Ovarian Syndrome

Abstract

Glucagon, produced by islet α cells, functions to increase blood glucose. Abnormal glucose levels are often seen in cystic fibrosis (CF), a systematic disease caused by mutations of the CF transmembrane conductance regulator (CFTR), and in polycystic ovarian syndrome (PCOS), an endocrine disorder featured with hyperandrogenism affecting 5–10% women of reproductive age. Here, we explored the role of CFTR in glucagon production in α cells and its possible contribution to glucagon disturbance in CF and PCOS. We found elevated fasting glucagon levels in CFTR mutant (DF508) mice compared to the wildtypes. Glucagon and prohormone convertase 2 (PC2) were also upregulated in CFTR inhibitor-treated or DF508 islets, as compared to the controls or wildtypes, respectively. Dihydrotestosterone (DHT)-induced PCOS rats exhibited significantly lower fasting glucagon levels with higher CFTR expression in α cells compared to that of controls. Treatment of mouse islets or αTC1-9 cells with DHT enhanced CFTR expression and reduced the levels of glucagon and PC2. The inhibitory effect of DHT on glucagon production was blocked by CFTR inhibitors in mouse islets, and mimicked by overexpressing CFTR in αTC1-9 cells with reduced phosphorylation of the cAMP/Ca2+ response element binding protein (p-CREB), a key transcription factor for glucagon and PC2. These results revealed a previously undefined role of CFTR in suppressing glucagon production in α-cells, defects in which may contribute to glucose metabolic disorder seen in CF and PCOS.

Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet

“…The lack of tools is further exacerbated by the low and heterogeneous expression pattern of CFTR compared to the usual target tissues, i.e., lung, gut and exocrine pancreas [8][9][10], in the pancreatic islet; clearly adding important methodological obstacles for its detection and subsequent characterization. As a result, immunoreactive CFTR and/or its function have not been detected in the pancreatic islet by some [11,12] yet it has been by others [13][14][15][16][17][18]. Islet or β-cell CFTR mRNA expression has been recently interrogated [11], or not found [19] based on RNA-sequencing data.…”

Elevation of antimüllerian hormone in women with polycystic ovary syndrome undergoing assisted reproduction: effect of insulin

“…olycystic ovary syndrome (PCOS), characterized by ovarian follicular arrest and hormonal disturbance, is a leading cause of female infertility, affecting 5%-10% women of reproductive age (1,2). A variety of hormones are dysregulated in PCOS, including excessive androgens (3), hypersecreted LH (4), reduced FSH (4), and disturbed metabolic hormones (e.g., insulin and glucagon) (5). In particular, insulin resistance accompanied by compensatory hyperinsulinemia is commonly found in women with PCOS (up to 75% of lean and 95% of overweight) (6,7).…”

Mechanisms of Post-Pancreatitis Diabetes Mellitus and Cystic Fibrosis-Related Diabetes: A Review of Preclinical Studies

“…Unlike beta cells, however, much less information is available on the role of CFTR in alpha cells. In pancreatic alpha cells, CFTR inhibits glucagon secretion (165)(166)(167), presumably by stimulating K ATP channels (167). Patients with CF exhibit dysregulated glucagon secretion, which probably also contributes to abnormalities in their glucose tolerance.…”