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.
Highlights
Glucagon, a 29 amino acid peptide hormone produced by pancreatic α cells, functions to increase blood glucose, opposing the actions of insulin in the peripheral tissues (Jiang and Zhang, 2003)
Pretreatment of wildtype mouse islets with a CFTR inhibitor (Inh172, 10 μM) for 48 h resulted in a significant increase in mRNA expression of both glucagon and prohormone convertase 2 (PC2) (Figures 2C,D) as compared to control islets treated with DMSO
The present results have demonstrated that CFTR plays a suppressive role in regulating glucagon production in pancreatic α cells
Summary
A 29 amino acid peptide hormone produced by pancreatic α cells, functions to increase blood glucose, opposing the actions of insulin in the peripheral tissues (Jiang and Zhang, 2003). Proglucagon is expressed in intestinal L cells or the neurons to produce glucagon-like peptide-1/2 (GLP-1/2) or oxyntomodulin by PC1/3 (Itoh et al, 1996; Nie et al, 2000; Wideman et al, 2007). Glucagon production relies on the gene transcription, as well as the enzyme conversion processes. The expression of PC2, the required enzyme for glucagon producing, depends on its promoter binding with p-CREB (Espinosa et al, 2008). P-CREB is a master factor for glucagon production at gene transcription level
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