Abstract
Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF-related diabetes (CFRD) is one of the most prevalent comorbidities of CF. Altered glucose homeostasis has been reported in CF patients. The mechanism has not been fully elucidated. Besides the consequence of pancreatic endocrine dysfunction, we focus on insulin-responsive tissues and glucose transportation to explain glucose homeostasis alteration in CFRD. Herein, we found that CFTR knockout mice exhibited insulin resistance and glucose tolerance. Furthermore, we demonstrated insulin-induced glucose transporter 4 (GLUT4) translocation to the cell membrane was abnormal in the CFTR knockout mice muscle fibers, suggesting that defective intracellular GLUT4 transportation may be the cause of impaired insulin responses and glucose homeostasis. We further demonstrated that PI(4,5)P2 could rescue CFTR related defective intracellular GLUT4 transportation, and CFTR could regulate PI(4,5)P2 cellular level through PIP5KA, suggesting PI(4,5)P2 is a down-stream signal of CFTR. Our results revealed a new signal mechanism of CFTR in GLUT4 translocation regulation, which helps explain glucose homeostasis alteration in CF patients.
Highlights
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in the Caucasian population
Second, and amplifying phase secretion in CF islets have been reported by numerous researchers (Sun et al, 2017; Kelly et al, 2019); it was found that serum insulin level of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)−/− mice showed no significant difference than WT and HET mice by ELISA (Figure 1D), indicating that the amount of insulin secretion by CFTR−/− mice was normal before CF-related diabetes (CFRD)
We discovered a previously unrecognized regulation effect of CFTR to the glucose transporter 4 (GLUT4) cellular translocation, which provides a new perspective on the mechanism of CFRD
Summary
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in the Caucasian population. It is caused by mutations in the CFTR gene. It is crucial to study the mechanism of CFRD thoroughly. One of the prevailing mechanistic beliefs is that CFRD results from defective insulin secretion of pancreatic β-cell, which is due to the combination of chronic pancreatitis and eventual loss of the islet cells (Cucinotta et al, 1994; Marshall et al, 2005; Costa et al, 2007; Mohan et al, 2009; Guo et al, 2014). Autopsy data confirmed the eventual loss of islet tissue and decreased β-cell
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