CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

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.

Publication DOI: https://doi.org/10.3389/fcell.2021.630654
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Additional Information: © 2021 Gu, Zhang, Wu and Gu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords: Cell and Developmental Biology,cystic fibrosis,CFTR,CF-related diabetes,glucose homeostasis disorder,GLUT4
Full Text Link:
Related URLs: https://www.fro ... 021.630654/full (Publisher URL)
PURE Output Type: Article
Published Date: 2021-02-15
Accepted Date: 2021-01-27
Submitted Date: 2020-11-19
Authors: Gu, Junzhong
Zhang, Weiwei
Wu, Lida
Gu, Yuchun (ORCID Profile 0000-0002-7558-0447)

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