CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

Junzhong Gu; Weiwei Zhang; Lida Wu; Yuchun Gu

doi:10.3389/fcell.2021.630654

CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

Junzhong Gu, Weiwei Zhang, Lida Wu^*, Yuchun Gu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	630654
Journal	Frontiers in Cell and Developmental Biology
Volume	9
DOIs	https://doi.org/10.3389/fcell.2021.630654
Publication status	Published - 15 Feb 2021

Bibliographical note

© 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.

Keywords

Cell and Developmental Biology
cystic fibrosis
CFTR
CF-related diabetes
glucose homeostasis disorder
GLUT4

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10.3389/fcell.2021.630654Licence: CC BY 3.0

CFTR Deficiency Affects Glucose Homeostasis
© 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.
Final published version, 4.42 MBLicence: CC BY 3.0

Cite this

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title = "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.",

keywords = "Cell and Developmental Biology, cystic fibrosis, CFTR, CF-related diabetes, glucose homeostasis disorder, GLUT4",

author = "Junzhong Gu and Weiwei Zhang and Lida Wu and Yuchun Gu",

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T1 - CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

AU - Gu, Junzhong

AU - Zhang, Weiwei

AU - Wu, Lida

AU - Gu, Yuchun

N1 - © 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.

PY - 2021/2/15

Y1 - 2021/2/15

N2 - 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.

AB - 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.

KW - Cell and Developmental Biology

KW - cystic fibrosis

KW - CFTR

KW - CF-related diabetes

KW - glucose homeostasis disorder

KW - GLUT4

UR - https://www.frontiersin.org/articles/10.3389/fcell.2021.630654/full

U2 - 10.3389/fcell.2021.630654

DO - 10.3389/fcell.2021.630654

M3 - Article

VL - 9

JO - Frontiers in Cell and Developmental Biology

JF - Frontiers in Cell and Developmental Biology

M1 - 630654

ER -

CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

Abstract

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