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The Calcium Channel Subunit Gamma-4 as a Novel Regulator of MafA in Pancreatic Beta-Cell Controls Glucose Homeostasis

Wu, Rui LU ; Karagiannopoulos, Alexandros LU orcid ; Eliasson, Lena LU orcid ; Renström, Erik LU ; Luan, Cheng LU and Zhang, Enming LU (2022) In Biomedicines 10(4).
Abstract

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are high-risk factors of diabetes development and may be caused by defective insulin secretion in pancreatic beta-cells. Glucose-stimulated insulin secretion is mediated by voltage-gated Ca2+ (CaV) channels in which the gamma-4 subunit (CaVγ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of CaVγ4 in controlling glucose homeostasis by employing the CaVγ4-/- mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that CaVγ4-/- mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated... (More)

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are high-risk factors of diabetes development and may be caused by defective insulin secretion in pancreatic beta-cells. Glucose-stimulated insulin secretion is mediated by voltage-gated Ca2+ (CaV) channels in which the gamma-4 subunit (CaVγ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of CaVγ4 in controlling glucose homeostasis by employing the CaVγ4-/- mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that CaVγ4-/- mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated insulin secretion is blunted in CaVγ4-/- mouse islets. Remarkably, CaVγ4 deletion results in reduced expression of the transcription factor essential for beta-cell maturation, MafA, on both mRNA and protein levels in islets from human donors and CaVγ4-/- mice, as well as in INS-1 832/13 cells. Moreover, we prove that CaMKII is responsible for mediating this regulatory pathway linked between CaVγ4 and MafA, which is further confirmed by human islet RNA-seq data. We demonstrate that CaVγ4 is a key player in preserving normal blood glucose homeostasis, which sheds light on CaVγ4 as a novel target for the treatment of prediabetes through correcting the impaired metabolic status.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biomedicines
volume
10
issue
4
article number
770
publisher
MDPI AG
external identifiers
  • pmid:35453520
  • scopus:85127899586
ISSN
2227-9059
DOI
10.3390/biomedicines10040770
language
English
LU publication?
yes
id
ad65b17f-ded3-486e-bbe6-8e4ab95df160
date added to LUP
2022-04-26 12:23:00
date last changed
2025-12-01 17:43:12
@article{ad65b17f-ded3-486e-bbe6-8e4ab95df160,
  abstract     = {{<p>Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are high-risk factors of diabetes development and may be caused by defective insulin secretion in pancreatic beta-cells. Glucose-stimulated insulin secretion is mediated by voltage-gated Ca2+ (CaV) channels in which the gamma-4 subunit (CaVγ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of CaVγ4 in controlling glucose homeostasis by employing the CaVγ4-/- mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that CaVγ4-/- mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated insulin secretion is blunted in CaVγ4-/- mouse islets. Remarkably, CaVγ4 deletion results in reduced expression of the transcription factor essential for beta-cell maturation, MafA, on both mRNA and protein levels in islets from human donors and CaVγ4-/- mice, as well as in INS-1 832/13 cells. Moreover, we prove that CaMKII is responsible for mediating this regulatory pathway linked between CaVγ4 and MafA, which is further confirmed by human islet RNA-seq data. We demonstrate that CaVγ4 is a key player in preserving normal blood glucose homeostasis, which sheds light on CaVγ4 as a novel target for the treatment of prediabetes through correcting the impaired metabolic status.</p>}},
  author       = {{Wu, Rui and Karagiannopoulos, Alexandros and Eliasson, Lena and Renström, Erik and Luan, Cheng and Zhang, Enming}},
  issn         = {{2227-9059}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{MDPI AG}},
  series       = {{Biomedicines}},
  title        = {{The Calcium Channel Subunit Gamma-4 as a Novel Regulator of MafA in Pancreatic Beta-Cell Controls Glucose Homeostasis}},
  url          = {{http://dx.doi.org/10.3390/biomedicines10040770}},
  doi          = {{10.3390/biomedicines10040770}},
  volume       = {{10}},
  year         = {{2022}},
}