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A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells

Ye, Yingying LU ; Barghouth, Mohammad LU ; Dou, Haiqiang ; Luan, Cheng LU ; Wang, Yongzhi LU ; Karagiannopoulos, Alexandros LU orcid ; Jiang, Xiaoping LU ; Krus, Ulrika LU ; Fex, Malin LU and Zhang, Quan , et al. (2022) In Nature Communications 13(1).
Abstract

Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (KATP) channels is a key event in this process. However, KATP channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers β-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion.... (More)

Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (KATP) channels is a key event in this process. However, KATP channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers β-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the β-cell) under experimental conditions emulating T2D (high glucose culture). β-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, β-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
issue
1
article number
4237
publisher
Nature Publishing Group
external identifiers
  • scopus:85134625105
  • pmid:35869052
ISSN
2041-1723
DOI
10.1038/s41467-022-31103-y
language
English
LU publication?
yes
id
4b1138d6-a170-4ee3-bad4-bee806b440fc
date added to LUP
2022-10-07 11:44:22
date last changed
2024-04-19 18:21:09
@article{4b1138d6-a170-4ee3-bad4-bee806b440fc,
  abstract     = {{<p>Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (K<sub>ATP</sub>) channels is a key event in this process. However, K<sub>ATP</sub> channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers β-cell electrical activity with resultant stimulation of Ca<sup>2+</sup>-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca<sup>2+</sup>-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the β-cell) under experimental conditions emulating T2D (high glucose culture). β-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, β-cell electrical activity and Ca<sup>2+</sup> elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion.</p>}},
  author       = {{Ye, Yingying and Barghouth, Mohammad and Dou, Haiqiang and Luan, Cheng and Wang, Yongzhi and Karagiannopoulos, Alexandros and Jiang, Xiaoping and Krus, Ulrika and Fex, Malin and Zhang, Quan and Eliasson, Lena and Rorsman, Patrik and Zhang, Enming and Renström, Erik}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-31103-y}},
  doi          = {{10.1038/s41467-022-31103-y}},
  volume       = {{13}},
  year         = {{2022}},
}