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

Yingying Ye, Mohammad Barghouth, Haiqiang Dou, Cheng Luan, Yongzhi Wang, Alexandros Karagiannopoulos, Xiaoping Jiang, Ulrika Krus, Malin Fex, Quan Zhang, Lena Eliasson, Patrik Rorsman, Enming Zhang, Erik Renström

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish
Article number4237
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Subject classification (UKÄ)

  • Cell and Molecular Biology

Fingerprint

Dive into the research topics of 'A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells'. Together they form a unique fingerprint.

Cite this