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

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.

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“…Support for this comes from recent literature findings, which have found that mechanosensitivity is an integral feature of rod photoreceptors and its possible role in retinal GCL damage. , Consistent with these reports, studies also suggest that T1DM rats have an exaggerated mechanoreflex, which was attenuated by blocking mechano-gated Piezo channels; similarly, inhibition of Piezo1 protected against thrombosis in a type 2 diabetes mellitus setting . Ye and co-worker recently established the role of Piezo1 as an important physiological regulator of insulin secretion. While iron is an essential ion for life, its overload, called “hemochromatosis”, can cause serious damage to various vital organs and is known to accelerate DC and DR. , Among the most well-known are the signaling pathways regulating hepcidin and retinal renin angiotensin system (RAS) involved in retinal and hepatic iron overload leading to organ damage. , On the other hand, disruption of the blood–aqueous barrier leads to iron overload in the lens that comes from the intraocular fluids .…”

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