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

ABSTRACT: PIEZO1 is a mechanosensitive ion channel involved in the regulation of a diverse range of physiological responses. We examined the role of the mechanosensor ion channel PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells. PIEZO1 expression is elevated in β-cells from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db 48 mouse). Silencing of Piezo1 inhibits glucose-induced Ca2+ signaling and insulin secretion. PIEZO1 translocates from the cytosol and plasmalemma into the nucleus in cells cultured at high glucose, experimental conditions emulating diabetes. The translocation of PIEZO1 into the nucleus in response to hyperglycemia suggests that PIEZO1 might be involved in transcriptional control in addition to serving as a mechanosensor in the plasma membrane. To address this, we performed mRNA sequencing in INS-1 832/13 cells to determine which genes are regulated by Piezo channels. Overall, we found 3292, 1656, and 1920 genes were significantly differentially expressed after silencing Piezo1, Piezo2, or both genes (adj.p-value < 0.05). Among these, the expression of the gene encoding cocaine- and amphetamine-regulated transcript (Cartpt) was increased >15-fold. We confirmed this effect by qPCR, which indicated a corresponding stimulation of expression. In insulin-secreting INS-1 832/13 cells, Cart has been reported to influence the expression and release of insulin. Thus, the impact of PIEZO1 on β-cell function may not be limited to electrical excitability but these changes are likely to operate on a slower timescale than the acute/electrical effects.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE197449 | GEO | 2022/05/20

REPOSITORIES: GEO

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Project description:Obesity-linked type 2 diabetes (T2D) is a major health problem of global epidemic proportions. The onset of T2D is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. In a commonly used model of obesity-linked T2D, the db/db mouse, we have recently shown that so-called β-cell dysfunction is symptomatic of a marked increase in insulin production attempting to compensate for increased metabolic load. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion (illustrated by severe chronic hyperinsulinemia), together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell’s adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in cell redox homeostasis, protein refolding, protein K48-linked deubiquitination, mRNA/protein export along the microtubules, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as phosphorylation-regulated sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking—core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global proteome and PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.

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

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