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Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation

机译：胰岛素充当抑制因子，以抑制pAR2诱导胰岛细胞转化率的能力

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Recently, we showed that pancreatitis in the context of profound beta-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced beta-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound beta-cell deficiency, implying the existence of a repressive factor from those cells. Here we show that the repressor from beta-cells is insulin. Treatment of primary islets with a PAR2 agonist (2fLI) in combination with inhibitors of insulin secretion and signaling was sufficient to induce insulin and PAX4 gene expression. Moreover, in primary human islets, this treatment also led to the induction of bihormonal islet cells coexpressing glucagon and insulin, a hallmark of islet cell transdifferentiation. Mechanistically, insulin inhibited the positive effect of a PAR2 agonist on insulin gene expression and also led to an increase in PAX4, which plays an important role in islet cell transdifferentiation. The studies presented here demonstrate that insulin represses transdifferentiation of alpha- to beta-cells induced by activation of PAR2. This provides a mechanistic explanation for the observation that alpha- to beta-cell transdifferentiation occurs only in the setting of severe beta-cell ablation. The mechanistic understanding of islet cell transdifferentiation and the ability to modulate that process using available pharmacological reagents represents an important step along the path towards harnessing this novel mechanism of beta-cell neogenesis as a therapy for diabetes.
机译：最近，我们表明，在深刻的β-细胞缺乏的背景下的胰腺炎足以诱导胰岛细胞转移细胞。在某些情况下，这种效果足以导致严重糖尿病恢复。最近，我们表明，胰腺炎诱导的转移细胞诱导β细胞新发生的分子机制是激活称为蛋白酶活化受体2（PAR2）的非典型GPCR。然而，PAR2诱导转移引起的能力仅在β细胞缺乏的设定中发生，暗示来自那些细胞的抑制因子的存在。在这里，我们表明来自β细胞的阻遏物是胰岛素。用PAR2激动剂（2FLI）与胰岛素分泌和信号传导的抑制剂组合治疗原发性胰岛（2FLI）足以诱导胰岛素和PAX4基因表达。此外，在原代人类胰岛中，该处理也导致了生物态胰岛细胞的诱导共存胰高血糖素和胰岛素，是胰岛细胞转移的标志。机械地，胰岛素抑制了PAR2激动剂对胰岛素基因表达的积极作用，并且也导致PAX4的增加，这在胰岛细胞转化中起重要作用。本文提出的研究表明，胰岛素抑制了通过PAR2激活诱导的α-β细胞的转染细胞。这提供了用于观察到仅在严重β细胞消融的设置中发生α至β细胞转晶的机械解释。使用可用药理学试剂调节该方法的机械理解及调节该方法的能力表示沿着利用这种新β-细胞新生机制作为糖尿病治疗的重要步骤。

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