Recently, we showed that pancreatitis in the context of profound β-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 β-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 β-cell deficiency, implying the existence of a repressive factor from those cells. Here we show that the repressor from β-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 α- to β-cells induced by activation of PAR2. This provides a mechanistic explanation for the observation that α- to β-cell transdifferentiation occurs only in the setting of severe β-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 β-cell neogenesis as a therapy for diabetes.

最近，我们发现β细胞严重缺乏的情况下的胰腺炎足以诱导胰岛细胞转分化。在某些情况下，这种作用足以使严重糖尿病康复。最近，我们发现胰腺炎通过转分化诱导 β 细胞新生的分子机制是激活一种称为蛋白酶激活受体 2 (PAR2) 的非典型 GPCR。然而，PAR2诱导转分化的能力仅发生在β细胞严重缺陷的情况下，这意味着这些细胞存在抑制因子。在这里，我们证明β细胞的阻遏物是胰岛素。用 PAR2 激动剂 (2fLI) 联合胰岛素分泌和信号传导抑制剂治疗原代胰岛足以诱导胰岛素和 PAX4 基因表达。此外，在原代人胰岛中，这种治疗还导致诱导双激素胰岛细胞共表达胰高血糖素和胰岛素，这是胰岛细胞转分化的标志。从机制上讲，胰岛素抑制了 PAR2 激动剂对胰岛素基因表达的积极作用，并导致 PAX4 增加，而 PAX4 在胰岛细胞转分化中发挥着重要作用。这里提出的研究表明，胰岛素抑制 PAR2 激活诱导的 α 细胞向 β 细胞的转分化。这为观察到α细胞向β细胞转分化仅发生在严重β细胞消融的情况下提供了机制解释。 对胰岛细胞转分化的机制理解以及使用现有药理学试剂调节该过程的能力代表了利用这种新的 β 细胞新生机制作为糖尿病治疗方法的重要一步。