Elevated levels of fasting insulin release and insufficient glucose-stimulated insulin secretion (GSIS) are hallmarks of diabetes. Studies have established cross-talk between integrin signaling and insulin activity, but more details of how integrin-dependent signaling impacts the pathophysiology of diabetes are needed. Here, we dissected integrin-dependent signaling pathways involved in the regulation of insulin secretion in β-cells and studied their link to the still debated autocrine regulation of insulin secretion by insulin/insulin-like growth factor (IGF) 2–AKT signaling. We observed for the first time a cooperation between different AKT isoforms and focal adhesion kinase (FAK)–dependent adhesion signaling, which either controlled GSIS or prevented insulin secretion under fasting conditions. Indeed, β-cells form integrin-containing adhesions, which provide anchorage to the pancreatic extracellular matrix and are the origin of intracellular signaling via FAK and paxillin. Under low-glucose conditions, β-cells adopt a starved adhesion phenotype consisting of actin stress fibers and large peripheral focal adhesion. In contrast, glucose stimulation induces cell spreading, actin remodeling, and point-like adhesions that contain phospho-FAK and phosphopaxillin, located in small protrusions. Rat primary β-cells and mouse insulinomas showed an adhesion remodeling during GSIS resulting from autocrine insulin/IGF2 and AKT1 signaling. However, under starving conditions, the maintenance of stress fibers and the large adhesion phenotype required autocrine IGF2-IGF1 receptor signaling mediated by AKT2 and elevated FAK-kinase activity and ROCK-RhoA levels but low levels of paxillin phosphorylation. This starved adhesion phenotype prevented excessive insulin granule release to maintain low insulin secretion during fasting. Thus, deregulation of the IGF2 and adhesion-mediated signaling may explain dysfunctions observed in diabetes.

中文翻译：

---

整合素和自分泌 IGF2 途径控制 β 细胞中的空腹胰岛素分泌。


空腹胰岛素释放水平升高和葡萄糖刺激胰岛素分泌（GSIS）不足是糖尿病的标志。研究已经确定了整合素信号传导和胰岛素活性之间的相互作用，但需要更多关于整合素依赖性信号传导如何影响糖尿病病理生理学的细节。在这里，我们剖析了参与 β 细胞胰岛素分泌调节的整合素依赖性信号通路，并研究了它们与仍存在争议的胰岛素/胰岛素样生长因子 (IGF) 2-AKT 信号传导对胰岛素分泌的自分泌调节的联系。我们首次观察到不同 AKT 亚型和粘着斑激酶 (FAK) 依赖性粘附信号之间的合作，该信号在禁食条件下控制 GSIS 或阻止胰岛素分泌。事实上，β 细胞形成含有整合素的粘附，为胰腺细胞外基质提供锚定，并且是通过 FAK 和桩蛋白进行细胞内信号传导的起源。在低葡萄糖条件下，β细胞采用由肌动蛋白应力纤维和大的外周粘着斑组成的饥饿粘附表型。相反，葡萄糖刺激会诱导细胞扩散、肌动蛋白重塑以及位于小突起中的含有磷酸-FAK 和磷酸桩蛋白的点状粘附。大鼠原代 β 细胞和小鼠胰岛素瘤在 GSIS 期间表现出由自分泌胰岛素/IGF2 和 AKT1 信号传导导致的粘附重塑。然而，在饥饿条件下，应力纤维和大粘附表型的维持需要AKT2介导的自分泌IGF2-IGF1受体信号传导以及升高的FAK激酶活性和ROCK-RhoA水平，但桩蛋白磷酸化水平较低。 这种饥饿粘附表型可以防止胰岛素颗粒过度释放，从而在禁食期间维持较低的胰岛素分泌。因此，IGF2 和粘附介导的信号传导的失调可以解释糖尿病中观察到的功能障碍。