Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing β-cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of β-cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of β-cell function and the prevention of β-cell death. Phosphoinositide 3-kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of β-cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide-based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the β-cell processes to ultimately determine the fate of β-cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance β-cell function and prevent β-cell death without inducing excessive β-cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite-derived protein, termed FhHDM-1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in β-cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM-1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by β-cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance β-cell function and survival.1型糖尿病(T1D)是一种自身免疫性疾病，由胰腺内分泌胰岛素的β细胞破坏引起。胰岛移植是一种治疗方法，然而，在胰岛准备和移植后期间，大量的β细胞会发生死亡。因此，T1D的防治有赖于β细胞功能的保护和β细胞死亡的预防。磷脂酰肌醇3-激酶(PI3K)/Akt信号通路对细胞存活、增殖和代谢有显著影响，是治疗T1D的有效靶点。越来越多的证据表明，PI3K/AKT信号是决定β细胞质量和功能的关键因素。通过直接(使用高度特异的蛋白质或基于多肽的生物制剂、寄生虫的产物和植物提取物的复杂成分)或间接(通过microRNA相互作用)调节PI3K/Akt通路，从而调节β-细胞过程，可最终决定β-细胞团的结局。一个重要的考虑是确定特定的PI3K/AKT途径调节剂，这些调节剂可以增强β细胞的功能，防止β细胞死亡，而不会诱导β细胞过度增殖，这可能会带来致癌副作用。在潜在的PI3K/Akt途径激动剂中，我们已经发现了一种新的寄生虫衍生蛋白，称为FhHDM-1(肝片吸虫蠕虫防御分子1)，能有效刺激β-细胞的PI3K/Akt途径，增强功能并防止死亡，而不像其他几个已发现的PI3K/Akt信号刺激因子那样同时诱导增殖。因此，FhHDM-1将为针对PI3K/Akt途径的生物制剂设计提供信息，以预防/改善T1D和T2D，T2D现在被广泛认为是一种以β细胞功能障碍和死亡为特征的炎症性疾病。本文将探讨PI3K/Akt信号通路的调控作为提高β细胞功能和存活的新策略.