Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes Translated title: 一种新兴的1型糖尿病治疗策略:靶向胰腺β细胞中的PI3K/Akt信号通路以增强其存活和功能

Abstract

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.

Abstract

Highlights

• Phosphoinositide 3‐kinase (PI3K)/Akt signaling is an emerging promising therapeutic target for diabetes.

• Modulation of the PI3K/Akt signaling pathway, via protein and peptide‐based biologics, parasite‐derived molecules, plant extracts, or through microRNA interactions, will regulate the processes that determine the function of β‐cells and the fate of β‐cell mass.

• Therapeutic approaches targeting PI3K/Akt signaling will have broad‐reaching applications for the prevention of type 1 diabetes, the preservation of islets prior and post transplantation, and the treatment of type 2 diabetes

Translated abstract

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