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.