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.