Evaluation of AKT1 Mediated MST1 Regulation by PTP1B Inhibition via Viscosol in Streptozotocin and High Fat Diet-Induced Type 2 Diabetic Mice Model

Abstract

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease which is distinguished by impaired insulin secretion, and β-cells death. MST1 is a widely distributed serine/threonine kinase and is the main upstream regulator of Hippo pathway. MST1 is recognized as a major factor responsible for inducing apoptosis in β-cells. Several studies have reported the hyperactivation of MST1, mTORC1, PHLPP2, and NLRP3 inflammasome in pancreatic cells in T2DM. In T2DM, PTP1B is over-expressed in many tissues such as liver, pancreas, and adipose tissue. Collected data shows that PTP1B overexpression is indirectly correlated with MST1 activation which is itself regulated by AKT1 in pancreatic β-cells. Therefore, we hypothesized that the PTP1B inhibitor, Viscosol which is isolated from Dodonaea viscosa, could inhibit the activation of MST1 and its mediated pathways related to apoptosis, autophagy, inflammation, and lipotoxicity. For this purpose, we designed HFD-low dose STZ-induced T2DM mice model and treated it with Viscosol. We assessed the in vivo effect of Viscosol against MST1-mediated apoptosis, autophagy, lipotoxicity, and inflammation. Furthermore, we determined the relative mRNA expression levels of our specific markers of insulin, Hippo, PHLPP2, mTORC1, and NLRP3 signalling pathways. The data revealed the reduction of PTP1B, MST1, PHLPP2, mTORC1 and NLRP3 and their down regulatory markers in our compound treated group. Moreover, in our compound treated group, we analyzed the inhibition of apoptosis, retrieval of PI3K/AKT signalling, autophagy activation and inhibition of lipid accumulation in the pancreas. Our findings suggest that Viscosol offers protective benefits against T2DM, demonstrating anti-apoptotic, hypoglycemic, anti inflammatory, and hypolipidemic activities in the pancreas. This implies Viscosol's potential as a therapeutic agent for T2DM and related complications, primarily through the inhibition of PTP1B and MST1. Keywords: T2DM, PTP1B, MST1, AKT1, Pancreatic β-cells, Apoptosis, Dodonaea viscosa