Targeted Inhibition of Protein Tyrosine Phosphatase 1B by Viscosol Ameliorates Type 2 Diabetes Pathophysiology and Histology in Diabetic Mouse Model

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most common forms of diabetes. We are living in the middle of a global diabetes epidemic. Emerging pieces of evidence are suggesting the increased expression of protein tyrosine phosphatase 1B (PTP1B) in the pancreas and adipose tissues during T2DM. The negative regulation of the insulin signaling pathway by PTP1B helps the researchers to consider it as a potential therapeutic target for the treatment of insulin resistance and its associated complications. From the literature, we found that compound 5,7-dihydroxy-3,6-dimethoxy-2-(4-methoxy-3-(3-methyl-2-enyl)phenyl)-4H-chromen-4-one (Viscosol) extracted from Dodonaea viscosa can inhibit PTP1B in vitro. Therefore, in this study, we aimed to evaluate the antidiabetic effect of this compound in a high-fat diet (HFD) and low-dose streptozotocin- (STZ-) induced T2DM mouse model. For this purpose, T2DM was induced in C57BL/6 male mice by using an already established protocol with minor modification. The compound-treated T2DM mice showed improvements in biochemical parameters, i.e., decrease in the fasting blood glucose level, increased body weight, improved liver profile, and reduction in oxidative stress. Furthermore, to elucidate the inhibition of PTP1B, the expression level of PTP1B was also measured at mRNA and protein levels by real-time PCR and western blot, respectively. Additionally, downstream targets (INSR, IRS1, PI3K, and GLUT4) were examined for confirming the inhibitory effect of PTP1B. Our results suggest that the compound can specifically inhibit PTP1B in vivo and might have the ability to improve insulin resistance and insulin secretion. Based on our experiment, we can confidently state that this compound can be a new PTP1B drug candidate for the treatment of T2DM in the coming future.