Viscosol-Mediated MST1 Inhibition Mitigates Hepatic Inflammation and Metabolic Pathways in Type 2 Diabetic Mice Model.

Abstract

Diabetes is an impaired metabolic disorder with severe hyperglycemia, insulin resistance and defective metabolism. Type 2 diabetes (T2DM) is the most common form of diabetes, accounting for about 95% of all diabetic cases. PTP1B overexpression in liver, pancreas and adipose is responsible for insulin resistance and activation of pathological pathways. Inhibition of PTP1B was suggested as a possible treatment for T2DM. MST1-hippo pathway regulates several downstream pathways in T2DM. Therefore, we hypothesized that the inhibitor for PTP1B could inhibit the activation of MST1, thereby significantly enhancing insulin sensitivity and preventing inflammation, apoptosis, hippo-pathway and gluconeogenesis in the liver. We have developed a T2D mice model that mimics human pathophysiology. We used a PTP1B inhibitor viscosol extracted from the Dodonaea viscosa plant. The compound was administered through an intraperitoneal injection. We used RT-qPCR to measure the relative expression of genes involved of insulin signaling, inflammation, apoptosis, hippo-pathway, and gluconeogenesis markers to support our hypothesis. PTP1B, PHLPP2 and MST1 inhibition via viscosol has hepatoprotective effects in our compound-treated group. MST1, PHLPP2 and PTP1B downregulation in the compound-treated group improves insulin signaling via increasing PI3K/AKT. Likewise, a significant decrease in inflammatory molecules (TNFα, IL-1β, , IL-18, and IL-6) and apoptotic molecules (JNK1, BIM and CASP3) was also observed in the liver of the compound-treated group. Viscosol was also found to inhibit the hippo-signaling pathway molecules (NF2, MST1, and LATS2) and improved the hepatic glucose output by inhibiting gluconeogenesis. Therefore, we conclude that our compound has effectively anti-diabetic effect and regulates hepatic insulin signaling, gluconeogenesis, hippo-pathway, inflammation, and hepatocyte apoptosis by inhibiting PTP1B and MST1 in a T2DM mice model. Keywords: Dodonaea viscosa, PTP1B, MST1 inhibition, insulin signaling, T2DM