Targeting Insulin Resistance in Hepatocytes: A Novel Insulin-Mimetic Agent Delivered via an Advanced Nanocarrier System

Abstract

Hepatic insulin resistance (IR) is a key contributor to the onset and progression of type 2 diabetes mellitus (T2DM), characterized by reduced insulin sensitivity, impaired glucose uptake, decreased glycogen synthesis, and excessive lipid accumulation in hepatocytes. Many vanadium compounds exhibit promising antidiabetic properties; however, their clinical application remains limited due to concerns about toxicity. Here, we investigate the impact of our newly developed Schiff base-binuclear oxidovanadium(V) complex (abbreviated as Van) in reversing IR and elucidate its pharmacological mechanism using an in vitro experimental model of hepatocarcinoma (HepG2) subjected to IR (IR-HepG2). We propose incorporating Van into liposomes as a nanotherapeutic strategy to increase its cellular uptake and maximize its therapeutic effectiveness. Our data show that Van effectively reverses IR in the IR-HepG2 cell model by increasing glucose uptake, promoting glycogen synthesis, and reducing lipid accumulation. The mechanism underlying Van’s ability to reverse IR involves the inhibition of protein tyrosine phosphatase (PTP)-1B protein expression and total PTPs’ activity, leading to the activation of the insulin receptor (InsR)/protein kinase B (AKT)/glycogen synthase kinase (GSK)3αβ pathway and a reduction in glucose-6-phosphatase (G6Pase) protein expression while maintaining unchanged phosphoenolpyruvate carboxykinase (PCK1) and glucose transporter (GLUT)2 synthesis. Moreover, we demonstrate that Van can be successfully incorporated into stable negatively charged liposomes, significantly enhancing its uptake by IR-HepG2 cells and improving therapeutic efficacy compared with free Van. This study presents a novel therapeutic approach for T2DM, specifically addressing IR and offering the first proof-of-concept that Van exhibits increased efficacy when it is precisely delivered to IR cells using nanotechnology.