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

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 <i>in vitro</i> 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.