48-PUB: Alpha-Lipoic Acid and Synthetic Analogs for Insulin-Independent GLUT-4 Activation: A Systematic Review

Introduction and Objective: Impaired GLUT-4 translocation and reduced skeletal muscle glucose uptake are central features of insulin resistance and type 2 diabetes. Alpha-lipoic acid (ALA) has been reported to enhance glucose uptake through insulin-independent activation of AMP-activated protein kinase (AMPK), while synthetic ALA analogs have been proposed to improve its pharmacokinetic and metabolic properties. The objective of this systematic review was to evaluate experimental, pharmacokinetic, and computational evidence supporting insulin-independent GLUT-4 activation by ALA and optimized synthetic analogs. Methods: A PRISMA-guided systematic review was conducted using PubMed, Scopus, Web of Science, and Google Scholar. Experimental, animal, human, pharmacokinetic, and computational studies evaluating ALA or ALA-derived analogs in relation to AMPK activation, GLUT-4 translocation, glucose uptake, or bioavailability were included. Data were synthesized narratively across study domains. Results: From 1,781 identified records, 51 studies met inclusion criteria. Across in vitro and in vivo models, ALA consistently activated AMPK and enhanced GLUT-4 translocation and glucose uptake, including in insulin-resistant conditions. Pharmacokinetic studies demonstrated low and variable oral bioavailability, rapid conversion to dihydrolipoic acid, and short plasma half-life, limiting clinical consistency. Studies of synthetic ALA analogs showed improved lipophilicity, predicted metabolic stability, and enhanced AMPK-related activity compared with native ALA. Conclusion: ALA exhibits robust insulin-independent metabolic effects mediated by AMPK activation and GLUT-4 recruitment, but its translational utility is constrained by unfavorable pharmacokinetics. Synthetic ALA analogs and bioinformatics-guided design represent promising strategies to enhance stability, potency, and therapeutic potential for improving glucose uptake in insulin-resistant states. Disclosure H.A. Darwish: None.