4-Hexylresorcinol Enhances Skeletal Muscle Glucose Handling through the AMPK-GLUT4 axis in Diabetic Rats

Abstract

BackgroundSkeletal muscle insulin resistance in diabetes is characterized by impaired GLUT4 availability and dysregulated AMP-activated protein kinase (AMPK) signaling. We investigated whether 4-hexylresorcinol (4HR) modulates glucose metabolism and AMPK-acetyl-CoA carboxylase (ACC)-GLUT4 signaling in vitro and in streptozotocin (STZ)-induced diabetic rats. MethodsDifferentiated C2C12 myotubes were treated with 4HR (0.1-10 {micro}M) and assessed for glucose uptake, GLUT4 translocation, protein stability, proteasome involvement, and AMPK/ACC phosphorylation. In vivo, streptozotocin (STZ)-induced diabetic rats received subcutaneous 4HR (10 mg{middle dot}kgL{superscript 1}, 5 times/week for 7 weeks). Glycemic control, insulin secretion, muscle glycogen content, and serum protein profiles were evaluated. Results4HR markedly increased glucose uptake (>5-fold vs. control, p<0.05), accompanied by increased phosphorylation of AMPK (Thr172) and ACC (Ser79), and redistribution of GLUT4 toward the cell periphery. Cycloheximide chase and proteasome inhibition experiments indicated partial stabilization of GLUT4. In diabetic rats, 4HR reduced fasting glycemia, improved glucose tolerance, elevated circulating insulin, and restored glycogen-rich fibers in skeletal muscle. Serum profiling revealed a metabolic and anti-inflammatory shift, with increased AMPK, p-ACC, GLUT1, LGR4, LDHA, and PGC-1, alongside suppression of NF-{kappa}B and TNF-. Conclusion4HR improves skeletal muscle glucose metabolism in STZ-induced diabetes, associated with activation of AMPK-ACC signaling, preservation of GLUT4 expression, and restoration of glycogen content. These findings highlight 4HR as a promising candidate for further investigation in diabetic muscle dysfunction and metabolic disease.