Dihydromyricetin improves skeletal muscle insulin resistance by inducing autophagy via the AMPK signaling pathway.

Abstract

Skeletal muscle insulin resistance (SMIR) plays an important role in the pathogenesis of type 2 diabetes. Dihydromyricetin (DHM), a natural flavonoid, exerts various bioactivities including anti-oxidative and hepatoprotective effects. Herein, we intended to determine the effect of DHM on SMIR and the underlying mechanisms. We found that DHM increased the expression of phosphorylated insulin receptor substrate-1, phosphorylated Akt and glucose uptake capacity in palmitate-treated L6 myotubes under insulin-stimulated conditions. The expression of light chain 3, Beclin 1, autophagy-related gene 5 (Atg5), the degradation of sequestosome 1 and the formation of autophagosomes were also upregulated by DHM. Suppression of autophagy by 3-methyladenine and bafilomycin A1 or Atg5 and Beclin1 siRNA abolished the favorable effects of DHM on SMIR. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK) and Ulk1, and decreased phosphorylated mTOR levels. AMPK inhibitor compound C (CC) and AMPK siRNA abrogated DHM-induced autophagy, subsequently suppressed DHM-induced SMIR improvement. Additionally, DHM inhibited the activity of F1F0-ATPase thereby activating AMPK. Finally, the results of in vivo study conducted in high fat diet-fed rats were consistent with the findings of in vitro study. In conclusion, DHM improved SMIR by inducing autophagy via the activation of AMPK signaling pathway.

• Authors: Linying Shi, Ting Zhang, Xinyu Liang, Qin Hu, Juan Huang, Yong Zhou, Mingliang Chen, Qianyong Zhang, Jundong Zhu, Mantian Mi
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 409 Pg. 92-102 (Jul 05 2015) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 25797177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Flavonols
• Macrolides
• 3-methyladenine
• bafilomycin A1
• AMP-Activated Protein Kinases
• Adenine
• dihydromyricetin

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adenine (analogs & derivatives, pharmacology)
• Animals
• Autophagy (drug effects)
• Cells, Cultured
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Diet, High-Fat
• Flavonols (administration & dosage, pharmacology)
• Gene Expression Regulation (drug effects)
• Insulin Resistance (physiology)
• Macrolides (pharmacology)
• Male
• Muscle, Skeletal (drug effects, metabolism)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)