Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Acta Pharmacol Sin. 2014 Oct;35(10):1285-92. doi: 10.1038/aps.2014.64. Epub 2014 Aug 25.


Aim: To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.

Methods: Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg(-1)·d(-1)) or HFD plus a positive control drug metformin (300 mg·kg(-1)·d(-1)) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.

Results: HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.

Conclusion: ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Diet, High-Fat / adverse effects*
  • Down-Regulation / drug effects
  • Gluconeogenesis / drug effects
  • Glucose / metabolism*
  • Glycogen / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Glycolysis / drug effects
  • Hyperglycemia / drug therapy
  • Hyperglycemia / metabolism
  • Insulin Resistance / physiology*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Metabolic Diseases / drug therapy
  • Metabolic Diseases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Thioctic Acid / pharmacology*
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Thioctic Acid
  • Glycogen
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Glucose