Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats

Acta Diabetol. 2017 Oct;54(10):943-951. doi: 10.1007/s00592-017-1027-5. Epub 2017 Aug 9.


Aims: Inflammation induced by hyperglycemia triggers the toll-like receptor (TLR) pathway into cells. Our hypothesis was that metformin treatment attenuates the TLR signaling pathways triggered by inflammation in skeletal muscle of hypoinsulinemic/hyperglycemic STZ-induced rats. Thus, we examined TLR signaling under hypoinsulinemia and hyperglycemia conditions and its correlation with insulin resistance in muscle of diabetic rats treated with metformin.

Methods: Ten-day diabetic rats were submitted to 7 days of saline (D group) or metformin (500 mg/kg once per day) (D + M group). The skeletal muscle was collected before the insulin tolerance test. Then, Western blotting analysis of skeletal muscle supernatant was probed with TLR4, TLR2, NF-κB, IκB, p-AMPK and p-JNK. TNF-α and CXCL1/KC content was analyzed by ELISA.

Results: Metformin treatment increased whole-body insulin sensitivity. This regulation was accompanied by a parallel change of p-AMPK and by an inverse regulation of TLR4 and NF-κB contents in the soleus muscle (r = 0.7229, r = -0.8344 and r = -0.7289, respectively, Pearson correlation; p < 0.05). Metformin treatment increased IκB content when compared to D rats. In addition, metformin treatment decreased p-JNK independently of TLR2 signal in diabetic rats.

Conclusion: In summary, the results indicate a relationship between muscular TLR4, p-AMPK and NF-κB content and insulin sensitivity. The study also highlights that in situations of insulin resistance, such as in diabetic subjects, metformin treatment may prevent attenuation of activation of the inflammatory pathway.

Keywords: Insulin resistance; NF-κB/IκB pathway; Skeletal muscle; Toll-like receptors; p-AMPK.

MeSH terms

  • Animals
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / immunology
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Insulin Resistance
  • Male
  • Metformin / administration & dosage*
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • Chemokine CXCL1
  • Hypoglycemic Agents
  • NF-kappa B
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Metformin