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

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Abstract

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.

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Acknowledgements

The authors thank the Fundação de Amparo à Pesquisa do Estado de Minas Gerais—FAPEMIG for its support. L.G.P., D.D.V., and L.N.B. were recipients of Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES and FAPEMIG fellowships. F.S.E. is a grant recipient of CNPq.

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Authors and Affiliations

  1. Institute of Genetics and Biochemistry (INGEB), Federal University of Uberlandia, Rua Acre, S/N, Bloco 2E, Sala 237, Campus Umuruama, Uberlândia, MG, CEP 38400-902, Brazil

    Leonardo Gomes Peixoto, Renata Roland Teixeira, Danielle Diniz Vilela, Lara Naves Barbosa, Douglas Carvalho Caixeta & Foued Salmen Espindola

  2. Institute of Biomedical Sciences, Federal University of Uberlandia, Uberlândia, MG, Brazil

    Simone Ramos Deconte, Fernanda de Assis de Araújo & Robinson Sabino-Silva

Authors
  1. Leonardo Gomes Peixoto
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  2. Renata Roland Teixeira
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  3. Danielle Diniz Vilela
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  4. Lara Naves Barbosa
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  5. Douglas Carvalho Caixeta
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  9. Foued Salmen Espindola
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Contributions

LGP, RRT, RSS and FSE conceived and designed the experiments. LGP, RRT, DDV, LNB, SRD and FAA performed the experiments. LGP, RRT, DDV, FAA, RSS and FSE analyzed the data. LGP, LNB, RRT and RSS wrote the paper. FSE supervised the entire project.

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Correspondence to Foued Salmen Espindola.

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This article does not contain any study with human. All procedures performed in this study involving animals were in accordance with the ethical standards of Ethics Committee of Federal University of Uberlândia.

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Peixoto, L.G., Teixeira, R.R., Vilela, D.D. et al. Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats. Acta Diabetol 54, 943–951 (2017). https://doi.org/10.1007/s00592-017-1027-5

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