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.
Institute of Biomedical Sciences, Federal University of Uberlandia, Uberlândia, MG, Brazil.
Acta Diabetol. 2017 Oct;54(10):943-951. doi: 10.1007/s00592-017-1027-5. Epub 2017 Aug 9.
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.
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.
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.
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.
高血糖引起的炎症会触发 Toll 样受体（TLR）途径进入细胞。我们的假设是二甲双胍治疗可以减轻链脲佐菌素诱导的低胰岛素血症/高血糖大鼠骨骼肌中炎症引发的 TLR 信号通路。因此，我们在低胰岛素血症和高血糖条件下检查了 TLR 信号及其与糖尿病大鼠肌肉胰岛素抵抗的相关性，并对接受二甲双胍治疗的大鼠进行了研究。
10 天糖尿病大鼠接受 7 天生理盐水（D 组）或二甲双胍（500mg/kg，每天一次）（D+M 组）治疗。在胰岛素耐量试验前采集骨骼肌。然后，用 TLR4、TLR2、NF-κB、IκB、p-AMPK 和 p-JNK 对骨骼肌上清液进行 Western 印迹分析。通过 ELISA 分析 TNF-α 和 CXCL1/KC 含量。
二甲双胍治疗增加了全身胰岛素敏感性。这种调节伴随着腓肠肌中 p-AMPK 的平行变化，以及 TLR4 和 NF-κB 含量的相反调节（皮尔逊相关；r=0.7229、r=-0.8344 和 r=-0.7289，分别为 0.7229、r=-0.8344 和 r=-0.7289，p<0.05）。与 D 大鼠相比，二甲双胍治疗增加了 IκB 含量。此外，在糖尿病大鼠中，二甲双胍治疗可独立于 TLR2 信号降低 p-JNK。
综上所述，结果表明肌肉 TLR4、p-AMPK 和 NF-κB 含量与胰岛素敏感性之间存在关系。该研究还强调，在胰岛素抵抗的情况下，如在糖尿病患者中，二甲双胍治疗可能会防止炎症途径的激活减弱。
