Genetic Variants of TLR4 and TLR4 Signal Pathway and its Association with Insulin Resistance and Diabetes Risk

Type 2 diabetes is characterized by long-term insulin resistance and beta-cell failure, and affects many organs such as heart and blood vessels, liver, kidney and the eye thus results in significant mortality and morbidity rates. Insulin resistance is a primary characteristic of type 2 diabetes. Normal amounts of insulin produced by the pancreas can not create the necessary or sufficient response in fat, muscle and liver cells for that reason insulin resistance develop. Toll-like receptors (TLRs), a family of transmembrane proteins, develop innate immune response against many pathogens. Inflammation impairs insulin sensitivity by way of TLR family, especially TLR4 activation. TLR4 signal is activated by LPS and that causes the NF-kappa B activation and expression of inflammatory regulatory genes such as TNF-alpha, IL-1, IL-6, iNOS, and MCP1. Activation of pro-inflammatory pathway causes insulin resistance and type 2 diabetes. The rs4986790 and rs4986791 genetic variants of TLR4 gene are associated with increased risk of type 2 diabetes, and genetic variants of TLR4 signaling pathway members, MyD88 (rs1319438, rs199396), IRAK1 (rs1059703, rs3027898, rs7061789), IRAK4 (rs1461567, rs4251513, rs1141168), TIRAP (rs8177374, rs8177400) ve TRAF6 (rs331455, rs331457), determined to be candidate variants for insulin resistance in type 2 diabetes.