Insulin resistance is associated with impaired
glucose uptake and altered
protein kinase B (Akt) signaling. Previous studies have suggested
asymmetric dimethylarginine (ADMA) and
inflammation are two distinguish factors that correlate with
insulin resistance (IR). How ADMA and
inflammation factors interact and synchronize in the regulation of IR in liver remain to be elucidated. In this study, we systematically investigated whether ADMA is involved in IR using primary hepatocytes, if yes, by via which molecular mechanism. Our results demonstrated that ADMA inhibits
insulin sensitivity in a concentration-dependent manner by activating
inflammation factors
tumor necrosis factor (TNF)-α,
interleukin (IL)-1, and
IL-6 in primary hepatocytes. Further analysis revealed that
mitogen-activated protein kinase (MAPK) signaling pathway act downstream of ADMA and
inflammation factors, and inhibition of MAPK pathway rescued the IR. Furthermore,
metformin effects has been found which could reverse ADMA-induced IR by suppressing MAPK signaling pathway. To our knowledge, we, for the first time, unveiled the complicated regulatory network and interactions among ADMA,
inflammation, and MAPK signaling pathway, which advanced current research on the development and regulation of IR in liver. This study also certainly provided novel insights on comprehensive diagonistics roles of ADMA as a potential
biomarker.