Figure 1: Insulin resistance in chronic kidney disease. Renal failure and adipose tissue lead to systemic inflammation and increased plasma levels of adipokines. TNF-α activates adipose tissue lipolysis, which generates free-fatty acids (FFAs). On muscle cells, FFAs activate transcription factors, such as peroxisome proliferator-activated receptor (PPAR), and generate messengers including diacylglycerol (DAG) and long-chain acyl-CoA (LCA-CoA), which will lead to protein kinase C (PKC) activation and dephosphorylation of insulin receptor substrate (IRS)-1/2. On muscle cells, TNF-α activates a series of kinases including IKK-β, c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), protein kinase C (PKC), Akt (PKB), mammalian target of rapamycin (mTOR), and glycogen synthase kinase 3 (GSK3) responsible for phosphorylation of insulin receptor (InsR) and IRS-1 on serine/threonine residues. Inhibition of IRS-1 function will block Akt leading to cytosol glucose transporter 4 (GLUT4) sequestration. Fetuin-A could also inhibit IRS and induce low-grade inflammation. IL-6 is responsible for the induction of different suppressors of cytokine signaling (SOCS) proteins through the Janus kinase/signal transducer and activator of transcription (Jak/STAT)-signaling pathway. SOCS will inhibit IRS-1/2 and protein kinase A. Endoplasmic reticulum stress seems to be another factor linking inflammation and insulin resistance at the molecular level. Red line illustrates the mechanism of CKD-related factors in IR.