Insulin Resistance and Muscle Metabolism in Chronic Kidney Disease

Figure 4

Infusion of angiotensin II (Ang II) is associated with an upregulation of various cytokines including interleukin 6 (IL-6), tumor necrosis factor (TNF), and reactive oxygen species. Chronic exposure to IL-6 impairs insulin signaling at the level of insulin receptor substrate (IRS-1) through mechanisms that involve activation of proinflammatory kinases. There is also upregulation of protein phosphatase 2Ca (PP2Ca) which is known to dephosphorylate and inactivate AMP-activated protein kinase (AMPK). Downstream targets of AMPK signaling including peroxisome-proliferator-activated receptor gamma coactivator-1α (PGC1-𝛼) and acetyl-coenzyme A carboxylase (ACC) are reduced. When ACC is phosphorylated, it is inactive and no longer able to catalyze the synthesis of malonyl-coenzyme A. Fatty acid oxidation is blocked and muscle ATP depletion occurs.