Figure 1

Role of mitochondria in the insulin resistance induced by free fatty acids (FFA). In the normal condition (A), mitochondrial function is normal and FFA are rapidly metabolized with low reactive oxygen species (ROS) production and without accumulation of lipid metabolites; normal insulin response is preserved in this condition. In pathological condition (B), the excess of plasma FFA levels induces high FFA uptake into the cell, modulating negatively the expression of genes related to mitochondrial biogenesis and oxidative capacity, and into the mitochondrion, increasing the electron flux through to electron transport chain and, consequently, ROS and RNS production. As a result, mitochondrial biogenesis and function are impaired, decreasing mitochondrial mass and oxidative capacity, leading to abnormal intracellular accumulation of lipid metabolites and ROS and RNS, which activate some protein kinases involved in the phosphorylation of IRS-1 on threonine and serine residues. When phosphorylated in threonine and serine residues, IRS-1 is not phosphorylated on tyrosine residues, preventing activation of downstream signalling pathways by insulin. In addition, RNS increases IRS-1 nitrosilation, resulting in high degradation of these protein, which can contribute to impaired insulin response