Figure 4.

Development of insulin resistance and the relevant role of mitochondrial ROS generation. Frequent hyperglycemia condition promotes ROS production by mitochondria through the ETC. ER function and folding capacity is affected by mitochondrial ROS production. This process is especially important in pancreatic β-cells, in charge of insulin production and secretion. Initially, excess nutrient overload increases insulin synthesis demand. Perpetuated hyperglycemia and hyperinsulinemia progress to insulin resistance in peripheral tissues. This fact forces β-cells to produce more insulin promoting ER stress, in parallel with increased oxidative stress and mitochondrial dysfunction. Oxidative stress in mitochondria and ER stress feedback each other directly through ROS and also indirectly (curve arrow), aggravating the oxidative stress and promoting further insulin resistance. This situation can progress to β-cell failure and the impairment of insulin release, thus provoking the inability to control glucose levels in blood characteristic of T2D patients. Insulin resistance is also associated with processes such to inflammation, lipotoxicity, and autophagy impairment that make oxidative stress and insulin resistance characteristic of T2D worse. ETC: Electron transport chain; ER: Endoplasmic reticulum; FFA: Free fatty acids; ROS: Radical oxygen species.