FIG. 7.

A: Schematic diagram represents the role of acute and chronic insulin in regulating IRS1 and IRS2 via p38 MAPK. B: Downregulation of IRS1 and IRS2 by metabolic stresses and/or environmental insults triggers insulin resistance in the liver and promotes insulin secretion from pancreatic β-cells. Activation of p38 in the heart by hyperinsulinemia or other metabolic stresses promotes IRS1 and IRS2 degradation and dysregulates cardiac glucose and lipid metabolism, mitochondrial biogenesis, calcium-handling, fibrosis, and motor gene expression, resulting in heart failure. HGP, hepatic glucose production.