Contrasting Effects of IRS-1 vs IRS-2 Gene Disruption on Carbohydrate and Lipid Metabolism in vivo

To examine the impact of homozygous genetic disruption of IRS-1 (IRS-1-/-) or IRS-2 (IRS-2-/-) on basal and insulin stimulated carbohydrate and lipid metabolism in vivo we infused 18-h fasted mice (WT, IRS1-/and IRS2-/-) with [3-3H]glucose and [H5]glycerol and assessed rates of glucose and glycerol turnover under basal (0-90 min) and hyperinsulinemic-euglycemic clamp (90-210 min; 5 mM glucose and 5 mU insulin*kg-1*min-1) conditions. Both IRS-1-/and IRS-2-/mice were insulin resistant as reflected by markedly impaired insulin stimulated whole-body glucose utilization compared to WT mice. Insulin resistance in the IRS-1-/mice could be ascribed mainly to decreased insulin stimulated peripheral glucose metabolism. In contrast, IRS-2-/mice displayed multiple defects in insulin mediated carbohydrate metabolism as reflected by (i) decreased peripheral glucose utilization, (ii) decreased suppression of endogenous glucose production and (iii) decreased hepatic glycogen synthesis. Additionally, IRS-2-/mice also showed marked insulin resistance in adipose tissue as reflected by reduced suppression of plasma FFA concentrations and glycerol turnover during the hyperinsulinemiceuglycemic clamp. These data suggest important tissue specific roles for IRS-1 and IRS-2 in mediating the effect of insulin on carbohydrate and lipid metabolism in vivo in mice. IRS-1 appears to have its major role in muscle whereas IRS-2 appears to impact on liver, muscle and adipose tissue.