Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo

To examine the impact of homozygous genetic disruption of insulin receptor substrate (IRS)-1 (IRS-1(-/-)) or IRS-S (IRS-2(-/-)) on basal and insulin-s timulated carbohydrate and lipid metabolism in vivo, we infused 18-h fasted mice (wild-type (WT), IRS-1(-/-), and IRS-2(-/-)) with [3-H-3]glucose and [H-2(5)]glycerol and assessed rates of glucose and glycerol turnover under basal (0-90 min) and hyperinsulinemic-euglycemic clamp (90-210 min; 5 mM gl ucose, and 5 milliunits of insulin kg(-1).min(-1)) conditions. Both IRS-1(- /-) and IRS-2(-/-) mice were insulin-resistant as reflected by markedly imp aired insulin-stimulated whole-body glucose utilization compared with WT mi ce. Insulin resistance in the IRS-1(-/-) mice could be ascribed mainly to d ecreased insulin-stimulated peripheral glucose metabolism. In contrast, IRS -2(-/-) mice displayed multiple defects in insulin-mediated carbohydrate me tabolism as reflected by (i) decreased peripheral glucose utilization, (ii) decreased suppression of endogenous glucose production, and (iii) decrease d hepatic glycogen synthesis. Additionally, IRS-2(-/-) mice also showed mar ked insulin resistance in adipose tissue as reflected by reduced suppressio n of plasma free fatty acid concentrations and glycerol turnover during the hyperinsulinemic-euglycemic clamp. These data suggest important tissue-spe cific roles for IRS-1 and IRS-2 in mediating the effect of insulin on carbo hydrate and Lipid metabolism in vivo in mice. IRS-1 appears to have its maj or role in muscle, whereas IRS-2 appears to impact on liver, muscle, and ad ipose tissue.