Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice

Insulin stimulates muscle and adipose tissue to absorb glucose through a si gnaling cascade that is incompletely understood. Insulin resistance, the in ability of insulin to appropriately stimulate glucose uptake, is a hallmark of type 2 diabetes mellitus. The development of experimental systems that model human insulin resistance is important in elucidating the defects resp onsible for the development of type 2 diabetes. When two strains of mice, B TBR and C57BL/6J (B6), are crossed, the resultant male offspring (BtB6) dem onstrate insulin resistance in muscle tissue. Here, we report an insulin re sistance phenotype in adipose tissue from lean, nondiabetic BtB6 mice simil ar to that observed in human muscle. Adipocytes isolated from insulin-resis tant male mice display 65% less insulin-stimulated glucose uptake compared with insulin-sensitive female mice. Similarly, adipocytes from insulin-resi stant mice have diminished insulin-stimulated IRS-1 phosphorylation and pho sphatidylinositol 3-kinase (PI3K) activation. However, normal activation of protein kinase B (Akt/PKB) by insulin is observed. Thus BtB6 mice demonstr ate the dissociation of insulin-stimulated PI3K activity and Akt/PKB activa tion and represent a useful model to investigate the causes of insulin resi stance in humans.