Insulin Resistance and Cardiovascular Disease1

I RESISTANCE describes an impaired biological response to insulin (1–4). In the early states of insulin resistance there is a compensatory increase in insulin concentrations. Although hyperinsulinemia may compensate for resistance to some biological actions of insulin, it may result in overexpression of actions in tissues that retain normal or minimally impaired sensitivity to insulin. Also, high concentrations of insulin can act through receptors for insulin-like growth factor I (IGF-I) (5–8). Thus, accentuation of some actions of insulin with concurrent resistance to other actions gives rise to diverse clinical manifestations and sequelae of the insulin resistance syndrome. In general, insulin resistance can be due to a prereceptor, receptor, or postreceptor abnormality (1). One signaling pathway for insulin and IGF-I is the phosphatidylinositide 3-kinase (PI3 -kinase) system. Upon binding to their receptors, there is autophosphorylation of the b-subunit, which mediates noncovalent but stable interactions between the receptor and cellular proteins (1). Several proteins are then rapidly phosphorylated on tyrosine residues by ligandbound insulin receptors, including insulin receptor substrate-1 (IRS-1) (1). IRS docking proteins bind strongly to the enzyme PI3 -kinase (1), a heterodimer consisting of a p85 regulatory subunit and a p110 catalytic subunit, via SH-2 domain interaction with the p85 subunit (1). Insulin and IGF-I stimulation increases the amount of PI3 -kinase associated with IRS, and the binding process is associated with increased activity of the enzyme. Activation of the enzyme is crucial for transducing the actions of these peptides in cardiovascular (CV) tissue (9–14) as well as conventional insulin-sensitive tissues (1). The interruption of this pathway creates a resistance to the actions of insulin/IGF-I in stimulating vascular nitric oxide (NO) production (9, 10), CV cation transport mechanisms (11–15), as well as glucose transport (1, 6) (Fig. 1) in classically sensitive tissues such as muscle and adipose tissue. PI3-kinase mediates the increases in NO, Na pump, K channel, and calcium (Ca) myofilament sensitivity by increasing the trafficking and translocation of NO synthase and cation pump units as well as glucose transporters (1, 9, 16) (Fig. 2). Therefore, resistance to the actions of insulin and IGF-I in these tissues occurs whenever there is reduced PI3 -kinase activation (Fig. 2).