Insulin Resistance and Cardiovascular Disease1

Abstract

INSULIN 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 β-subunit, which mediates noncovalent but stable interactions between the receptor and cellular proteins (1). Several proteins are then rapidly phosphorylated on tyrosine residues by ligand-bound 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, 12–15), 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 (Ca2+) 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). The actions of insulin and IGF-I on cation metabolism and vascular tone. The actions of insulin and IGF-I on cation metabolism and vascular tone. The interactions of insulin/IGF-I and the RAS in cardiovascular tissue (−) indicates insulin/IGF-I signaling steps that are inhibited by Ang II. The interactions of insulin/IGF-I and the RAS in cardiovascular tissue (−) indicates insulin/IGF-I signaling steps that are inhibited by Ang II. Evidence has been garnered indicating that insulin resistance and the resultant hyperinsulinemia are causally related to hypertension (Table 2). First, untreated essential hypertensive patients have higher fasting and postprandial insulin levels than normotensive subjects regardless of body mass; a direct correlation between plasma insulin concentrations and blood pressure levels exists (17, 18). Second insulin resistance and hyperinsulinemia exist in rats with genetic hypertension such as the Dahl hypertensive (19), the spontaneously hypertensive (20), and the Zucker obese hypertensive rat strain (21). Finally, the relationship between insulin and hypertension seen in essential hypertension does not occur with secondary hypertension (20, 22). Accordingly, insulin resistance and hyperinsulinemia are not consequences of hypertension, but, instead, a genetic predistribution may contribute to both disorders. This concept is supported by the finding of altered glucose metabolism in normotensive offspring of hypertensive persons (22–24). Mechanisms for the development of hypertension in insulin resistance/hyperinsulinemia include activation of the sympathetic nervous system, renal sodium retention, altered transmembrane cation transport, growth-promoting effects of vascular smooth muscle cells, and vascular hyperreactivity (1–3). Cardiovascular risk factors that cluster with microalbuminuria Cardiovascular risk factors that cluster with microalbuminuria Four large prospective studies (25–28) have shown that hyperinsulinemia is a predictor of coronary artery disease (CAD), with a few prospective reports not demonstrating such a relationship. The greatest association of hyperinsulinemia with CAD has been found in Finland in a population with a very high frequency of CAD (25). Results of a prospective investigation of 2103 men from Quebec (29) clearly showed that high fasting insulin concentrations are an independent predictor of CAD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence. Several rec