Insulin Resistance, Hypertension, and Coronary Heart Disease

Gerald Reaven, MD

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In This Article

Insulin Resistance, Essential Hypertension, and Coronary Heart Disease

Although coronary heart disease (CHD) is the major cause of morbidity and mortality in patients with essential hypertension, not all hypertensive individuals are at equal risk. The following section presents evidence in support of the view that the subset of patients with hypertension at greatest CHD risk is those individuals who are also insulin resistant/hyperinsulinemic.

As discussed earlier, not all patients with essential hypertension are insulin resistant. As a consequence, the CHD risk factors associated with insulin resistance will vary significantly in patients with equal degrees of blood pressure elevation. The results in Figure 2 demonstrate how different two groups of patients with essential hypertension can be when the subjects with hypertension seen in Figure 1 were subdivided into hyperinsulinemic (insulin resistant) and normoinsulinemic (insulin sensitive) subgroups.[9] As shown in Figure 2, the plasma insulin concentrations in response to an oral glucose challenge are much higher in the insulin-resistant group. This is not surprising, since the two groups were stratified based on this criterion. However, it is also clear from Figure 2 that plasma glucose concentrations in response to the oral glucose challenge were also significantly higher in the insulin-resistant patients with hypertension. Since insulin resistance, hyperinsulinemia, and glucose intolerance have all been predictive of increased CHD risk,[20,21,22,23] their existence in a subset of patients with hypertension supports the view that not all patients with high blood pressure are at equal risk to develop CHD.

Plasma insulin (left panel) and glucose (right panel) concentrations in response to a 75 g oral glucose challenge in hyperinsulinemic (insulin resistant ) and normoinsulinemic (insulin sensitive ) patients with hypertension. Reprinted with permission from J Intern Med. 1992;231:235-240.[9]

Insulin resistance and compensatory hyperinsulinemia are associated with a dyslipidemia characterized by a high plasma TG and low HDL-C concentration.[10,24] The prevalence of both of these changes is increased in patients with essential hypertension,[25,26] and the data in Table I illustrate that an atherogenic lipoprotein profile can be seen in normotensive first-degree relatives of patients with high blood pressure.[14] In addition to being highly correlated with insulin resistance/hyperinsulinemia, a high plasma TG and a low HDL-C concentration are also well recognized CHD risk factors.[27,28,29,30] Of more direct relevance are the data in Table II indicating that asymptomatic patients with high blood pressure identified as demonstrating cardiac ischemia by Minnesota Code Criteria were insulin resistant, hyperinsulinemic, and dyslipidemic, with higher TG and lower HDL-C concentrations than well matched hypertensive patients whose electrocardiograms were considered normal.[31] Finally, the relationship between the dyslipidemia characteristic of insulin resistance and CHD in patients with essential hypertension has been emphasized by recent reports from the Copenhagen Male Study[32,33] demonstrating the power of a high TG and low HDL-C concentration in predicting myocardial infarction in this patient population. In the absence of measures of either insulin resistance or plasma insulin levels, these authors used the changes in lipid metabolism as markers of the insulin resistance syndrome. The results of their analysis revealed that CHD events in patients with essential hypertension varied dramatically as a function of their plasma concentration ratio of TG/HDL-C, being markedly accentuated in those whose concentration ratio was in the highest tertile (insulin resistance syndrome) and essentially unchanged in the insulin-sensitive patients in the lowest tertile of TG/HDL-C concentrations.[33]

The first step in the process of atherogenesis is the binding of circulating mononuclear cells (MNCs) to the endothelium.[34] The effect of hypertension on this process was evaluated by isolating MNCs from patients with hypertension and quantifying their binding to cultured endothelial cells. Using this approach we were able to demonstrate that MNCs isolated from patients with essential hypertension adhered with significantly (p <0.001) greater avidity to endothelium than did MNCs from a matched control group with normal blood pressure.[35] However, the enhanced binding of MNCs isolated from patients with hypertension to endothelium appeared to be more closely related to the degree of insulin resistance than blood pressure, per se, and the relationship between insulin-mediated glucose disposal and MNC binding was highly correlated in both normotensive (r=0.86; p <0.001) and hypertensive (r=0.74; p <0.001) individuals.

The interaction between circulating MNCs and the endothelium is modulated by the activity of cellular adhesion molecules (CAMs) secreted by endothelial cells. CAMs can be identified in the circulation, and elevated plasma concentrations of CAMs have been noted in association with a variety of conditions associated with insulin resistance, including essential hypertension.[36,37] To explore the possibility that the insulin resistance commonly seen in patients with hypertension was responsible for the increased plasma concentration of CAMs, we[38] defined in a group of healthy volunteers the relationship between insulin-mediated glucose disposal and the plasma concentrations of three CAMs -- E selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cellular adhesion molecule-1 (VCAM-1). The results demonstrated that statistically significant relationships existed between degree of insulin resistance and E selectin (r=0.54; p <0.005), ICAM-I (r=0.67; p <0.001) and VCAM-1 (r=0.41; p <0.005). Furthermore, plasma concentration of MNC binding to cultured endothelium was significantly correlated with the plasma concentrations of E selectin (r=0.5; p <0.005), ICAM-1 (r=0.47; p <0.001), and VCAM-1 (r=0.21; p <0.30). Thus, it appears that the subset of patients with essential hypertension who are insulin resistant have an increase in the endothelial production of CAMs, thereby increasing the likelihood that circulating MNCs will bind to endothelium and initiate the process of atherogenesis.

Another abnormality of endothelial function that may contribute to increased CHD risk in insulin-resistant individuals with hypertension is the dysregulation of asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of nitric oxide synthase, recently shown to be elevated in patients with essential hypertension,[39] which has also received considerable attention as an important CHD risk factor.[40] Given this background, we thought it important to measure insulin-mediated glucose disposal, the plasma-insulin response to oral glucose, and plasma ADMA concentrations in normal volunteers and patients with essential hypertension.[41] The results indicated that plasma ADMA concentrations and degree of insulin resistance were significantly correlated in both healthy volunteers (r=0.73; p <0.001) and patients with essential hypertension (r=0.70; p <0.003). Furthermore, plasma ADMA concentrations were similar in normotensive individuals and hypertensive patients when the two diagnostic groups were stratified into insulin-resistant or insulin-sensitive subgroups. Thus, as with the MNC binding and the plasma concentration of CAMs, the reported increase in plasma ADMA concentrations in patients with essential hypertension seems to be more a matter of insulin resistance than the increase in blood pressure.

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