Insulin Resistance, Hypertension, and Coronary Heart Disease

Gerald Reaven, MD

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In This Article

Introduction

The goals of this review are two-fold: to examine the evidence in support of a role for insulin resistance and compensatory hyperinsulinemia in the pathogenesis of essential hypertension, and to evaluate the hypothesis that insulin resistance and its manifestations play major roles in the development of coronary heart disease in patients with essential hypertension. In both instances, only experimental results in human beings will be considered. Although it remains a scientific issue of great importance, the scope of this review precludes a discussion of the mechanistic link between insulin resistance/hyperinsulinemia and essential hypertension.

In 1966, Welborn et al.[1] studied 19 individuals diagnosed as having essential hypertension and demonstrated that patients with high blood pressure had significantly higher plasma insulin concentrations than a control population. However, it was not until about 20 years later that several research groups[2,3,4,5,6] confirmed the original observation of Welborn et al.[1] There is also evidence that hypertension is associated with glucose intolerance.[5,6,7] The combination of glucose intolerance and hyperinsulinemia strongly suggested that a defect in insulin-stimulated glucose uptake was likely to exist in some patients with hypertension, and there is now considerable evidence indicating that this is the case.[4,5,6,8]

These earlier observations stimulated a great deal of research activity focusing on the relationship between insulin resistance and/or compensatory hyperinsulinemia and hypertension, and there now appears to be general agreement that insulin resistance and compensatory hyperinsulinemia are commonly seen in patients with essential hypertension. However, not all patients with essential hypertension are insulin resistant and hyperinsulinemic. Since resistance to insulin-mediated glucose uptake and compensatory hyperinsulinemia are continuous variables, not dichotomous ones, obtaining a precise estimate of the frequency of abnormalities of insulin metabolism in patients with essential hypertension is not as simple as it may seem. The results of the study illustrated in Figure 1 represent an effort to address this issue by comparing the distribution of plasma insulin concentrations 2 hours after the ingestion of 75 g of glucose in 41 patients with hypertension and 41 normotensive subjects.[9] These hypertensive patients were identified as part of a routine health survey, and the normotensive subjects were participants in the same survey, selected to match the patients with respect to variables such as sex, degree of obesity, ethnic background, type of employment, and level of physical activity. Only 10% of the normotensive subjects had 2-hour plasma insulin concentrations greater than 80 µU/mL, compared with 45% of the patients with hypertension. In light of these and other findings,[8] approximately 50% of patients with hypertension can be considered to be insulin resistant and hyperinsulinemic.

Frequency distribution of the plasma insulin response 2 hours after a 75 g oral glucose challenge in normotensive (clear bar) and hypertensive (filled bar) volunteers. Reprinted with permission from J Intern Med. 1992;231:235-240.[9]

Based on the above considerations, it seems reasonable to conclude that a substantial proportion of patients with essential hypertension are resistant to insulin-mediated glucose disposal and are hyperinsulinemic. In addition, they will tend to be somewhat glucose intolerant, with elevated plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations as discussed subsequently. In other words, hypertension in these patients exists as one of the manifestations of the insulin resistance syndrome.

Insulin resistance and compensatory hyperinsulinemia appear to be neither necessary nor sufficient for essential hypertension to develop. The results noted in Figure 1 demonstrated that a significant proportion of patients with essential hypertension were insulin sensitive. Furthermore, blood pressure does not increase in all subjects who are insulin resistant and hyperinsulinemic, and for any number of reasons, hyperinsulinemia in these individuals does not lead to an increase in blood pressure. On the other hand, insulin-resistant subjects are more likely to develop hypertension than are insulin-sensitive individuals, and this situation resembles the pathophysiologic role of insulin resistance in the development of type 2 diabetes.[10] Hyperglycemia develops in insulin-resistant individuals when they no longer are able to secrete the large amount of insulin necessary to overcome insulin resistance. Similarly, it seems likely that hypertension only develops when some unknown compensatory response (or responses) is no longer able to overcome the metabolic changes associated with insulin resistance and compensatory hyperinsulinemia that favor an increase in blood pressure.

There are three lines of evidence providing substantial support of the view that insulin resistance/hyperinsulinemia antedates hypertension.

  1. Neither insulin resistance nor hyperinsulinemia are increased in prevalence in patients with secondary forms of hypertension.[11,12]

  2. Normotensive, first-degree relatives of patients with high blood pressure who are at increased risk to develop hypertension are relatively insulin resistant and hyperinsulinemic when compared with normotensive individuals without a family history of hypertension.[13,14,15] Furthermore, these observations are independent of differences in overall or regional adiposity.

  3. Several prospective studies have shown that baseline hyperinsulinemia, as a surrogate measure of insulin resistance, predicts the development of essential hypertension.[16,17,18,19,20] Perhaps the publication that is the most relevant to the focus of this review is the results observed in 1865 children and adolescents followed over a 6-year period.[19] In addition to showing that the higher the fasting insulin concentration at baseline, the greater the increase in blood pressure over the 6-year period of observation, evidence was presented that "high insulin levels seem to precede the development of a potentially atherogenic risk factor profile including low HDL-C, high triglyceride, and elevated systolic blood pressure."

The evidence summarized to this point suggests that insulin resistance and compensatory hyperinsulinemia are increased in prevalence in approximately 50% of individuals with hypertension, and the presence of these abnormalities in normotensive individuals predicts the eventual development of essential hypertension. Furthermore, there is no evidence that the decrease in insulin-mediated glucose disposal and increase in plasma insulin concentration described in patients with essential hypertension is secondary to high blood pressure, per se.

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