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(Circulation. 1996;93:1777-1779.)
© 1996 American Heart Association, Inc.

Articles

Insulin Resistance and Atherosclerosis

Common Roots for Two Common Diseases?

Heinrich Taegtmeyer, MD, DPhil

From the University of Texas-Houston Medical School, Department of Internal Medicine, Division of Cardiology.

Correspondence to Heinrich Taegtmeyer, MD, DPhil, Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, 6431 Fannin, Suite 1.246, Houston, TX 77030. E-mail ht@heart.med.uth.tmc.edu.

Key Words: Editorials • atherosclerosis • diabetes mellitus • diagnosis • carotid arteries

	Introduction

Top Introduction References

 
Growing up in postwar Germany as I did taught me something that is hard to forget. When people had relatively little to eat, diseases such as NIDDM and atherosclerosis were almost unheard of. Today, these diseases occur in epidemic proportions. Furthermore, atherosclerosis is now the most common and deleterious complication of NIDDM. This issue of Circulation contains the first, long-awaited results of the Insulin Resistance Atherosclerosis Study, which examines the association between insulin sensitivity and IMT of the carotid artery as an index of atherosclerosis. The study is based on observations in three distinctly different ethnic groups of approximately equal size in four communities of the United States.¹ The results show an inverse relation between insulin sensitivity and atherosclerosis in Hispanic and non-Hispanic white Americans but not among black Americans. When the investigators adjusted their results for the traditional risk factors of coronary artery disease, glucose tolerance, measures of adiposity, and fasting insulin levels, this inverse relation was reduced but not eliminated. The powerful analysis suggests therefore that insulin resistance per se is an independent cause of atherosclerosis in non-Hispanic and Hispanic whites. It also suggests that the inverse relation between insulin sensitivity and atherosclerosis is stronger than the relation between insulin and atherosclerosis. The ethnic differences are not so readily explained, although it is of interest that non-Hispanic and Hispanic whites share the same characteristics.

The findings of the present study¹ provide support for the clinical observation that diabetes and macrovascular disease not only coexist but may spring from common roots. On the one hand, the results suggest that it is possible to identify patients early who are at risk for the development of atherosclerotic vascular disease. On the other hand, they provide a challenge for the practicing physician to diagnose and treat subclinical forms of glucose intolerance in patients with coronary, peripheral, and cerebrovascular disease. The clue to understanding atherosclerosis may lie in the understanding of insulin resistance. Beyond these general conclusions, the results are important for the following three reasons.

First, it has long been known that among patients with heart disease, those also afflicted with diabetes are at especially high risk of morbidity and mortality from vascular disease. The conclusions of the present study are in line with Paul D. White's comment in 1931 that "diabetes favors arteriosclerosis" and that an "excess of insulin does not apparently affect the heart seriously,"² although much has been learned about diabetes and heart disease in subsequent years. During the last three decades, the Framingham Study has taught us that glucose intolerance and hypertension are interrelated phenomena that predispose to the development of premature atherosclerotic cardiovascular disease.³ It also indicates that both diabetic and hypertensive patients feature additional atherogenic risk factors, such as dyslipidemia, elevated fibrinogen, hyperuricemia, and left ventricular hypertrophy. Diabetes and hypertension share a strong propensity for excess weight. Furthermore, insulin has also been linked to disturbances in the fibrinolytic system.⁴

Second, in the Framingham Study,³ insulin resistance, hyperinsulinemia, hypertension, obesity, hypertriglyceridemia, and low HDL cholesterol have been shown to coexist with accelerated atherogenesis. Each of these factors, alone or in combination, has been held responsible for the increased propensity of diabetic patients to develop coronary artery disease. Although the standard risk factors for coronary artery disease (smoking, hyperlipidemia, and hypertension) explain part of the increased risk for the development of cardiovascular disease in diabetes, glucose intolerance adds another risk factor. In spite of this association, much of the effort of primary and secondary prevention of coronary heart disease in patients with diabetes remains directed at the modification of the classic risk factors alone. Another population-based survey, the San Antonio Heart Study, found a high degree of overlap between type II diabetes (ie, NIDDM), obesity, hypertension, impaired glucose tolerance, hypertriglyceridemia, and hypercholesterolemia.⁵ Thus, there is a strong suggestion that an insulin-resistance syndrome underlies each of these six disorders and carries an increased risk of coronary artery disease.⁶ However, a direct proof of this association between insulin resistance and vascular atherosclerosis has been elusive because of the difficulties involved in screening patients for insulin resistance.

In the present study,¹ the authors used the minimal model analysis of the frequently sampled intravenous glucose tolerance test as a means to assess insulin sensitivity. Although this procedure is less labor intensive than the gold standard of the glucose clamp,⁷ a direct comparison of the two methods shows a reasonable but less than perfect correlation (r=.73) between the two techniques.⁸ Even in the present study, there is still potential for error, especially in nondiabetic patients. The same concerns apply to the accuracy of measurement of atherosclerotic changes by assessment of IMT with B-mode vascular ultrasound.⁹ The strength of the association of risk factors obviously is related to the ability to measure them accurately.

Similarly, there is a need for better definition of terms. In 1988, Reaven¹⁰ used the term "Syndrome X" to describe a constellation of metabolic and hemodynamic changes associated with coronary artery disease and postulated a causal effect of impaired insulin-mediated glucose disposal and compensatory hyperinsulinemia. Since the term "Syndrome X" has been used by cardiologists to describe patients with symptoms of angina pectoris, abnormal ECGs, and normal coronary arteriograms,¹¹ there is still some confusion in the literature. It adds to the confusion that patients with microvascular angina also exhibit impaired glucose tolerance,¹² hyperinsulinemia, and insulin resistance.¹³ It is, however, unclear whether this relation is causal or coincidental.¹³ In contrast, prospective epidemiological studies have demonstrated clearly that abnormal glucose tolerance and hyperinsulinemia increase the risk for development of angiographically demonstrable coronary artery disease^{14 15} and are associated with increased mortality from coronary artery disease.¹⁶ In addition, data from the original Framingham cohort showed an association between prevalent cardiovascular disease and glycosylated hemoglobin across the entire spectrum of HbA_1c.¹⁷ Thus, it is tempting to speculate that there is a causal relation between insulin resistance, hyperinsulinemia, and the degree of glycemic control on the one hand and the development of atherosclerosis on the other.

It has been shown that near-normal glycemic control reduces the risk for development and progression of the microvascular and neurological complications of IDDM to a greater extent than the progression of macrovascular disease.¹⁸ Although the data of the Diabetes Control and Complications Trial cannot be strictly extrapolated to NIDDM because of basic differences in the pathophysiology of the two types of diabetes, we do know that normalization of blood sugar levels in NIDDM patients may require large doses of insulin. The relationship between glycemic control and vascular disease in NIDDM is itself in question. A substudy of the University Group Diabetes Program¹⁹ showed that intensive or variable insulin therapy did not affect cardiovascular morbidity and mortality.¹⁹ The next logical question, therefore, is whether hyperinsulinemia itself is a risk factor for atherosclerotic cardiovascular disease. According to a recent review of 25 prospective studies that correlated plasma insulin levels with heart disease, epidemiological evidence does not support the notion that hyperinsulinemia is a major risk factor for heart disease.²⁰ It seems reasonable to conclude that randomized intervention trials and prospective epidemiological studies have failed to answer the questions whether insulin delays (by reduction of hyperglycemia) or accelerates the development of arteriosclerotic cardiovascular disease or whether there is a causal relation between insulin levels and vascular disease at all. The available evidence suggests that it is insulin resistance per se, not hyperinsulinemia, that is associated with atherosclerosis, thrombogenesis, hypertension, obesity, and diabetes.²¹ The present study¹ makes the point that hyperinsulinemia and reduced insulin sensitivity are not the same.

Third, both reduced insulin sensitivity and atherosclerosis exist long before the clinical disease reveals itself. They share a common history. Do they also share a common heritage? The question is whether insulin resistance represents more than a marker for an "atherogenic syndrome." The present study¹ does not answer this question. However, the plot for a common heritage is thickening. It has already been proposed that diabetes and atherosclerotic cardiovascular disease share the same genetic and environmental roots.²² The "common soil hypothesis," originally advanced by Jarrett,²³ is based on the observation that cardiovascular complications are as common in newly diagnosed diabetics as in patients whose diabetes is of long duration. If atherosclerosis were a complication of NIDDM, then the frequency of atherosclerosis would increase with the increased duration of diabetes, in much the same way as the level of chronic hyperglycemia in IDDM is a concomitant factor associated with the vascular complications of diabetes.²⁴ Nondiabetic patients, who are only at risk by virtue of having impaired glucose tolerance, seem to have the same rate of cardiovascular disease as patients with long-established diabetes.²⁵ Fetal and earlylife nutritional deficiencies appear to predispose individuals to both NIDDM and cardiovascular disease in later life. Taken together, these observations have led to speculation that atherosclerosis and diabetes may arise from the same environmental and genetic roots. The proof for this hypothesis, however, has been elusive thus far.

There are two ways to test the hypothesis. The first is a descriptive approach, which examines insulin resistance as a marker or mechanism for the "atherogenic syndrome"²⁶ in large population-based surveys such as the present study.¹ An attractive feature of this approach is that the results can be translated into clinical practice today. If we have not done so already, we will test more patients with coronary and other vascular disease for impaired glucose tolerance. Conversely, we will look even harder for coronary disease in patients with impaired glucose tolerance. Treatment plans can be modified by changing diet, drugs, and exercise. The second approach is a genetic approach that uses linkage analysis and positional cloning of candidate genes.²⁷ The advantage of a molecular diagnosis is that it can be made well in advance of the appearance of clinical signs or symptoms that may take years, in the case of insulin resistance and atherosclerosis, to develop. However, recent successes with positional cloning in the isolation of genes for rare monogenic diseases such as cystic fibrosis are difficult to duplicate with common complex diseases that are influenced by more than one gene or environmental factor and do not exhibit a simple mode of inheritance. The strict one-to-one relationship between phenotypes and genotypes in monogenic disorders breaks down for complex diseases that more likely are influenced by multiple genes.²⁷ In addition, most complex diseases, such as insulin resistance and atherosclerosis, are also influenced by multiple environmental factors. To sort through these issues is an arduous task, and we are still far from the reality of a molecular diagnosis by a simple blood test.

The results of the IRAS presented in this issue of Circulation¹ are a milestone on the way to a better definition of the increased prevalence of premature cardiovascular disease in NIDDM. We begin to recognize that the pathogenesis of vascular disease in NIDDM is different from the pathogenesis of vascular disease in IDDM. The present study shows that impaired insulin sensitivity is an independent risk factor for atherosclerosis in Hispanic and non-Hispanic whites and that both insulin resistance and atherogenesis may share common roots. Like the results of many good clinical studies, the findings give rise to a host of new questions: What is the mechanism? What are the commonalities between skeletal muscle (the site of insulin resistance) and vascular smooth muscle/endothelium (the site of atherosclerosis)? Do the changes in IMT parallel similar changes in the coronary arteries? Does an impairment in insulin-mediated skeletal-muscle vasodilation contribute not only to decreased insulin sensitivity²⁸ but also to the development of atherosclerosis? What is the role of proinsulin? What is the reason for the striking difference between ethnic groups? Are there well-defined, gene-linked mutations that can be detected by molecular diagnosis? Or are the mutations so diverse that no two affected persons show the same change? Will it be possible to screen for individuals at risk and identify patients early in the course of the disease? Or, more importantly, will interventions that improve insulin sensitivity retard or reverse the development of atherosclerosis? The wish list is long. It shows that the most exciting times in research on insulin resistance and atherosclerosis are still to come! In the meantime, we would do well to get used to the idea that impaired insulin sensitivity is a risk factor for atherosclerotic vascular disease and that both may share common roots. It is never too soon for early diagnosis and intervention, especially in times of plenty.

	Selected Abbreviations and Acronyms

 

IDDM = insulin-dependent diabetes mellitus IMT = intimal-medial thickness IRAS = Insulin Resistance and Atherosclerosis Study NIDDM = non–insulin-dependent diabetes mellitus

	Acknowledgments

 
The author is supported by a grant from the National Institutes of Health (RO1-HL 43133). I wish to thank Drs Eddy Barasch, Philip Orlander, Alton L. Steiner, and Miriam Taegtmeyer for helpful comments.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

© 1996 American Heart Association, Inc.

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