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(Circulation. 1996;93:1780-1783.)
© 1996 American Heart Association, Inc.

Articles

Insulin Resistance, Its Consequences, and Coronary Heart Disease

Must We Choose One Culprit?

G.M. Reaven, MD; Y-D.I. Chen, MD, PhD

From the Department of Medicine, Stanford University School of Medicine, Stanford, Calif, and Shaman Pharmaceuticals, Inc, South San Francisco, Calif.

Key Words: Editorials • insulin • atherosclerosis • coronary disease

	Introduction

Top Introduction References

 
Approximately 25 years ago, our research group^{1 2} used quantitative methods to show that resistance to insulin-mediated glucose disposal was present in patients with either impaired glucose tolerance or NIDDM. These initial observations have been confirmed on multiple occasions since then, and there is now a large body of evidence that shows that this defect is present in the vast majority of glucose-intolerant individuals.^{3 4 5 6 7 8} In addition, several reports^{9 10 11} demonstrated that first-degree relatives of patients with NIDDM are also relatively insulin resistant compared with well-matched volunteers without a family history of NIDDM. Finally, prospective studies^{12 13 14 15 16} have identified insulin resistance and/or compensatory hyperinsulinemia as the initial defect in the development of NIDDM. Thus, the central role of insulin resistance in the pathogenesis and clinical course of patients with NIDDM has been well established. Of greater relevance to the IRAS study of "Insulin Sensitivity and Atherosclerosis" published in this issue of Circulation¹⁷ is recent awareness that the ability of insulin to mediate glucose disposal can differ by as much as 10-fold in subjects with normal glucose tolerance.^{18 19} Because the degree of insulin resistance in a substantial portion of these persons approaches that seen in patients with impaired glucose tolerance or NIDDM, it is assumed that they are able to secrete enough insulin to overcome the insulin resistance and maintain normal glucose tolerance.

Unfortunately, the philanthropic response on the part of the pancreatic ß-cell is not without cost, and in 1988,²⁰ it was emphasized that these individuals were at increased risk to have higher plasma TG and lower HDL cholesterol concentrations and higher blood pressure. More importantly, it was suggested that the cluster of abnormalities associated with insulin resistance, designated as Syndrome X, significantly increased the risk of CHD. Given this background, it should come as no surprise to the reader that we were delighted to see the results of the IRAS investigators. Although many publications have identified an association between various facets of Syndrome X and CHD, this is the first report in which quantitative methods have been applied to measure insulin action, the step we believe to be most fundamental in the development of this syndrome. Indeed, for this reason alone, demonstration by the IRAS investigators that it is possible to measure insulin sensitivity in 1400 subjects is of great importance.

In addition to showing that there is a significant association between differences in insulin sensitivity and IMT of the internal carotid artery, the results of the IRAS also emphasize that the magnitude of the relationship is quite robust. Indeed, the conclusion of the investigators,¹⁷ consistent with their data, is that "moderate differences in insulin sensitivity were associated with differences in IMT nearly as large as those associated with many of the traditional cardiovascular risk factors." In this context, it would have been useful if the IRAS investigators had been somewhat more pathophysiological in their approach to data analysis. For example, LDL cholesterol and HDL cholesterol are similar in that both are considered to be traditional risk factors for CHD, but they are quite different in that concentrations of HDL cholesterol but not LDL cholesterol are highly correlated with insulin resistance.^{20 21} Consequently, it would have been interesting to have seen the impact on the relationship between insulin sensitivity and IMT if these two variables had been entered into the statistical models separately. In addition, because high TG and low HDL cholesterol concentration are both associated with insulin resistance,^{20 21} we find it inexplicable that TG concentration was not entered into any of the statistical models. The fact that TG concentration was not considered in the statistical analysis is an important issue, and we will return to it.

Finally, consideration of the importance of traditional risk factors in the genesis of CHD is not as easy to address as it might seem. Thus, in addition to the previously mentioned association between insulin resistance and TG and HDL cholesterol concentrations,^{20 21} it should be remembered that there is also a relationship between insulin resistance and hypertension.²² To this must be added the fact that smokers are more insulin resistant and dyslipidemic than nonsmokers.^{23 24} Consequently, even our "traditional" view of traditional risk factors for CHD may need modification to take into consideration the impact of insulin resistance on these variables.

The IRAS investigators¹⁷ stress that longitudinal studies will be necessary to further clarify the various relationships described in their report. We welcome this cautionary statement, because great care must be taken when one extrapolates from cross-sectional relationships to causality. However, we think it is important to also urge caution before we accept two very important conclusions drawn by the IRAS investigators. Our first concern, and the simplest one, relates to their statement that "this relationship of [insulin sensitivity] with atherosclerosis was not seen in black subjects." By implication, it is suggested that insulin resistance or its consequence does not play a role in the pathogenesis of CHD in blacks. We believe this is a dangerous conclusion to be drawn from a cross-sectional study conducted in several different centers, with 60% of the blacks enrolled from just one center (and none from two of the centers), and given that this was not a population-based study. Of greater concern is the fact that the baseline characteristics of the black subjects were quite different from the other two population groups; eg, they had greater values for IMT, were the most insulin resistant, weighed the most, and had a higher proportion of diabetes, and more than half the group was hypertensive. (It should be noted that blacks were more insulin resistant despite the fact that they had the lowest ratio of waist-to-hip girth.)

Although none of the issues outlined above rule out the possibility that there is an ethnic difference in the association between insulin resistance and atherogenesis in blacks compared with the two other ethnic groups studied, we are uncomfortable with this conclusion. First, the lack of a relationship between insulin sensitivity and IMT in blacks may simply be a reflection of a "plateau effect"; ie, this group was so insulin resistant, hypertensive, diabetic, and atherogenic that the relationship between variation in insulin sensitivity and IMT could no longer be discerned. In short, the untoward effects of insulin resistance had been realized already. Second, we do not find compelling the view that the similarity between the findings in Hispanics and non-Hispanic whites, as differentiated from blacks, is because the two former population groups are ethnically closer together than either group is with individuals of African descent. It is clear that the association between insulin resistance and atherosclerosis is not limited to populations of European ancestry. For example, all of the relationships between insulin resistance and its consequences, including documented CHD, have been shown to exist in individuals of Chinese ancestry.^{25 26 27} Furthermore, insulin resistance in Japanese patients with angiographically documented CHD has been demonstrated recently, including evidence of a significant relationship between degree of insulin resistance and severity of CHD.²⁸ Finally, the IRAS investigators¹⁷ comment that the lack of a relationship between insulin resistance and atherosclerosis is "reminiscent of the lack of association of [insulin sensitivity] with blood pressure in blacks in some studies." The fact that a population-based study did not reveal any correlation between blood pressure and insulin resistance must be put into perspective with the observation that blacks with high blood pressure have been shown to be insulin resistant compared with normotensive members of the same ethnic group.²⁹ Thus, although it is possible, we would be surprised if blacks, as distinct from several population groups, were unique in that insulin resistance or its consequences do not increase risk of CHD.

Of even greater concern to us is the conclusion, at least in non-Hispanic whites and Hispanics, that "insulin resistance may have an independent effect on atherogenesis," unrelated to any other risk factor! Although it is always tempting to imply pathophysiological causality from epidemiological data, it is an enticement that is probably best spurned. In the first place, one should consider the shortcomings of the statistical methods used. For example, the authors¹⁷ conclude "that the relation of insulin sensitivity with atherosclerosis is stronger than that between insulin measures and atherosclerosis." However, this does not rule out the possibility that the compensatory hyperinsulinemia that is directly related to degree of insulin resistance in nondiabetic subjects^{18 19} plays a role, direct or indirect, in the pathogenesis of atherosclerosis. The reproducibility of the method used to quantify insulin sensitivity in this study¹⁷ has been estimated to have a coefficient of variation of 15% when the study is performed twice in the same person.³⁰ In contrast, the plasma insulin concentration 2 hours after an oral glucose tolerance test varied by more than 30% in half of a group of normal subjects studied 48 hours apart in a clinical research setting.³¹ It is obvious that the more precisely two variables are measured, the greater the chances that a relationship between them might be discerned. In addition, the complexity involved in the regulation of the variable in question cannot be ignored. Thus, although the method used to quantify insulin sensitivity is complicated, the phenomenon measured is a straightforward one. Conversely, the measurement of plasma insulin concentration is quite simple, but the variable in question is a complex result of degree of insulin resistance, plasma glucose concentration, and pancreatic insulin secretory response,¹⁹ not to mention differences in insulin catabolic rate. This issue is further confounded by the variable relationship that exists between insulin resistance and hyperinsulinemia in the three study groups. There is an approximate 10-fold variability between degrees of insulin resistance in normal subjects, with a strong, direct relationship between degree of insulin resistance and extent of the plasma insulin response.^{18 19} In contrast, there is much less variability in the degree of insulin resistance in patients with NIDDM.^{8 20} Indeed, it is stated by the IRAS investigators¹⁷ that no insulin sensitivity was detected in 15% of the population, or 210 subjects, primarily those with NIDDM. Thus, 50% of the patients with NIDDM who were studied were absolutely insulin resistant by the technique used. Furthermore, the relationship between insulin resistance and plasma insulin response to glucose can range from a positive to a negative one in this heterogeneous population.³² Consequently, we find it necessary to question the wisdom of attempting to glean a common relationship between insulin resistance, plasma insulin response, and IMT given the heterogeneity of the associations that exist within each subgroup on which the analysis was based.

Finally, what we find most confusing in the article by the IRAS investigators¹⁷ is the exclusion of TG metabolism from their analysis of the link between insulin resistance and CHD. Perhaps the best way to approach this issue is first to focus on the relationship between insulin resistance, compensatory hyperinsulinemia, ambient FFA concentrations, hepatic VLDL-TG secretion, and plasma TG concentrations. Specifically, if an insulin-sensitive person is infused with glucose, it will lead to an increase in plasma insulin concentration, an increased rate of insulin-mediated disposal, a fall in plasma FFA and glycerol concentrations, and, in the absence of the essential substrate, a decline in hepatic VLDL-TG secretion and plasma TG concentration. This series of events does not in the least mimic patients with endogenous hyperglyceridemia, who are insulin resistant and hyperinsulinemic^{33 34} and have higher FFA and glycerol concentrations despite their higher insulin levels.³⁵ Multiregression analysis of these data³⁵ indicated that the daylong plasma TG response to conventional meals was significantly correlated with both daylong insulin and FFA responses. Patients with type I diabetes in poor glycemic control are also insulin resistant and have markedly elevated FFA concentrations.³⁶ However, their daylong free insulin levels are not elevated, and they have normal values for hepatic VLDL-TG secretion rates and plasma TG concentrations.³⁶ The significance of these different clinical vignettes is important for the following reasons. First, they reinforce the difficulty inherent in the attempt to differentiate the pathophysiological impact of insulin resistance from that of hyperinsulinemia; in the case of VLDL-TG metabolism, it appears that both changes are likely to be necessary. Second, the association between insulin resistance, compensatory hyperinsulinemia, and hypertriglyceridemia is by far the oldest and best-established downstream consequence of insulin resistance.^{33 34 35} Third, although controversy may continue as to whether or not hypertriglyceridemia is an independent risk factor for CHD,³⁷ there is no doubt that the higher the plasma TG concentration, the smaller and denser the LDL particles,³⁸ the greater the degree of postprandial lipemia,³⁹ and the higher the levels of plasminogen activator inhibitor-I.⁴⁰ All of these latter changes increase the risk of CHD, as acknowledged by the IRAS investigators.¹⁷ In light of this information and as alluded to previously, we cannot understand why the plasma TG concentration was not included in the statistical models used in Table 2 of the IRAS report¹⁷ to evaluate the independent risk factor status of insulin resistance.

In conclusion, we applaud the effort of the IRAS investigators to quantify insulin action in 1400 subjects, and we believe their demonstration of a relationship between degree of insulin resistance and IMT is a finding of enormous importance. The sooner insulin resistance and its consequences become accepted as "traditional" risk factors for CHD, the better. On the other hand, we are quite concerned, in a practical sense, that the link between insulin resistance and CHD is presumed not to be operative in blacks, and in a physiological sense, we find it difficult to believe that insulin resistance by itself, and not its consequences, leads to CHD. At this point, it might be best to simply acknowledge that there is a relationship between insulin resistance and the cluster of abnormalities associated with this defect and an increased risk of CHD, without attempting to define the ultimate mechanism responsible for the association or deciding that the relationship is not a universal one.

	Selected Abbreviations and Acronyms

 

CHD = coronary heart disease FFA = free fatty acid IMT = intimal-medial thickness IRAS = Insulin Resistance and Atherosclerosis Study NIDDM = non–insulin-dependent diabetes mellitus TG = triglyceride

	Footnotes

 
Reprint requests to G.M. Reaven, MD, Shaman Pharmaceuticals, Inc, 213 E Grand Ave, South San Francisco, CA 94080-4812.

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

	References

Top Introduction References

 

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