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ORIGINAL ARTICLE

Abnormalities of Coagulation and Fibrinolysis in Insulin Resistance

Evidence for a common antecedent?

John S. Yudkin, MD, FRCP

Insulin resistance is associated not only with the classic cardiovascular risk factors of hypertension and dyslipidemia, but also with several disorders of coagulation and fibrinolysis. Elevated concentrations of the fibrinolytic inhibitor plasminogen activator inhibitor-1 are associated with insulin resistance. In experimental systems, increased expression and secretion of plasminogen activator inhibitor-1 by hepatocyte and endothelial cell lines can be induced by insulin, proinsulin-like molecules, triglyceride-rich lipoproteins and oxidized LDL, as well as by inducing insulin resistance in isolated hepatocytes. Concentrations of the endothelial cell protein von Willebrand factor are elevated in insulin-resistant states, suggesting that abnormalities of capillary endothelium, as well as those reported for endothelium-dependent vasodilatation, may play a role in the etiology of insulin resistance. Levels of a third coagulation factor, fibrinogen, are elevated in insulin-resistant subjects, an association that suggests a possible role for acute-phase cytokines in the abnormalities of coagulation and endothelial function. It is proposed that the recent observations of secretion of interleukin-6 by adipose tissue, combined with the actions of adipose tissue–expressed tumor necrosis factor- in obesity-induced insulin resistance, could underlie the associations of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease.

Diabetes Care 22 (Suppl. 3):C25–C30, 1999

An excess risk of coronary heart disease (CHD) is shared by people with frank diabetes and with lesser degrees of glucose intolerance (1), suggesting that hyperglycemia per se is not the major player in this excess risk. A number of studies have documented that hyperinsulinemia predicts the incidence of CHD in diverse populations (2–4), and a recent report from Quebec suggests that this association is independent of the classic risk factors, including concentrations of HDL cholesterol (5). In the absence of hyperglycemia, hyperinsulinemia is an indicator of insulin resistance (6). The conclusion drawn from these observations is that, independent of the classic risk factors associated with insulin resistance, obesity, hypertension, and dyslipidemia (7), either insulin resistance or hyperinsulinemia is a risk factor for CHD. This may, moreover, be the case both in nondiabetic and in diabetic populations (8).

Several actions of insulin itself might accelerate the atherothrombotic process (9), an interpretation that would cast doubts on the wisdom of insulin therapy in the high-cardiovascular-risk, insulin-resistant patient with type 2 diabetes. Conversely, it is possible that insulin resistance is associated with risk factors for cardiovascular disease other than those measured in the population studies and that the accelerated cardiovascular disease is a consequence of such mechanisms. Among such risk factors are several of the coagulation factors that have been reported as abnormal in patients with diabetes (Table 1), and which in turn may be regarded as cardiovascular risk factors. Of these abnormalities, three are indeed associated with insulin resistance: plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor, and fibrinogen.

In this review, I argue that the associations of these disorders of coagulation and fibrinolysis with insulin resistance argue against a prime role for insulin resistance in cardiovascular risk. It is proposed that the observations suggest instead the existence of a common antecedent, which is responsible for both the insulin resistance and the coagulation abnormalities. Recent findings on the role of adipose tissue–derived proinflammatory cytokines in the etiology of insulin resistance offer a novel interpretation of the link between insulin resistance and cardiovascular risk. Although many other abnormalities of coagulation are well recognized in diabetes, in particular abnormalities of platelet function, their links with insulin resistance are not as clear and as such, are not considered further in this article.

PAI-1— PAI-1 is a fast-acting inhibitor of fibrinolysis that alters the thrombotic-fibrinolytic equilibrium in favor of occlusion. Activity of PAI-1 is raised in young men surviving a myocardial infarction and predicts recurrent events (10). We have found raised levels of PAI-1 in patients with type 2 diabetes (11), particularly in the presence of CHD (12), although levels are generally normal in uncomplicated type 1 diabetes. We have reported that elevated levels of PAI-1 in patients with diabetes may help explain the worse outcome of diabetic patients after myocardial infarction (13).

PAI-1 is powerfully associated with hyperinsulinemia and insulin resistance in population studies (14,15), but the mechanism of such an association is potentially complex. Thus, a number of factors associated with the insulin resistance cluster are able to induce expression or secretion of PAI-1 by isolated liver cell or endothelial cell lines in tissue culture, including triglyceride-rich lipoproteins (16), oxidized LDL (17), proinsulin-like molecules (18), and insulin itself (19). There is, however, evidence from an elegant study by Juhan-Vague and her group (20) that insulin resistance itself is able to increase the secretion of PAI-1 from isolated hepatocytes, an effect that is synergistic with insulin.

Of the three coagulation factors under consideration, then, PAI-1 is the one that best satisfies candidature for the insulin resistance syndrome. Nevertheless, the metabolic abnormalities associated with insulin resistance (hypertriglyceridemia, hyperproinsulinemia and small dense phenotype of LDL), as well as the potential contribution of adipose tissue to circulating levels of PAI-1 (21), may further elevate PAI-1 levels in insulin-resistant subjects.

VON WILLEBRAND FACTOR— Von Willebrand Factor (vWF) is synthesized and secreted by endothelial cells and, to a lesser extent, by megakaryocytes (22). Circulating concentrations of vWF, interpreted as a marker of endothelial damage, are elevated in smokers and in subjects with a wide variety of other cardiovascular risk factors (23), and predict cardiovascular events in patients with angina (24). Endothelial injury and activation have been proposed as initiating factors in atherogenesis (25) and, through the secretion of vWF and other procoagulant and adhesion molecules, may also contribute to a prothrombotic state (23).

In population studies, concentrations of vWF have been found to correlate with those of insulin (26,27). Furthermore, in 33 patients with type 2 diabetes, we found a relationship between endothelial dysfunction, as evidenced by raised concentrations of vWF, and a measure of insulin resistance (28). This could imply that endothelial dysfunction may be a feature of the insulin resistance syndrome. There is, indeed, substantial evidence for an association between the insulin resistance cluster and another phenotype attributed to endothelial dysfunction. Several studies in both diabetic and nondiabetic subjects have documented insulin resistance or hyperinsulinemia in patients with microalbuminuria (29–31), which is another cardiovascular risk factor implying underlying endothelial dysfunction (32). Yet, although the direction of the cause-and-consequence arrow is conceptually unproblematic in most of the candidate members of the expanded insulin resistance cluster shown in Fig. 1, it is more difficult to conceptualize a causative link between insulin resistance and either microalbuminuria itself or endothelial damage in general. Possible mechanisms of endothelial damage associated with insulin resistance include the adverse effects both of oxidized small dense LDL and of nonesterified fatty acids on the endothelium (33,34), although such effects are on resistance vessel (endothelium-dependent vasodilatation)—not capillary (increased albumin loss from the vascular compartment)—endothelial function.

Figure 2—Associations between insulin resistance, CHD, and microalbuminuria—consequences of a common antecedent?

An alternative interpretation is that insulin resistance and microalbuminuria might be the common consequences of an antecedent (Fig. 2), such as endothelial dysfunction. We have argued (23) that capillary endothelial integrity may be necessary for the active transport of insulin from the circulating compartment into the interstitial space, thereby explaining observations of a concentration gradient of insulin across the capillary wall (35) and of the delay in reaching steady-state glucose uptake during a stepped hyperinsulinemic clamp (36). Much debate has taken place on the contribution of insulin-mediated increases in muscle blood flow to the changes in muscle glucose uptake during a euglycemic-hyperinsulinemic clamp (37,38), but it could be postulated that in the presence of resistance vessel endothelial dysfunction, a failure of an insulin-mediated increase in blood flow could further contribute to insulin resistance (39).

In addition to the dysfunctional endothelium playing a role in insulin resistance, other aspects of endothelial pathology could underlie additional components of the insulin resistance cluster (23). The enzyme lipoprotein lipase is bound by glycosaminoglycans to the capillary endothelial surface, and defects in lipoprotein lipase binding and action might underlie the dyslipidemia associated with insulin resistance (40). A defect in basal nitric oxide production could account for the association of endothelial dysfunction/insulin resistance with elevated blood pressure (41). And finally, to return to the starting point of this section, endothelial activation might underlie a number of the abnormalities of coagulation and fibrinolysis—including vWF—that cluster with hyperinsulinemia or insulin resistance in population studies (26,27).

FIBRINOGEN— Although it is difficult to attribute microalbuminuria, elevated concentrations of vWF, or other markers of endothelial dysfunction to being a consequence of hyperinsulinemia or insulin resistance, there are other abnormalities associated with this cluster for which cause-and-consequence explanations are even more problematic. Fibrinogen is an acute-phase protein, synthesized by the liver in response to circulating concentrations of interleukin-6 (42), but also regulated to some degree by polymorphisms in the fibrinogen gene (43). We (44) and others (26,45,46) have reported relationships between concentrations of fibrinogen and those of insulin in population studies and have argued that this observation raises questions about the centrality of insulin resistance to the cluster of metabolic, hemostatic, and hemodynamic abnormalities with which it is linked.

We have further explored the relationships between acute-phase activation and insulin resistance variables in a population of 107 healthy nondiabetic Caucasian subjects (47). In these subjects, we found significant relationships between concentrations of C-reactive protein, the classic acute-phase protein, and measures of insulin resistance, triglycerides, blood pressure, and (inversely) HDL cholesterol (Table 2). These relationships were also found between circulating concentrations of the two proinflammatory cytokines, tumor necrosis factor- (TNF-) and interleukin-6 (IL-6), and levels of most of the insulin resistance variables. Furthermore, a composite score of insulin resistance related to a score of acute-phase variables (TNF-, IL-6, C-reactive protein, and fibrinogen) with a correlation coefficient of r = 0.59 (P< 0.0001), implying that even using these crude measures, acute-phase activation statistically "explains" ~35% of the variance of insulin resistance. Moreover, these associations were largely independent of obesity, as removing the measures of body fat from the insulin resistance score reduced the correlation coefficient only to r = 0.53. The confounding effects of cigarette smoking and prevalent CHD were not able to explain these relationships.

These observations raise the possibility that acute-phase activation might somehow underlie a number of the components of the insulin resistance cluster (Fig. 2), including those, such as fibrinogen, that are difficult to conceptualize as a direct consequence of insulin resistance.

We also explored the relationship between the acute-phase markers and a series of indicators of endothelial activation, including vWF, and again found strong correlations compatible with the known effects of proinflammatory cytokines on endothelial cell function (48–50). In such a fashion, might the production of proinflammatory cytokines also explain the association of insulin resistance with endothelial dysfunction and microalbuminuria and, perhaps more remotely, with CHD itself?

A number of questions remain. First, what is the origin of the elevated concentrations of proinflammatory cytokines in a healthy population? Second, are there plausible biological mechanisms that might explain the association between cytokine production and insulin resistance? And finally, are there experimental data to support the postulated cause-and-consequence relationship?

We sought relationships between concentrations of proinflammatory cytokines and titers of antibodies to three organisms that have been proposed to play a potential role in atherogenesis: Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus (51). The relationships were weak and generally insignificant (47). Much more powerful were the relationships between concentrations of both cytokines and measures of global, and particularly central, obesity (Table 2), which suggests the possibility of an adipose tissue source for these cytokines. Both cytokines are expressed in adipose tissue (52,53), and adipocytes release TNF- in vitro (54). We have recently reported significant secretion of IL-6, but not TNF-, by a subcutaneous adipose tissue bed (55). There has been much interest in the possible role of adipose tissue–expressed TNF- in defects of insulin action in obesity and diabetes (56,57), as well as in abnormalities in lipid metabolism (58); and IL-6 shares some of these actions (59,60). If these cytokines are mediating the effect of obesity on insulin resistance, dyslipidemia, and endothelial dysfunction, it is likely that the role of TNF- is a paracrine one, as local concentrations in adipose tissue, or perhaps in skeletal muscle, are more likely to approximate those needed for metabolic effects in vitro (56). The production of TNF- in adipose tissue may also play a role in the increased production of PAI-1 in obese subjects (61). The other cytokine, IL-6, if playing any significant metabolic function, is more likely to play an endocrine role, because its role in the hepatic acute-phase response depends on signaling at a site distant from its place of synthesis. As to the experimental evidence in support of such a hypothesis, studies of infusion of TNF- soluble receptor or neutralizing antibody have provided conflicting evidence (62,63), and similar studies testing a possible role for IL-6 remain to be done. In the interim, it remains possible that the associations reflect the adipose tissue source of the cytokines and that some other product of the adipocyte, such as nonesterified fatty acids, is responsible for the insulin resistance (64) and the endothelial dysfunction (33,34) associated with obesity.

CONCLUSIONS— In this article, the relationships between insulin resistance and three coagulation factors have been explored, with inferences drawn on the possible mechanisms underlying the associations (Fig. 3). For PAI-1, both the effect of insulin resistance on the hepatocyte and the influence of several associated phenotypes on liver and endothelial cells provide ample evidence in favor of a cause-and-effect relationship. For vWF, a marker of endothelial activation and damage, an alternative explanation is that insulin action requires endothelial integrity at both the resistance vessel and capillary level. However, the association between the acute-phase marker fibrinogen and insulin resistance suggests a role for proinflammatory cytokines in the insulin resistance cluster and perhaps also in the association between the cluster and endothelial dysfunction. The interpretation of the conflicting hypotheses is important, because a common antecedent, such as endothelial dysfunction or adipose tissue–expressed cytokines (Fig. 2), would exonerate insulin from accusations of threat to the vascular system, a refutation that the results of the UK Prospective Diabetes Study (65) have finally provided.

Acknowledgments— The author would like to acknowledge Group Support from the British Diabetic Association and Project Grant support from the British Heart Foundation (Grants 95097, 95145, and 97150), the Wellcome Trust (Grant M96-3405), and the Jules Thorn Charitable Trust (Grant 97/184).

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From the Centre for Diabetes and Cardiovascular Risk, University College London, London, U.K.

Address correspondence and reprint requests to Professor John S. Yudkin, MD, FRCP, Centre for Diabetes and Cardiovascular Risk, Department of Medicine, University College London, G Block, Archway Wing, Whittington Hospital, Archway Road, London N19 3UA, U.K. E-mail: j.yudkin@ucl.ac.uk.

Received for publication 6 July 1998 and accepted in revised form 29 October 1998.

Abbreviations: CHD, coronary heart disease; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor 1; TNF-, tumor necrosis factor-; vWF, von Willebrand Factor.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

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