Insulin Resistance and Cardiovascular Disease1

Samy I. McFarlane, Maryann Banerji and James R. Sowers

Division of Endocrinology, Diabetes, and Hypertension, State University of New York Downstate and Brooklyn Veterans Affairs Medical Center, Brooklyn, New York 11203

Address all correspondence and requests for reprints to: James R. Sowers, M.D., F.A.C.P., Division of Endocrinology, Diabetes, and Hypertension, State University of New York Health Science Center, 450 Clarkson, Box 1205, Brooklyn, New York 11203. E-mail: jsowers{at}netmail.hscbklyn.edu


    Introduction
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
INSULIN RESISTANCE describes an impaired biological response to insulin (1, 2, 3, 4). In the early states of insulin resistance there is a compensatory increase in insulin concentrations. Although hyperinsulinemia may compensate for resistance to some biological actions of insulin, it may result in overexpression of actions in tissues that retain normal or minimally impaired sensitivity to insulin. Also, high concentrations of insulin can act through receptors for insulin-like growth factor I (IGF-I) (5, 6, 7, 8). Thus, accentuation of some actions of insulin with concurrent resistance to other actions gives rise to diverse clinical manifestations and sequelae of the insulin resistance syndrome.

In general, insulin resistance can be due to a prereceptor, receptor, or postreceptor abnormality (1). One signaling pathway for insulin and IGF-I is the phosphatidylinositide 3-kinase (PI3 -kinase) system. Upon binding to their receptors, there is autophosphorylation of the ß-subunit, which mediates noncovalent but stable interactions between the receptor and cellular proteins (1). Several proteins are then rapidly phosphorylated on tyrosine residues by ligand-bound insulin receptors, including insulin receptor substrate-1 (IRS-1) (1). IRS docking proteins bind strongly to the enzyme PI3 -kinase (1), a heterodimer consisting of a p85 regulatory subunit and a p110 catalytic subunit, via SH-2 domain interaction with the p85 subunit (1). Insulin and IGF-I stimulation increases the amount of PI3 -kinase associated with IRS, and the binding process is associated with increased activity of the enzyme. Activation of the enzyme is crucial for transducing the actions of these peptides in cardiovascular (CV) tissue (9, 10, 11, 12, 13, 14) as well as conventional insulin-sensitive tissues (1). The interruption of this pathway creates a resistance to the actions of insulin/IGF-I in stimulating vascular nitric oxide (NO) production (9, 10), CV cation transport mechanisms (11, 12, 13, 14, 15), as well as glucose transport (1, 6) (Fig. 1Go) in classically sensitive tissues such as muscle and adipose tissue. PI3-kinase mediates the increases in NO, Na+ pump, K+ channel, and calcium (Ca2+) myofilament sensitivity by increasing the trafficking and translocation of NO synthase and cation pump units as well as glucose transporters (1, 9, 16) (Fig. 2Go). Therefore, resistance to the actions of insulin and IGF-I in these tissues occurs whenever there is reduced PI3 -kinase activation (Fig. 2Go).



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Figure 1. The actions of insulin and IGF-I on cation metabolism and vascular tone.

 


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Figure 2. The interactions of insulin/IGF-I and the RAS in cardiovascular tissue (-) indicates insulin/IGF-I signaling steps that are inhibited by Ang II.

 

    Insulin resistance, hypertension, and CV disease (CVD)
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Evidence has been garnered indicating that insulin resistance and the resultant hyperinsulinemia are causally related to hypertension (Table 2Go). First, untreated essential hypertensive patients have higher fasting and postprandial insulin levels than normotensive subjects regardless of body mass; a direct correlation between plasma insulin concentrations and blood pressure levels exists (17, 18). Second insulin resistance and hyperinsulinemia exist in rats with genetic hypertension such as the Dahl hypertensive (19), the spontaneously hypertensive (20), and the Zucker obese hypertensive rat strain (21). Finally, the relationship between insulin and hypertension seen in essential hypertension does not occur with secondary hypertension (20, 22). Accordingly, insulin resistance and hyperinsulinemia are not consequences of hypertension, but, instead, a genetic predistribution may contribute to both disorders. This concept is supported by the finding of altered glucose metabolism in normotensive offspring of hypertensive persons (22, 23, 24). Mechanisms for the development of hypertension in insulin resistance/hyperinsulinemia include activation of the sympathetic nervous system, renal sodium retention, altered transmembrane cation transport, growth-promoting effects of vascular smooth muscle cells, and vascular hyperreactivity (1, 2, 3).


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Table 2. Cardiovascular risk factors that cluster with microalbuminuria

 
Four large prospective studies (25, 26, 27, 28) have shown that hyperinsulinemia is a predictor of coronary artery disease (CAD), with a few prospective reports not demonstrating such a relationship. The greatest association of hyperinsulinemia with CAD has been found in Finland in a population with a very high frequency of CAD (25). Results of a prospective investigation of 2103 men from Quebec (29) clearly showed that high fasting insulin concentrations are an independent predictor of CAD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence. Several recent studies (30, 31, 32, 33) have shown a relationship between carotid wall atherosclerotic lesions, angina, and insulin levels/resistance. One report (34) suggested that insulin levels predicted blood pressure elevations in children. Other data (35) suggest that a high ratio of estrogen to testosterone combined with hyperinsulinemia predisposes to premature coronary heart disease and related mortality in men. Collectively, these observations suggest that CV interactions of altered sex hormone profiles and high levels of insulin may aggravate hypertension and increase the risk of CV mortality in both men and women.

Aerobic exercise has been demonstrated to improve insulin sensitivity, improve the lipoprotein profile, and lower blood pressure, thus, correcting many of the abnormalities associated with the insulin resistance syndrome (1, 35). These beneficial effects may relate to improved blood flow to insulin-sensitive tissues, increased insulin sensitive slow twitch skeletal muscle fibers, reductions in insulin resistant-abdominal fat, and increased postreceptor insulin action (1, 35, 36, 37, 38, 39, 40). Further, moderate alcohol consumption and aspirin use may have beneficial effects, decreasing insulin resistance, increasing high density lipoprotein (HDL) cholesterol, reducing platelet aggregation/adhesion, etc. (39, 40, 41, 42). These strategies along with weight reduction may partially abrogate the rise in insulin resistance and type II diabetes that is occurring in Western societies.


    Role of obesity in insulin resistance
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
In Westernized, industrialized cultures, obesity plays an important role in the pathophysiology of insulin resistance and associated CVD disease (35, 36, 37, 38, 39). Obesity contributes significantly to impaired glucose tolerance, hyperinsulinemia, type 2 diabetes, dyslipidemia, and hypertension (35, 36, 37, 38, 39) (Table 1Go). If obesity is defined as a body mass index of 20% above desirable (a body mass index of ~27 kg/m2), 35 million Americans can be considered obese. The elderly population is the most rapidly growing portion of the United States population and increasingly contributes to the prevalence of obesity, hypertension, and diabetes in this country (39).


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Table 1. Metabolic and cardiovascular risk factors associated with insulin resistance and/or visceral obesity

 
Visceral obesity is an especially strong risk factor for insulin resistance/hyperinsulinemia, dyslipidemia, type 2 diabetes, hypertension, coagulation abnormalities, and premature CVD (37, 38) (Table 1Go). Insulin resistance and hyperinsulinemia in those with visceral obesity relate to the metabolic characteristics of the fat that is present in the omental and para-intestinal regions (37, 38, 39). Compared with peripheral fat cells, visceral fat is more resistant to the metabolic effects of insulin and more sensitive to lipolytic hormones (37, 38). Consequently, increased release of free fatty acids (FFA) into the portal system provides increased substrate for hepatic triglyceride synthesis and may impair first pass metabolism of insulin. The dyslipidemia of visceral obesity is that of increased apolipoprotein B concentrations, increases in the proportion of small dense low density lipoprotein particles, decreased HDL cholesterol, and elevated triglycerides (37, 38).

There are accumulating data indicating that visceral obesity and attendant risk factors are associated with increased risk for CVD. In the Quebec Cardiovascular Study, a prospective investigation in which more than 2000 middle-aged men were followed over 5 yr, 2 clinical characteristics associated with visceral obesity were the strongest independent risk factors for ischemic heart disease: fasting hyperinsulinemia and increased apolipoprotein B concentrations (37). Visceral obesity is often accompanied by insulin resistance and hyperinsulinemia. This hyperinsulinemia may, in turn, contribute to increased CVD and stroke (25, 26, 27, 28, 29, 30, 31, 32, 33, 34).

Visceral obesity is also associated with increased levels of plasminogen activator inhibitor-1 (PAI-1) (43) (Table 1Go). PAI-1 complexes with tissue-type plasminogen activator and eliminates its fibrinolytic activity (42, 43, 44, 45, 46). Low levels of plasminogen activator compared with PAI-1 levels is a predictor for CVD (42, 43). Hyperinsulinemia itself appears to be a potent stimulator for PAI-1 production (44), and levels of this atherogenic factor are particularly high in insulin-resistant type II diabetic patients (45, 46). Other risk factors associated with visceral obesity and insulin resistance include hypertension, increased fibrinogen, blood viscosity, and C-reactive protein (42, 43). All of these atherogenic risk factors are reduced by modest weight reduction (39, 40). Particularly in males, this is probably related to the fact that initial weight loss is associated with a predominant reduction in visceral fat, the adipose tissue most strongly linked to these risk factors (39, 40, 41).

Hyperuricemia appears to be a risk factor for CHD and may be a component of the insulin resistance syndrome (47, 48, 49, 50). Hypothesized mechanisms by which high serum uric acid may increase CHD risk include enhanced platelet aggregation and adhesion, concurrence of dyslipidemia, hypertension, increased blood viscosity, and enhanced propensity to coagulation (40, 42).


    Microalbuminuria, insulin resistance, and CVD
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Microalbuminuria is defined as the presence of urinary albumin above the normal but below the detectable range with the conventional urine dipstick methodology. In diabetic patients, this consists of a urinary albumin excretion rate of 20–200 µg/min (30–300 mg/24 h), as rates within this range have been shown to predict the progression of diabetic nephropathy (39). Microalbuminuria, using the above definition, represents a significant risk factor for CVD in patients with (or without) clinical diabetes. In population-based studies an increased urinary albumin excretion rate has been shown to cluster with other CVD risk factors (51, 52, 53, 54, 55, 56, 57) (Table 2Go). Indeed, microalbuminuria has been correlated with insulin levels (after an oral glucose load) (51), salt sensitivity, resistance to insulin-stimulated glucose uptake (51, 52), central obesity (17, 52), dyslipidemia (52), left ventricular hypertrophy, and the absence of nocturnal drops in both systolic and diastolic blood pressures (51, 53). Several recent prospective studies examining the progression of albuminuria in type II diabetes have found that elevated systolic blood pressure is a significant determining factor in the development of microalbuminuria (53). This is very important, because insulin-resistant patients, like those with clinical diabetes, have a predilection toward elevated systolic blood pressures (53). Indeed, there is increasing evidence that microalbuminuria is an integral component of the metabolic syndrome associated with hypertension (17, 45).

A group of nondiabetic, normotensive, first degree relatives of patients with type II diabetes mellitus has been observed who were insulin resistant and also had microalbuminuria (54). In a prospective investigation, microalbuminuria in nondiabetic persons preceded and even predicted the onset of type II diabetes mellitus (55). In this prospective investigation, persons with microalbuminuria who had not developed clinical diabetes after 3.5 yr still manifested multiple CVD risk factors, including hypertension, dyslipidemia (characterized by low HDL and elevated triglyceride), and high plasma levels of insulin (55), all components of the insulin-resistant syndrome associated with hypertension. These data provide evidence that microalbuminuria is an important component of the CV metabolic syndrome.

There have been a number of studies that have attempted to define pathophysiological factors that may underline and link microalbuminuria with various CVD risk factors. One investigative group (56) measured fractional disappearance of 125I-labeled albumin from the total plasma pool in 27 clinically healthy microalbuminuric patients and compared this measurement in nonalbuminuric controls. They concluded from their data that microalbuminuria reflects a generalized transmembrane leakiness. This same group also reported that microalbuminuria was observed in conjunction with other CVD risk factors, such as low HDL cholesterol and high fasting insulin levels (56). A potent relationship between elevated plasma levels of von Willebrand factor (a measure of endothelial cell dysfunction), increased oxygen free radical activity and other markers of CVD risks/complications have been found in persons with microalbuminuria. These observations collectively indicate that microalbuminuria clusters with most of the other CVD risk factors, and that it reflects generalized CV/renal endothelial dysfunction, insulin resistance, and enhanced oxidative stress (Table 2Go).


    Abnormalities of coagulation in insulin resistance
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Disturbances of the fibrinolytic system have been observed in subjects with hypertension and insulin resistance (2, 45) (Table 1Go). Elevated levels of fibrinogen and thrombin-antithrombin complexes seen in this syndrome increased the survival of provisional clot matrix upon transformation of fibrinogen to fibrin at sites of injured endothelium (2, 45). Increased coagulability in association with the insulin resistance syndrome may include deficiencies of endogenous antithrombolic factors (i.e. factors C and S and antithrombin III) that normally inhibit clot generation (2, 45). Circulating levels of lipoprotein(a) [Lp(a)] are often elevated in the metabolic syndrome (57). Lp(a) has a striking structural homology to plasminogen. By inhibiting fibrinolysis, increased levels of Lp(a) potentially delay thrombolysis and thus contribute to plaque progression. Elevated levels of fibrinogen have also been observed in the insulin-resistant state (57), and hyperfibringenemia is a powerful independent risk factor for CVD as well as being synergistic with the effects of dyslipidemia and hypertension (58).


    Endothelial dysfunction and insulin resistance
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Hypertension, especially that associated with enhanced salt sensitivity (59), is often associated with insulin resistance in studies of both lean and obese subjects (60, 61) (Table 2Go). In studies of insulin resistance using the euglycemic hyperinsulinemic clamp technique, skeletal muscle accounts for the majority of whole body glucose uptake (59, 60, 61, 62). Normally, there is a close relationship between insulin-dependent glucose utilization and incremental muscle blood flow in response to insulin. Peripheral vasodilatation taking place during systemic infusion of insulin is abolished by the administration of inhibitors of the NO synthase enzyme, suggesting a crucial role for NO in the normal vasodilatory response to insulin. This response is lost in insulin-resistant/obese persons suggesting resistance to the action of insulin to induce vascular NO production (45). Indeed, considerable data suggest that insulin sensitivity is selectively impaired in extrahepatic tissues in subjects predisposed to the development of hypertension. In this regard, there exists a strong clustering of markers of endothelial damage and insulin resistance in subjects predisposed to salt-sensitive hypertension (59).

In obese subjects with insulin resistance, multiple defects in vascular insulin action have been observed (59, 60, 61, 62). First, resistance to insulin-mediated glucose uptake has been reported in these individuals (60, 62). Second, insulin stimulation of blood flow is blunted in these individuals (59, 60, 62). More recently, in studies of vascular compliance, investigators have observed that the ability of insulin to decrease aortic wave reflection, as determined from augmentation and the augmentation index, was severely blunted in obese subjects (61). This defect was not observed in the basal state, but became evident only after insulin stimulation, suggesting that the defect was a consequence of impaired insulin action. These observations suggest that insulin resistance extends to large conduit vessels as well as to vessels regulating peripheral blood flow. Work conducted by one group suggests that elevated levels of nonesterified FFA in obesity/insulin resistance may contribute to vascular resistance to the actions of insulin (63). This is consistent with the idea that the increase in type I (aerobic, red) skeletal muscle fibers with regular exercise enhances insulin sensitivity (2). These fibers have greater insulin sensitivity than type II fibers (2). Such muscle fibers primarily rely on FFA as their fuel and improve insulin sensitivity in part by decreasing plasma FFA. In contrast, a preponderance of type II (anaerobic, white) muscle fibers, which is typically observed in subjects with a sedentary lifestyle, contributes to insulin resistance.


    Abnormal divalent cation metabolism and vascular insulin/IGF-I resistance
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Insulin and IGF-I have functional and receptor homology in CV tissue as well as classical insulin-responsive tissue such as adipose tissue and skeletal muscle (5, 6, 7). IGF-I, unlike insulin, is synthesized by vascular smooth muscle cells (VSMC) and cardiomyocytes (5, 6, 7). Production of IGF-I in CV tissues is stimulated by mechanical stress, insulin, angiotensin II (Ang II), and other growth factors (5, 6, 7, 8). Both insulin and IGF-I reduce vascular tone, in part through effects on cation metabolism (Fig. 1Go). Both peptides attenuate calcium (Ca2+) influx into VSMC by decreasing receptor-mediated and voltage-operated Ca2+ channel currents associated with VSMC contractile responses (5, 6, 7, 15). Both peptides increase Ca2+-adenosine triphosphatase (Ca2+-ATPase) activity in plasma membranes and intracellular organelles, and activate Ca2+ dependent potassium (K) channels (5, 6, 7, 8). As NO activates Ca2+-dependent K channels, effects of insulin/IGF-I on these channels is mediated in part via increased NO production by endothelial cells and VSMC. Another mechanism by which insulin/IGF-I decreases VSMC intracellular Ca2+/vasoconstriction, is through stimulation of the Na+,K+-ATPase pump, through both transcriptional and posttranslational modifications of the pump (5, 6, 7). As the Na+,K+-ATPase pump stimulates the transport of Na+ and K+ ions against concentration gradients, energy must be supplied through ATP hydrolysis (15). ATP generated by aerobic glycolysis is preferentially used for this process, suggesting that insulin/IGF-I-mediated glucose transport is a potential mechanism by which these peptides stimulate pump activity. Recently, it has been demonstrated that insulin/IGF-I activation of the PI3-kinase pathway is critical for the ability of these peptides to stimulate the pump (11). Thus, altered PI3-kinase responses to insulin/IGF-I may explain the decreased ability of those peptides to mediate vasodilation in insulin-resistant patients. As Ang II has been shown to interfere with PI3 activation in VSMC (13) and cardiomyocytes (14) (Fig. 2Go) overexpression of the tissue renin-angiotensin system (RAS) may be one of the major factors in CV insulin/IGF-I resistance (5, 6, 7, 8).

The increased peripheral vascular resistance that often accompanies insulin resistance may be due in part to altered VSMC divalent cation metabolism. Agonist-induced VSMC intracellular Ca2+ and vascular reactivity are both increased in the Zucker obese insulin-resistant rat (6). Decreased VSMC magnesium ([Mg2+]i) may also be an important contributing factor for increased vascular resistance in the state of insulin resistance (15). Under normal circumstances, insulin increases cellular uptake of Mg2+, and in states of decreased cellular insulin action, there is a reduction in [Mg2+]i. Recently, using nuclear magnetic resonance imaging techniques, we have shown that IGF-I also increases tissue Mg2+ concentrations (15). Depletion of VSMC [Mg2+]i due to insulin/IGF-I resistance leads, in turn, to increased peripheral vascular resistance. Thus, the VSMC [Ca2+/Mg2+] ratio is increased in insulin-resistant states, and this causes additional insulin resistance and hypertension.


    Role of the RAS in insulin resistance
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 
Two recent large clinical trials have provided data suggesting that angiotensin-converting enzyme (ACE) inhibitor therapy decreased the propensity to develop type II diabetes in patients with hypertension and/or those at high risk for CVD (64, 65). This is of major importance, as recent observations indicate that hypertensive patients are often insulin resistant and have a considerably increased risk of developing diabetes over time (66). The fact that ACE inhibitors have been found to decrease the progression to type II diabetes in these high risk patients is consistent with the idea that they improve insulin sensitivity (67).

The RAS is expressed extensively throughout the CV system (13, 14). By immunohistochemistry, there is considerable ACE activity in endothelial cells as well as VSMC and heart tissue. Conversion from Ang I to Ang II by local ACE has been described, and this can be blocked with an ACE inhibitor. The mechanism by which overexpression of the RAS may cause resistance in CV tissues is currently unclear. It has been suggested that increased microvascular blood flow would occur to insulin-sensitive tissues such as skeletal muscle tissue and adipocytes (68). Another mechanism by which ACE inhibitors may improve insulin sensitivity is by decreasing the inhibitory effects of Ang II on insulin signaling. In cardiac tissue, in contrast to insulin/IGF-I, Ang II acutely inhibits basal as well as insulin-stimulated PI3-kinase activity (14). In VSMC, although stimulation with Ang II increases basal PI3-kinase activity, it inhibits insulin-stimulated PI3-kinase activity (13, 14) (Fig. 2Go). Indeed, there are recent data (10) from our laboratory as well as others, that insulin/IGF-I vascular resistance may be mediated via abnormal signaling of the PI3-kinase pathway. This reduced signaling leads to decreased NO synthase/Na+,K+ gene activation/expression and the increased peripheral vascular resistance characteristic of insulin-resistant states (2, 3, 4, 5, 6). Thus, insulin resistance is a predisposing factor for hypertension, dyslipidemia, hypercoagulability, endothelial dysfunction, albuminuria, and premature CVD. Weight reduction and exercise remain the cornerstones for approaching the CVD risks associated with insulin resistance. Recent clinical trials as well as prior experimental evidence suggest that ACE inhibitor therapy may also reduce insulin resistance and the propensity to develop type 2 diabetes mellitus.


    Acknowledgments
 
We acknowledge Paddy McGowan for her usual excellent work in preparing this manuscript.


    Footnotes
 
1 This work was supported by grants from the NIH (RO1-HL-63904–01), the V.A. Merit Review, and the American Diabetes Association (to J.R.S.). Back

Received July 12, 2000.

Revised September 22, 2000.

Accepted October 11, 2000.


    References
 Top
 Introduction
 Insulin resistance,...
 Role of obesity in...
 Microalbuminuria, insulin...
 Abnormalities of coagulation in...
 Endothelial dysfunction and...
 Abnormal divalent cation...
 Role of the RAS...
 References
 

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