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
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Introduction
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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. 1
) 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. 2
). Therefore, resistance to the
actions of insulin and IGF-I in these tissues occurs whenever there is
reduced PI3 -kinase activation (Fig. 2
).

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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.
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Insulin resistance, hypertension, and CV disease (CVD)
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Evidence has been garnered indicating that insulin
resistance and the resultant hyperinsulinemia are causally related to
hypertension (Table 2
). 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).
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.
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Role of obesity in insulin resistance
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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 1
). 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).
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 1
). 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 1
).
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
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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 20200 µg/min
(30300 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 2
). 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 2
).
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Abnormalities of coagulation in insulin resistance
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Disturbances of the fibrinolytic system have been observed in
subjects with hypertension and insulin resistance (2, 45)
(Table 1
). 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).
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Endothelial dysfunction and insulin resistance
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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 2
). 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.
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Abnormal divalent cation metabolism and vascular insulin/IGF-I
resistance
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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. 1
). 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. 2
)
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.
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Role of the RAS in insulin resistance
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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. 2
). 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.
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Acknowledgments
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We acknowledge Paddy McGowan for her usual excellent work in
preparing this manuscript.
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Footnotes
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1 This work was supported by grants from the NIH (RO1-HL-6390401),
the V.A. Merit Review, and the American Diabetes Association (to
J.R.S.). 
Received July 12, 2000.
Revised September 22, 2000.
Accepted October 11, 2000.
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