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Original Studies |
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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 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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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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Insulin resistance, hypertension, and CV disease (CVD) |
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TopIntroductionInsulin 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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). 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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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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TopIntroductionInsulin 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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). 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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). 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).
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Microalbuminuria, insulin resistance, and CVD |
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TopIntroductionInsulin 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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). 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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TopIntroductionInsulin 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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). 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 |
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TopIntroductionInsulin 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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). 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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TopIntroductionInsulin 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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). 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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TopIntroductionInsulin 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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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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Footnotes |
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Received July 12, 2000.
Revised September 22, 2000.
Accepted October 11, 2000.
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References |
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TopIntroductionInsulin 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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1-adrenergic reactivity in dorsal hand veins. Hypertension. 30:1150–1155.This article has been cited by other articles:
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|
 |
|
  A. Y.Y. Cheng and L. A. Leiter Cardiovascular risk and glycemic control Can. Med. Assoc. J., April 28, 2009; 180(9): 907 - 908. [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Cooper-DeHoff, M. A. Pacanowski, and C. J. Pepine Cardiovascular therapies and associated glucose homeostasis: implications across the dysglycemia continuum. J. Am. Coll. Cardiol., February 3, 2009; 53(5 Suppl): S28 - S34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Kosmala, T. M. O'Moore-Sullivan, R. Plaksej, J. Kuliczkowska-Plaksej, M. Przewlocka-Kosmala, and T. H. Marwick Subclinical Impairment of Left Ventricular Function in Young Obese Women: Contributions of Polycystic Ovary Disease and Insulin Resistance J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3748 - 3754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
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 |
|
 D. A. Calhoun, D. Jones, S. Textor, D. C. Goff, T. P. Murphy, R. D. Toto, A. White, W. C. Cushman, W. White, D. Sica, et al. Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research Circulation, June 24, 2008; 117(25): e510 - e526. [Abstract] [Full Text] [PDF]
|
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 |
|
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|
|
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 |
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|
 C. Schindler Review: The metabolic syndrome as an endocrine disease: is there an effective pharmacotherapeutic strategy optimally targeting the pathogenesis? Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 7 - 26. [Abstract] [PDF]
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 E. Ingelsson, J. Sundstrom, L. Lind, U. Riserus, A. Larsson, S. Basu, and J. Arnlov Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men Eur. Heart J., July 2, 2007; 28(14): 1739 - 1745. [Abstract] [Full Text] [PDF]
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J. Girouard, Y. Giguere, J.-M. Moutquin, and J.-C. Forest Previous Hypertensive Disease of Pregnancy Is Associated With Alterations of Markers of Insulin Resistance Hypertension, May 1, 2007; 49(5): 1056 - 1062. [Abstract] [Full Text] [PDF]
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 C. S. Stump, M. T. Hamilton, and J. R. Sowers Effect of Antihypertensive Agents on the Development of Type 2 Diabetes Mellitus Mayo Clin. Proc., June 1, 2006; 81(6): 796 - 806. [Abstract] [Full Text] [PDF]
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 A. Morganti Randomized Clinical Trials on Surrogate End Points: Are They Useful for Evaluating Cardiovascular and Renal Disease Protection in Hypertension? The Case for Yes J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S141 - S144. [Abstract] [Full Text] [PDF]
|
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|
V. Koka, W. Wang, X. R. Huang, S. Kim-Mitsuyama, L. D. Truong, and H. Y. Lan Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II-Generating Pathway in Diabetic Complications Circulation, March 14, 2006; 113(10): 1353 - 1360. [Abstract] [Full Text] [PDF]
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 |
|
 P. V. G. Katakam, J. A. Snipes, C. D. Tulbert, K. Mayanagi, A. W. Miller, and D. W. Busija Impaired endothelin-induced vasoconstriction in coronary arteries of Zucker obese rats is associated with uncoupling of [Ca2+]i signaling Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R145 - R153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Brantsma, S. J.L. Bakker, H. L. Hillege, D. de Zeeuw, P. E. de Jong, R. T. Gansevoort, and the PREVEND Study Group Urinary Albumin Excretion and Its Relation With C-Reactive Protein and the Metabolic Syndrome in the Prediction of Type 2 Diabetes Diabetes Care, October 1, 2005; 28(10): 2525 - 2530. [Abstract] [Full Text] [PDF]
|
|
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 |
|
 G D Kolovou, K K Anagnostopoulou, and D V Cokkinos Pathophysiology of dyslipidaemia in the metabolic syndrome Postgrad. Med. J., June 1, 2005; 81(956): 358 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. De Cosmo, A. Minenna, O. Ludovico, S. Mastroianno, A. Di Giorgio, L. Pirro, and V. Trischitta Increased Urinary Albumin Excretion, Insulin Resistance, and Related Cardiovascular Risk Factors in Patients With Type 2 Diabetes: Evidence of a sex-specific association Diabetes Care, April 1, 2005; 28(4): 910 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sekikawa, H. Ueshima, W. R. Zaky, T. Kadowaki, D. Edmundowicz, T. Okamura, K. Sutton-Tyrrell, Y. Nakamura, K. Egawa, H. Kanda, et al. Much lower prevalence of coronary calcium detected by electron-beam computed tomography among men aged 40-49 in Japan than in the US, despite a less favorable profile of major risk factors Int. J. Epidemiol., February 1, 2005; 34(1): 173 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Blazer-Yost, J. C. Vahle, J. M. Byars, and R. L. Bacallao Real-time three-dimensional imaging of lipid signal transduction: apical membrane insertion of epithelial Na+ channels Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1569 - C1576. [Abstract] [Full Text] [PDF]
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|
|
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V. A. Fonseca, J. Diez, and D. B. McNamara Decreasing Restenosis Following Angioplasty: The potential of peroxisome proliferator-activated receptor {gamma} agonists Diabetes Care, November 1, 2004; 27(11): 2764 - 2766. [Full Text] [PDF]
|
|
|
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 |
|
 S.-H. H. Juo, H.-F. Lin, T. Rundek, E. A. Sabala, B. Boden-Albala, N. Park, M.-Y. Lan, and R. L. Sacco Genetic and Environmental Contributions to Carotid Intima-Media Thickness and Obesity Phenotypes in the Northern Manhattan Family Study Stroke, October 1, 2004; 35(10): 2243 - 2247. [Abstract] [Full Text] [PDF]
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 |
|
 J. R. Sowers Treatment of Hypertension in Patients With Diabetes Arch Intern Med, September 27, 2004; 164(17): 1850 - 1857. [Abstract] [Full Text] [PDF]
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M. Terzolo, B. Allasino, S. Bosio, E. Brusa, F. Daffara, M. Ventura, E. Aroasio, G. Sacchetto, G. Reimondo, A. Angeli, et al. Hyperhomocysteinemia in Patients with Cushing's Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3745 - 3751. [Abstract] [Full Text] [PDF]
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J. VrbIkova, D. Cibula, K. Dvorakova, S. Stanicka, G. Sindelka, M. Hill, M. Fanta, K. Vondra, and J. Skrha Insulin Sensitivity in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2942 - 2945. [Abstract] [Full Text] [PDF]
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 F. R. DANESH and Y. S. KANWAR Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy FASEB J, May 1, 2004; 18(7): 805 - 815. [Abstract] [Full Text] [PDF]
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J. R. Sowers Insulin resistance and hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1597 - H1602. [Abstract] [Full Text] [PDF]
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G. L. Bakris and J. R. Sowers When Does New Onset Diabetes Resulting From Antihypertensive Therapy Increase Cardiovascular Risk Hypertension, May 1, 2004; 43(5): 941 - 942. [Full Text] [PDF]
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 N. Winer and J. R. Sowers Epidemiology of Diabetes J. Clin. Pharmacol., April 1, 2004; 44(4): 397 - 405. [Abstract] [Full Text] [PDF]
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 V. Fonseca, C. Desouza, S. Asnani, and I. Jialal Nontraditional Risk Factors for Cardiovascular Disease in Diabetes Endocr. Rev., February 1, 2004; 25(1): 153 - 175. [Abstract] [Full Text] [PDF]
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M. F. Muldoon, R. H. Mackey, K. V. Williams, M. T. Korytkowski, J. D. Flory, and S. B. Manuck Low Central Nervous System Serotonergic Responsivity Is Associated with the Metabolic Syndrome and Physical Inactivity J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 266 - 271. [Abstract] [Full Text] [PDF]
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S. I. McFarlane, N. Winer, and J. R. Sowers Role of the Natriuretic Peptide System in Cardiorenal Protection Arch Intern Med, December 8, 2003; 163(22): 2696 - 2704. [Abstract] [Full Text] [PDF]
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L. Ibanez and F. de Zegher Flutamide-Metformin Therapy to Reduce Fat Mass in Hyperinsulinemic Ovarian Hyperandrogenism: Effects in Adolescents and in Women on Third-Generation Oral Contraception J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4720 - 4724. [Abstract] [Full Text] [PDF]
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S. De Cosmo, R. Trevisan, M. Dalla Vestra, M. Vedovato, A. Argiolas, A. Solini, A. Saller, F. Damone, A. Tiengo, V. Trischitta, et al. PC-1 Amino Acid Variant Q121 Is Associated With a Lower Glomerular Filtration Rate in Type 2 Diabetic Patients With Abnormal Albumin Excretion Rates Diabetes Care, October 1, 2003; 26(10): 2898 - 2902. [Abstract] [Full Text] [PDF]
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R. H. Knopp, B. Retzlaff, B. Fish, C. Walden, S. Wallick, M. Anderson, K. Aikawa, and S. E. Kahn Effects of Insulin Resistance and Obesity on Lipoproteins and Sensitivity to Egg Feeding Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1437 - 1443. [Abstract] [Full Text] [PDF]
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L. Ibanez, K. Ong, A. Ferrer, R. Amin, D. Dunger, and F. de Zegher Low-Dose Flutamide-Metformin Therapy Reverses Insulin Resistance and Reduces Fat Mass in Nonobese Adolescents with Ovarian Hyperandrogenism J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2600 - 2606. [Abstract] [Full Text] [PDF]
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M. Schachter, A. Raziel, S. Friedler, D. Strassburger, O. Bern, and R. Ron-El Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine Hum. Reprod., April 1, 2003; 18(4): 721 - 727. [Abstract] [Full Text] [PDF]
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S. I. McFarlane and J. R. Sowers Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 516 - 523. [Full Text] [PDF]
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A. Angeli and M. Terzolo Adrenal Incidentaloma--A Modern Disease with Old Complications J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4869 - 4871. [Full Text] [PDF]
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 D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers Metformin: An Update Ann Intern Med, July 2, 2002; 137(1): 25 - 33. [Abstract] [Full Text] [PDF]
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J. R. Sowers Endothelial Vasodilation Effects of Statins in Type 2 Diabetic Patients : Response to van Venrooij et al. Diabetes Care, July 1, 2002; 25(7): 1242 - 1243. [Full Text] [PDF]
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S. I. McFarlane, R. Muniyappa, R. Francisco, and J. R. Sowers Pleiotropic Effects of Statins: Lipid Reduction and Beyond J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1451 - 1458. [Abstract] [Full Text] [PDF]
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S. I. McFarlane, S. J. Jacober, N. Winer, J. Kaur, J. P. Castro, M. A. Wui, A. Gliwa, H. Von Gizycki, and J. R. Sowers Control of Cardiovascular Risk Factors in Patients With Diabetes and Hypertension at Urban Academic Medical Centers Diabetes Care, April 1, 2002; 25(4): 718 - 723. [Abstract] [Full Text] [PDF]
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 L. H. Canani, D. P.K. Ng, A. Smiles, J. J. Rogus, J. H. Warram, and A. S. Krolewski Polymorphism in Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 Gene (ENPP1/PC-1) and Early Development of Advanced Diabetic Nephropathy in Type 1 Diabetes Diabetes, April 1, 2002; 51(4): 1188 - 1193. [Abstract] [Full Text] [PDF]
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M. Terzolo, A. Pia, A. Ali, G. Osella, G. Reimondo, S. Bovio, F. Daffara, M. Procopio, P. Paccotti, G. Borretta, et al. Adrenal Incidentaloma: A New Cause of the Metabolic Syndrome? J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 998 - 1003. [Abstract] [Full Text] [PDF]
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M. J. Quon Limitations of the Fasting Glucose to Insulin Ratio as an Index of Insulin Sensitivity J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4615 - 4617. [Full Text] [PDF]
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