The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease
Fadi A. El-Atat,
Sameer N. Stas,
Samy I. McFarlane and
James R. Sowers
Department of Internal Medicine, University of Missouri-Columbia and H. S. Truman VAMC, Columbia, Missouri; Divisions of Cardiovascular Medicine and Endocrinology, Diabetes and Hypertension, Department of Medicine, State University of New York-Downstate Medical Center, Brooklyn, New York; USA and VA Medical Center, Brooklyn, New York.
Correspondence to Dr. James R. Sowers, Professor of Medicine and Physiology, University of Missouri-Columbia, Department of Internal Medicine, MA410 Health Science Center, One Hospital Drive, Columbia, MO 65212. Phone: 573–884–2013; Fax: 573–884–1996; E-mail: Sowersj{at}health.missouri.edu
The incidence of end-stage renal disease (ESRD) has risen dramaticallyin the past decade, mainly due to the increasing prevalenceof diabetes mellitus, and both impaired glucose tolerance andhypertension are important contributors to rising rates of ESRD.Obesity, especially the visceral type, is associated with peripheralresistance to insulin actions and hyperinsulinemia, which predisposesto development of diabetes. A common genetic predispositionto insulin resistance and hypertension and the coexistence ofthese two disorders predisposes to premature atherosclerosis.A constellation of metabolic and cardiovascular derangements,which also includes dyslipidemia, dysglycemia, endothelial dysfunction,fibrinolytic and inflammatory abnormalities, left ventricularhypertrophy, microalbuminuria, and increased oxidative stress,is referred to as the cardiometabolic syndrome. The componentsof this syndrome, individually and interdependently, substantiallyincrease the risk of renal disease, cardiovascular disease (CVD)and mortality. Similar findings and cardiorenal risk factorscan occur in subjects with android obesity without excess bodyweight.
Recently, microalbuminuria has been gaining momentum as a componentand marker for the cardiometabolic syndrome, in addition tobeing an early marker for progressive renal disease in patientswith this syndrome or in those with diabetes. Furthermore, itis now established as an independent predictor of CVD and CVDmortality. This review examines the relationship between insulinresistance/hyperinsulinemia and hypertension in the contextof cardiometabolic syndrome, progressive renal disease and acceleratedCVD. The importance of microalbuminuria as an early marker forthe cardiometabolic syndrome is also discussed in this review.
The cardiometabolic syndrome is currently estimated to affect24% of the adult population (1). In addition to diabetes, whichis the leading cause of end-stage renal disease (ESRD) in westernizedsocieties, other metabolic and cardiovascular abnormalitiesassociated with the cardiometabolic syndrome contribute to progressiverenal disease, cardiovascular disease (CVD), and CVD mortality(Table 1) (2). Of particular importance are hypertension andinsulin resistance/hyperinsulinemia, which frequently coexistand contribute substantially to CVD and ESRD (3–10). Thereappears to be a common genetic predisposition to both insulinresistance and hypertension. Furthermore, insulin resistance/hyperinsulinemiacontributes to the elevated BP through several mechanisms, oneof which is tissue angiotensin II (AngII) and aldosterone actions,leading to vascular resistance to the effects of insulin (Figure 1)(6,7,9–14). Other mechanisms include enhanced sympatheticnervous system (SNS) activity, dyslipidemia, atherosclerosis,enhanced oxidative stress, hypercoagulability, left ventricularhypertrophy (LVH), renal functional and structural changes andglomerulosclerosis, progressive renal disease, and eventuallyESRD (3–5, 15–21) (Figure 2). Microalbuminuria,in addition to being an early marker for nephropathy, is anestablished marker for increased CVD morbidity and mortalityin patients with hyperinsulinemia and hypertension (22). Furthermore,it is increasingly recognized as a marker for the cardiometabolicsyndrome (23–26).
Figure 2. Mechanisms responsible for hypertension and progressive renal failure in the insulin-resistant state. Structural and functional alterations in the kidneys collaborate, resulting in activation of the sympathetic nervous system (SNS) and the renin-angiotensin aldosterone system (RAAS) and leading to fluid retention. Once ESRD develops, it perpetuates hypertension.
Epidemiology of Insulin Resistance, Associated Cardiometabolic Derangements and Progressive Renal Disease
There has been an alarming growth of the prevalence of chronickidney disease (CKD) (Figure 3) and ESRD (Figures 4, 5, and 6) over the last decade, in concert with a striking increasein the burden of diabetes, the leading cause of ESRD (Figures5 and 6). Additionally, increasing rates of obesity (Figure 4)and associated insulin resistance and hypertension (Figures5 and 6) are major contributors to ESRD (2). The costs attributedto ESRD have risen from 4.8% a decade ago to 6.3% of all Medicareexpenditures, consuming a total of $22.83 billion currently(2). ESRD treatment is initiated earlier, reflecting in part,an increasing burden of associated comorbidities, includingdiabetes and other cardiometabolic abnormalities (2), with increasinglevels of inflammatory markers, correlating with a decline inkidney function (2). Furthermore, the USRDS 15th annual reportprojects that by the year 2030, the ESRD population will increaseby 460,000 new cases annually and the prevalent population willreach 2.24 million, with two thirds of these numbers havingdiabetes as the primary cause of renal disease (2).
Figure 3. Trends in the size of Medicare CKD population by diabetes status reported by the United States Renal Data Systems Survey (USRDS) 15th annual report, 2003 (2).
Figure 4. Estimated prevalence of cardiovascular risk factors as assessed by the National Health and Nutrition Examination Surveys I, II, and II incidence of ESRD reported by the USRDS, 2001 (40).
Figure 5. Adjusted ESRD incident rates, by primary diagnosis, and diabetes in the general population reported by the USRDS 15th annual report, 2003 (2).
Figure 6. Prevalent counts and adjusted rates of ESRD patients, by primary diagnosis, reported by the USRDS 15th annual report, 2003 (2).
In parallel with the growth in kidney disease, the prevalenceof obesity/insulin resistance and impaired glucose metabolismhas been increasing rapidly, currently meeting epidemic proportions(1,27). The prevalence of diagnosed and undiagnosed diabetescombined, which constitute a major portion of the insulin-resistantpopulation is estimated at 8% of adult population (21,27). Aneven greater number of patients have the cardiometabolic syndrome(24%) (1). Furthermore, obesity appears to be one of the mostimportant risk factors for ESRD and is of increasing significanceas its prevalence rises in this country.
This alarming growth of cardiometabolic abnormalities and resultantrenal disease emphasizes the importance of prevention and controlof these derangements (2,9). Indeed, the increasing awarenessand improvement of control of these risk factors, although stillsuboptimal, may be the reason behind the slowing trend of ESRDincident rates between 1998 and 2001 (2).
Visceral obesity triggers a litany of maladaptive cardiovascular,renal, metabolic, prothrombotic and inflammatory responses,some of which form the "cardio-metabolic syndrome" (Table1;Figure 2) (3–5,14). These responses, including hyperinsulinemia/insulinresistance, dysglycemia, dyslipidemia, hyperleptinemia, hypercortisolemia,altered vascular structure and function, enhanced SNS and renin-angiotensin-aldosteronesystem (RAAS) activities, hypercoagulability, and an alteredKallikrein-Kinin system, individually and interdependently,contribute to progressive renal disease/ESRD, hypertension,and other CVD morbidity and mortality (Figure 7) (3–5,16).In fact, the parallel increase in the prevalence of obesityand ESRD suggests that obesity is one of the most importantprecursors of ESRD (4) (Figure 4).
Figure 7. A summary of the mechanisms by which obesity/insulin resistance leads to cardiovascular morbidity and mortality. NAP - natriuretic peptide; SNS - sympathetic nervous system; RAAS - renin-angiotensin aldosterone system; HR - heart rate; PRD - progressive renal disease; ESRD - end-stage renal disease; LVH - left ventricular hypertrophy; HF - heart failure; - increase.
Insulin resistance and hyperinsulinemia in those with visceralobesity relate to the metabolic characteristics of the fat thatis present in the omental and para-intestinal regions (13,14).Compared with peripheral fat cells, visceral fat is more resistantto the metabolic effects of insulin and more sensitive to lipolytichormones (13). Consequently, increased release of free fattyacids (FFA) into the portal system provides increased substratefor hepatic triglyceride synthesis and may impair first passmetabolism of INS (13,14).
Furthermore, data from the NHANES survey show a remarkable andlinear relationship between rise in body mass index (BMI) andsystolic BP (SBP), and diastolic BP (DBP), and pulse pressuresin the American population (3). In regression models correctedfor age-related increase in BP, a gain of 1.7 kg/m2 for menand 1.25 kg/m2 for women in BMI or an increase 4.5 cm for menand 2.5 cm for women in waist circumference corresponds to anincrease in SBP of 1 mmHg (3). Obesity by itself possibly accountsfor 78% and 65% of essential hypertension in men and women,respectively, according to data from the Framingham Cohort (19).Animal experiments and human studies have confirmed this causationand given insight into the mechanisms involved (3–5,14).
The role of inflammation in the insulin resistance syndromehas been gaining momentum (3,4,13). Central adipose tissue iscurrently recognized as a rich milieu and source of inflammatorycytokines, such as tumor necrosis factor- (TNF-), interleukin-6(IL-6), and C-reactive protein (CRP), and plasminogen activatorinhibitor (PAI-1). It is thought that the central adipocytesynthesizes TNF-, which in turn stimulates IL-6, considereda major regulator in the production of acute phase reactantssuch as CRP, PAI-1, and fibrinogen from the hepatocyte (3,13).As such, obesity has been suggested to be a low-grade inflammatorycondition increasingly important in the causation and progressionof hypertension and endothelial dysfunction (3,4,13). A directcause-and-effect relationship, however, has not been clearlyestablished. It is not known, for example, whether long-termtreatment with nonsteroidal anti-inflammatory drugs reducesthe level of inflammatory cytokines or alleviates hypertensiveand vascular disease in obese patients (3).
Moreover, there are accumulating data to indicate that visceralobesity and attendant risk factors are associated with increasedrisk for CVD. In the Quebec Cardiovascular Study, a prospectiveinvestigation in which more than 2000 middle-aged men were followedover 5 yr, two clinical characteristics associated with visceralobesity were the strongest independent risk factors for coronaryheart disease (CHD): fasting hyperinsulinemia and increasedapolipoprotein B concentrations (13). Visceral obesity is oftenaccompanied by insulin resistance and hyperinsulinemia. Thishyperinsulinemia may, in turn, contribute to increased CVD (12–14).
Extensive studies also confirmed the role of obesity in thedevelopment of progressive renal disease (3–6). Obesityis associated with activation of RAAS and SNS activities, hyperinsulinemia/insulinresistance, dyslipidemia, dysglycemia, endothelial dysfunction,which individually and interdependently contribute to renalfunctional and structural changes, progressive renal disease,and eventually, ESRD (3,4,6,10).
Collectively, the interaction among the various metabolic andhemodynamic abnormalities associated with visceral obesity andinsulin resistance/hyperinsulinemia predispose patients to atherosclerosis,premature CVD, including hypertension, progressive renal diseaseand eventually, ESRD.
Insulin Resistance/Hyperinsulinemia and Hypertension: Coexistence and Genetic Predisposition
The association of hypertension, insulin resistance, and resultanthyperinsulinemia is well established (3–10,14). In untreatedessential hypertensive patients, fasting and postprandial insulin(INS) levels are higher than in normotensive controls, regardlessof the BMI, with a direct correlation between plasma INS concentrationsand BP. Insulin resistance and hyperinsulinemia also exist inrats with genetic hypertension such as Dahl hypertensive andspontaneously hypertensive rat (SHR) strains (3). On the otherhand, the association of insulin resistance and essential hypertensiondoes not occur in secondary hypertension (6). This suggestsa common genetic predisposition for essential hypertension andinsulin resistance, a concept that is also supported by thefinding of altered glucose metabolism in normotensive offspringof hypertensive patients (8). This concept is further supportedby the discovery of some genetic defects in people with combinationsof insulin resistance, obesity, dyslipidemia, dysglycemia andhypertension (28,29). These defects include a mutation in the3-adrenergic receptor, which regulates lipolysis in visceralfat, and the presence of two mutated genes on chromosome 7q,one that controls insulin levels and hypertension and the other,leptin, a peptide that regulates food intake (3,28). Deficiencyin CD36, a known fatty acid transporter, is also believed tobe involved in the predisposition to insulin resistance andhypertension in Asians (29).
A genetic predisposition to insulin resistance and hypertensionis present in type 2 diabetic patients, who constitute a largechunk of the insulin-resistant population, and elevated BP inthese subjects is primarily due to essential hypertension (7,8).However, in type 1 diabetes mellitus, hypertension is oftensecondary to overt nephropathy (7). Elevated BP, in turn, exacerbatesnephropathy; thus these comorbid states reinforce each other(3,13).
In addition to the genetic predisposition, insulin resistance/hyperinsulinemiais incriminated in the development of hypertension through abnormalitiesin insulin signaling and associated cardiovascular and metabolicderangements (6–9). These would include cell membraneion exchange, enhanced SNS and RAAS and suppressed atrial natriureticpeptide (ANP) activities, sodium retention, volume expansion,progressive renal disease/ESRD, cardiac hyperreactivity, LVH,dyslipidemia, dysglycemia and increased oxidative stress (7)(Figures 1 and 2).
Of importance is that there is little direct or experimentalevidence that hyperinsulinemia, per se, can raise BP despitethe correlation of insulin/resistance/hyperinsulinemia and hypertensionin clinical studies. People with insulinomas do not appear tohave increased arterial pressure (30). Furthermore, insulin-infuseddogs do not have an increase in BP (31). On the other hand,there is experimental evidence for the role of insulin resistancein the etiology of hypertension. Insulin, acting through PI3-k/AKTpathways, leads to increased NO production from the endothelialcells (EC) and decreased myosin light chain activation/vasoconstrictionin VSMC, ultimately a vasodilator effect. In the insulin-resistantstate, there is inhibition of these INS signaling pathways,thus contributing to vasoconstriction (12).
Direct Effects of INS/IGF-1 and AngII Counterregulatory Actions
In the insulin-resistant state, the selective resistance toINS and its homologous autocrine/paracrine peptide insulin likegrowth factor-1 (IGF-1) signaling in the endothelial, vascularsmooth muscle cell (VSMC), and skeletal muscle cells is due,in part, to the antagonistic action of AngII (Figure 1) (10–14).AngII, acting through its ANG type 1 receptor (AT1R), inhibitsthe actions of INS in vascular and skeletal muscle tissue, inpart, by interfering with INS signaling through phosphatidylinositol3-kinase (PI3-K) and protein kinase (AKT) metabolic pathways(12). This leads to decreases in nitric oxide (NO) productionin EC, increased myosin light chain activation/vasoconstrictionin VSMC, and reduced skeletal muscle glucose transport. In fact,one mechanism by which INS and (IGF-1) attenuate vascular contractilityis through effects on VSMC divalent cation metabolism (7,10,12).These peptides reduce Ca2+ influx into VSMC by attenuating bothvoltage- and receptor-operated Ca2+ channels, limit the releaseof Ca2+ from intracellular organelles, and stimulate the Na+,K+-ATPasepump, leading ultimately to reduced intracellular Ca2+ concentration([Ca2+]i) and thus contributing to vascular relaxation (7,12).Also, insulin and IGF-1 increase the cellular uptake of Mg2+,an ultimately beneficial vasorelaxant effect. AngII, throughincreasing oxidative stress and RhoA activity inhibits theseeffects, thus contributing to vasoconstriction (7,12).
Both INS and IGF-1 exert their effects on vascular tone, inpart via metabolic actions exerted on EC (7,9,12,14). Both peptidesstimulate NO production, a process mediated by PI3-K/AKT signalingpathways, and AngII inhibits this vasorelaxant effect of insulin/IGF-1(7,9,12). In addition, AngII antagonizes the INS-induced increasein GLUT-4 transport to the skeletal muscle cell membrane, therebyreducing cellular glucose uptake (7,12). The generation of reactiveoxygen species (ROS) appears to be one of the mechanisms bywhich AngII interferes with INS and IGF-1 signaling in thesetissues (12,13).
Another role for hyperinsulinemia in the etiology of hypertensionrelated to insulin resistance is via upregulation of AT1R byposttranscriptional mechanisms such as stabilization of mRNAand prolongation of its half-life (12,13). This potentiatesthe physiologic actions of AngII, which include peripheral vasoconstrictionand plasma volume expansion (12,13).
In concert with the above-described actions of insulin on vasculature,clinical studies have shown that lessening of insulin resistanceimproves BP control (7,11). For instance, aerobic exercise traininghas been shown to improve insulin sensitivity and lower BP amongsedentary, non-diabetic, hypertensive subjects (7,16). Followingan 8-wk treatment with an insulin-sensitizing agent, patientswith essential hypertension and mild diabetes exhibited a significantimprovement in BP control and glucose metabolism (11). Thesefindings were enhanced by a recent study, using another insulin-sensitizingagent in which treatment of nondiabetic hypertensive patientsincreased insulin sensitivity, reduced SBP and DBP, and inducedfavorable changes in markers of cardiovascular risk (17). Anotheroral hypoglycemic agent, metformin, improved BP control in arodent model of insulin resistance (18). Collectively, thesefindings suggest that insulin resistance and hypertension areinterrelated processes that are responsive to drugs that targetinsulin sensitivity.
Both animal and human studies suggest that increased SNS activity,where vascular and renal INS actions are selectively preserved,may be another mediator of hypertension in insulin resistance/hyperinsulinemiastate via stimulating renal sodium reabsorption with subsequentvolume expansion and increasing cardiac output (CO) (7,32).This is especially true in obese subjects. Although there arevariations between different ethnic groups, insulin resistanceand hyperinsulinemia are more pronounced and are more stronglyassociated with hypertension in obese subjects than lean individuals(6). In the Normative Aging Study, SNS activity was elevatedwith hyperinsulinemia and correlated with BMI (33). In thisstudy also, both insulin concentrations and urinary norepinephrineexcretion correlated significantly with BP, a relation thatpersisted even after adjustment for BMI and other variables(33). Further evidence for the involvement of SNS in the relationbetween hyperinsulinemia and hypertension comes from diet studiesand the pathogenesis of obesity-hypertension. It has been foundthat obese subjects have elevated SNS activity, measured bothdirectly and indirectly (4,6,34). To support the hypothesisfurther, sympathetic denervation of the kidneys has a significantnegative effect on renal sodium retention and thereby on obesityhypertension (4,5). In dogs fed a high-fat diet, renal nervesappear crucially important for sodium retention and hypertension(35). In dogs with denervated kidneys, sodium retention wasmarkedly attenuated, thereby leading to a lower BP. It thereforeappears that renal nerves play a pivotal role in salt retention,impaired pressure natriuresis, and hypertension (35,36). Furthermore,food intake, primarily, fat and carbohydrate, increases SNSactivity, whereas fasting and weight loss decrease it in bothanimal and humans (32,36). INS is believed to partially mediatethis effect of diet centrally; it stimulates the uptake andmetabolism of glucose in the regulatory cells anatomically relatedto the ventromedial nucleus of the hypothalamus, suppressingan inhibitory pathway between these cells and the brainstem,and subsequently disinhibiting the sympathetic outflow fromthe brainstem (37). This would preserve energy balance throughregulating thermogenesis, although an unwanted byproduct results,which is the sympathetic stimulation of the heart, kidneys,and vasculature, contributing to hypertension. In insulin resistance,which is selective with preserved insulin effects on the sympatheticsystem, the associated hyperinsulinemia leads to exaggerationof the SNS response to diet, contributing to the pathophysiologyof hypertension in hyperinsulinemia. Other mechanisms and mediatorspostulated as causative in the genesis of enhanced adrenergicactivity in the insulin-resistant state include renal afferentnerves stimulated by increased intrarenal pressures and subsequentactivation of renal mechanoreceptors, plasma FFA, AngII, elevatedleptin levels, potentiation of central chemoreceptor sensitivity,and impaired baroreflex sensitivity (4–6, 34, 36).
Adipose tissue, especially visceral type, possesses a localRAAS, which has more significant local paracrine as well assystemic effects than the subcutaneous fat (4,10). In insulinresistance/hyperinsulinemia, which is frequently associatedwith visceral obesity, RAAS activity is increased (4,10). Thiscontributes to the cardiometabolic derangements associated withinsulin resistance, including increased SNS activity, sodiumretention and volume expansion, progressive renal disease, elevatedBP, inhibition of INS signaling, and concentric LVH (3–6,13).
In addition to the increased adipose tissue RAAS activity, systemicRAAS effects are also enhanced in the insulin-resistant/hyperinsulinemicstate, despite a state of sodium retention and volume expansion(3–5,13). It has been postulated that increased FFA, throughtheir effects on the liver, may be contributing to the elevatedaldosterone in insulin resistance (3). Also, it has been reportedthat AngII, angiotensin-converting enzyme (ACE) levels and plasmarenin activity (PRA) correlate with BMI (5). Furthermore, weightloss, on short-term basis, resulted in significant reductionin PRA, aldosterone, and mean arterial pressure (MAP) in a studyof 25 obese patients, supporting the relation between BMI andRAAS activity in insulin resistance (34).
RAAS also seems to play an important role in insulin sensitivity.Several large trials, including the Captopril Prevention Project(CAPPP) (38) and the Heart Outcomes Prevention Evaluation Study(HOPE) (39) generated data suggesting that ACE inhibitors decreasethe propensity to develop type 2 diabetes in hypertensive andhigh-risk patients, respectively. Also, there is a similar beneficialeffect for angiotensin receptor blockers (ARB) in preventingdevelopment of diabetes (40). These beneficial effects of RAASblockade on insulin sensitivity have been confirmed by in vivostudies where AT1R blocking agents resulted in an improvementin INS-mediated glucose utilization in INS-resistant rodents(41). These studies and the fact that hypertension per se isan insulin-resistant state (7,13,14) suggest that RAAS may havea crucial role in the pathophysiology of insulin resistanceand that ACE inhibitors and ARB may improve insulin sensitivity.Two postulated mechanisms for this insulin-sensitizing effectof ACE inhibitors include improvement in microvascular bloodflow to peripheral tissues and reversal of the inhibitory effectsof AngII on INS signaling (42).
The natriuretic peptide system consists of the atrial natriureticpeptide (ANP), the brain natriuretic peptide (BNP), and theC-type natriuretic peptide (CNP), each encoded by a separategene. They are synthesized predominantly in the heart, brain,and kidneys and work via specific receptors, namely NPr-A, NPr-B,and NPr-C (3). The natriuretic peptides have a protective roleon the development of hypertension due to their natriureticand vasodilator effects as well as due to their inhibitory effecton the SNS and the RAAS (3). In obesity/hyperinsulinemia, overexpressionof NPr-C receptor and lower levels and function of ANP witha possible role for a promotor variant at position –55in the NPr-C gene, have been reported, contributing to increasedsodium retention (3,43,44). Nannipieri et al. (45). assessedthe interaction between insulin and ANP in type 2 diabetes comparedwith healthy subjects. They concluded that there was dual disruptionof ANP levels and function control in type 2 diabetic persons.ANP release was resistant to volume stimulation in type 2 diabeticpatients, and natriuresis was resistant to ANP action. Thisfurther emphasizes the role of ANP in BP regulation in the insulin-resistantstate. Weight loss may partially reverse these abnormalitiesin patients with the cardiometabolic syndrome and in those withtype 2 diabetes mellitus (44).
Natural History: Functional and Structural Changes, Compensatory Responses, and Late Nephronal Damage
Insulin resistance/hyperinsulinemia state is associated withactivation of both RAAS and SNS activities, contributing toincreased renal sodium reabsorption, associated fluid retentionand hypertension (Figure 2) (3–6,13,32,34,36). Also, thisstate is accompanied by increased EC proliferation and intrarenallipid and hyaluronate deposition in the matrix and inner medulla(Figure 2) (3–5,44,46). These depositions increase intrarenalpressure and volume in the tightly encapsulated kidney, leadingto parenchymal prolapse and urine outflow obstruction, whichresult in slow tubular flow and subsequently increased sodiumreabsorption, especially in the loop of Henle (4,5). This leadsto inappropriately small natriuretic response to saline loadat mean and glomerular pressure, often referred to as "impairedpressure natriuresis" (4–6,13,46).
These functional and structural changes in the kidney provokecompensatory lowered renal vascular resistance, elevated kidneyplasma flow, glomerular hyperfiltration, and stimulation ofRAAS, despite volume expansion. Neurohumoral factors like AngII,sympathetic system, and cytokines are synergistically involvedin these compensatory mechanisms. For instance, AngII, in additionto its systemic effects on BP, directly contributes to increasedglomerular capillary pressure through vasoconstriction of theefferent arterioles and upregulation of renal injury response(7,44,46). These alterations with the hypertension associatedwith the insulin-resistant state help overcome the increasedtubular reabsorption and maintain sodium balance (3,4,44,46).Although no glomerular damage has yet occurred, persistenceof these compensatory responses, increasing glomerular wallstress, in the presence of hypertension, dyslipidemia and dysglycemia,will precipitate gradual nephron loss, glomerulosclerosis andeventually ESRD (Figure 2) (4,7,46). This glomerulosclerosisin the hyperinsulinemic/insulin-resistant kidney is peculiarand characterized by lower rate of nephrotic syndrome, fewerlesions of segmental sclerosis and a greater glomerular sizecompared with the idiopathic variety (4,12).
Hypertension is believed to contribute to renal disease by increasingglomerular capillary pressure, proteinuria, endothelial dysfunction,and sclerosis, leading to nephronal damage (7). Dyslipidemia,on the other hand, enhances renal dysfunction through filteredlipoproteins, damaging glomerular and tubular cells, in additionto enhancing endothelial dysfunction and atherosclerosis andparticipating in the aforementioned deleterious renal functionaland structural changes, eventually leading to nephron damage(3). Dysglycemia is not only involved in the aforementionedrenal changes, but it also exerts a direct toxic effect on nephronsthrough glycosylation of glomerular proteins (46–48).
In summary, persistence of insulin resistance and suboptimalcontrol of associated cardiometabolic abnormalities cause renalinjury with functional as well as structural nephron loss contributingto elevated BP, which in turn leads to further renal injury,thereby setting off a vicious circle of events leading to furtherelevated BP and renal injury. Interestingly enough, it is difficultto dissociate the "cause" from "effect" in this circle, becausethe overall burden of insulin resistance may be strongly time-dependent(Figure 2) (4).
Renal Disease and Insulin Resistance: Ethnic Differences and Relative Weight of Risk Factors
Overt nephropathy is detected simultaneously with diagnosisof type 2 diabetes, while it develops later on in type 1 diabetes.This emphasizes the role of insulin resistance and associatedabnormalities in the etiology of renal disease, since type 2diabetic patients are insulin-resistant long before they developovert diabetes (12,13). Also, the parallel increase in the prevalenceof obesity and ESRD (Figure 4) besides the close associationbetween obesity and type 2 diabetes and hypertension which arethe 2 major risk of ESRD, has lead to speculate that obesity,which is frequently associated with insulin resistance/hyperinsulinemia,may account for at least half of the ESRD in the United States(4), supporting the role of insulin resistance in renal disease.In fact, insulin resistance is now an established modifiablerisk factor for chronic kidney disease (CKD) and ESRD and anindependent predictor of CVD mortality in people with ESRD (49).Furthermore, people with renal disease have higher insulin resistancecompared with subjects with normal renal function (49). Adipocytokines,including TNF-, IL-6, and leptin, are believed to mediate increasedinsulin resistance in ESRD (50). In uremic patients, the levelsof these adipocytokines are even higher, further worsening insulinsensitivity (2,12,50).
The effect of insulin resistance and associated cardiovascularand metabolic derangements on renal function is heterogenousbetween different ethnicities, suggesting a possible geneticrole (2,47). The adjusted incidence of ESRD in African-Americansand Native Americans is about 4 times that in the rest of theUS population and is disproportionate to their percentage ofthe population (2,47). Also, the relative weight of risk factorson progressive renal disease in the insulin-resistant statevaries with ethnicity (7,47). For instance, the role of hypertensionin progressive renal disease is more enhanced in African-Americans,with higher salt sensitivity and endothelin-1 levels, and nativeAmerican Indians; the target organ damage at any level of BPis greater than in other ethnicities (47). Thus, it comes ofno surprise that hypertension is the leading cause of ESRD inthe African-American population (7,47).
Microalbuminuria: A Marker of the Cardiometabolic Syndrome, Endothelial Dysfunction, Progressive Renal Disease, and CVD
Accumulating data indicate that microalbuminuria, defined asurine albumin excretion of 20 to 200 µg/min or 30 to 300mg/d, clusters with several metabolic and vascular abnormalitiesof the cardiometabolic syndrome (23,32,51) and is indeed a partof and even an early marker for this syndrome (23–26).Among others, the use of quartiles, different cut-off levelsfor abnormal values, different measures for insulin resistanceand obesity, and different statistical methodologies led toinconsistent reporting of various components of the cardiometabolicsyndrome as the strongest associated abnormality with microalbuminuria.However, enough evidence has been garnered confirming the associationbetween microalbuminuria and each of hypertension (23,32) andcentral obesity (24). Also, studies confirmed the associationof microalbuminuria with salt sensitivity, the absence of nocturnaldrops in both SBP and DBP, dyslipidemia, and LVH (13,14,48).Furthermore, although researchers have reported mixed resultson the association between microalbuminuria and hyperinsulinemia,multiple studies confirmed this relation with an additionalassociation between microalbuminuria and high fasting bloodsugar (FBS) values (23,24,48,52). The Insulin Resistance inAtherosclerosis Study revealed that an increasing degree ofinsulin sensitivity was associated with a decreasing prevalenceof microalbuminuria (24). Others reported that microalbuminuriain type 2 diabetes was associated with insulin resistance, arelation that was independent of BP or glucose levels (48).Also, an investigation of 5659 men and women from the ThirdHealth and Nutrition Examination Survey (NHANES III), whichis one of the most comprehensive and nationally representativesurveys, confirmed the association between MA and the cardiometabolicsyndrome, with the strongest association being with high FBSand high BP (23). Furthermore, the Framingham follow-up on glucose-intolerantnormotensive subjects showed a twofold higher prevalence ofMA in comparison with normal controls (52).
More importantly, microalbuminuria is now established as a modifiablepredictor of CVD and CVD mortality (22,23,48,51). Of the individualcomponents that constitute the cardiometabolic syndrome, microalbuminuriaconfers the strongest risk of cardiovascular death (23). However,despite its strong association with CVD, the exact pathogeneticmechanisms that link microalbuminuria to CVD remains unknown.Evidence has been garnered that microalbuminuria is a markerof generalized endothelial dysfunction and consequently a riskfactor for CVD (18,22). In recent studies, this endothelialdysfunction has been characterized by the presence of transmembraneleakiness (32). It is presently unclear whether transmembraneleakiness should be viewed as the culminating event of differentatherogenic factors acting in concert to promote endothelialdysfunction or whether it should be considered as the underlyingsubstrate that enhances the atherogenicity of the differentcomponents of the cardiometabolic syndrome. For one, the increasein vascular permeability can promote the penetration of atherogeniclipoprotein particles in the arterial wall. One possible explanationis that endothelial dysfunction might promote increased penetrationof atherogenic lipoprotein particles in the arterial wall, butglucose control, insulin resistance, procoagulant state, andadhesion molecules have all been implicated in the pathogenesis(53). In addition, microalbuminuria has also been associatedwith alterations in hemodynamic and vascular responses. Thisis exemplified by studies that have demonstrated that the compensatoryvasodilation seen after relief from prolonged ischemia or infusionof vasodilators such as nitroglycerin is blunted in people withmicroalbuminuria (32). In general, microalbuminuria can be construedas a signal from the kidney that abnormalities in endothelialfunction and vascular responses are present and can be seenas an early marker of generalized endothelial dysfunction, atherosclerosis,increased CVD risk, and progressive renal disease (48). In thislight, the reduction of microalbuminuria should be implementedas a therapeutic goal to reduce overall CVD risk (48).
In recent studies, measures that normalize the different componentsof cardiometabolic syndrome resulted in significant reductionsin urine microalbumin excretion. For instance, weight loss canreduce microalbuminuria. Reductions in urine microalbumin excretioncorrelated significantly with weight loss as little as 5% frombaseline (32). Measures that enhance insulin sensitivity, reduceBP, and improve glycemic control have all been shown to reducemicroalbuminuria (7,32,54). The use of statins for the treatmentof dyslipidemia has been shown to improve endothelial functionand reduce microalbuminuria, beneficial effects that extendwell beyond its lipid-lowering properties (13). Even loweringplasma triglyceride levels has been shown to stabilize urinealbumin excretion (32).
In summary, microalbuminuria can be viewed as a part of andan early marker for the cardiometabolic syndrome, includingendothelial dysfunction and progressive renal disease, and amodifiable predictor for CVD and CVD mortality. The reductionof microalbuminuria may reflect the adequacy with which thedifferent components of the cardiometabolic syndrome are controlledand should be instituted as a therapeutic goal in an effortto reduce overall CVD risk, including progressive renal disease,and mortality.
Atherosclerosis
Several studies confirmed the role of insulin resistance, hyperinsulinemiaand associated cardiometabolic abnormalities as important riskfactors in the development of both incident and prevalent atherosclerosis,renal disease, stroke, CVD, and CVD mortality (Figure 7) (55–57).One such trial, the Insulin Resistance in Atherosclerosis study,which investigated 1600+ triethnic cohort, measured insulinsensitivity directly via frequently sampled intravenous glucosetolerance test (FSIVT), which correlates well with the goldstandard measure of insulin sensitivity, the euglycemic hyperinsulinemicclamp technique, in relation to carotid intimal medial thickness(IMT) (56). Another study, the Atherosclerotic Risk in Communities(ARIC), measured insulin sensitivity indirectly via assessingfasting serum INS and glucose levels, in relation to carotid-IMT(55). Other measurements for insulin resistance included 2-hINS levels after glucose load and proinsulin levels. Measuresfor assessment of atherosclerosis also included coronary angiograms(57). In fact, several large studies revealed that hyperinsulinemiais not only associated with but also a predictor of CHD (13,57).An important study from Quebec on 2103 men confirmed the associationbetween hyperinsulinemia and CHD using an insulin assay withoutcrossreactivity with proinsulin to measure fasting insulin levels(20). These studies confirmed a positive association betweenatherosclerosis and reduced insulin sensitivity, hyperinsulinemia,hyperglycemia, hypertension, dyslipidemia, elevated plasma fibrinogenand plasminogen activator inhibitor (PAI)-I levels, centralobesity and physical inactivity.
Several mechanisms have been proposed to explain the role ofinsulin resistance, hyperinsulinemia, and associated abnormalitiesin the development of atherosclerosis. These include both directeffects on the arterial wall and indirect actions on lipid andglucose metabolism, neurohumoral and hormonal factors, ultimatelyleading to endothelial injury, LDL uptake by subendothelialmacrophages to foam cells, VSMC proliferation, and eventuallyatherosclerotic plaque formation (7,12,13). The direct effectscould be through insulin participating in cholesterol transportinto VSMC, stimulating cholesterol synthesis and proliferationof these cells. The indirect effects are mediated by the majorCVD risk factors clustering with hyperinsulinemia. In fact,elevated FFA (secreted by visceral adipocytes) and abnormalitiesin lipoproteins, neurohumoral and hormonal factors, acting onthe liver and other target organs, lead to a constellation oflipid, glucose, fibrinolytic and inflammatory abnormalitiesin levels and composition as well as perturbations of the interactionbetween these factors and cellular receptors, contributing tothe development of atherosclerosis, thrombosis, and eventuallyCHD and CKD (3). Furthermore, the progressive decline in renalfunction associated with insulin resistance is accompanied bya reduction in the clearance of insulin, proinsulin, other neurohumoraland hormonal mediators, believed to contribute to atherosclerosis(2,49). Also, it exacerbates hypertension, insulin resistance,and other associated cardiometabolic disorders, contributingfurther to accelerated atherosclerosis, increased CVD events,and mortality, as well as establishing a vicious cycle wherebyprogressive renal disease and CVD exacerbate each other (2).
Vascular Adaptations
An alteration in ions at the cellular and molecular level appearsto be important in regulating vascular smooth muscle tone. These,as previously mentioned, may be deregulated in the obese/insulin-resistantresulting in abnormal vascular responsiveness (3). Weight lossmay reverse this deregulation, resulting in a clearly significantdecrease in PVR and MAP (58).
Cardiac Adaptations
The vascular and cardiometabolic disorders associated with insulinresistance, including volume expansion, hypertension, LVH, anddyslipidemia, synergistically increase CVD risk as confirmedby the PROCAM study (Figure 7) (4,5,7). Lean hypertensive individualstend to have a concentric LVH in response to sustained hypertension,leading eventually to cardiac dilation and heart failure (HF)(3). On the other hand, the predominant pattern of cardiac hypertrophynoted in insulin-resistant hypertensive individuals is eccentric(4,5). The presence of both insulin resistance and hypertensionin the same patient results in a mixed pattern of cardiac hypertrophy,caused by an elevation in both cardiac preload and afterload,and a heavier heart (4). Insulin resistance results in increasedpreload due to an expanded vascular volume, and the high afterloadcan be accounted for by the presence of hypertension and sympatheticsystem activation. Since LVH by itself is a major risk factorfor sudden death and death due to progressive cardiac decompensation,it may partially explain the increased incidence of CVD morbidityand mortality in the obese/insulin-resistant (3). Furthermore,HF is twice as common in obese/insulin-resistant subjects comparedwith normal individuals, even after adjustment for comorbidconditions. Also, the myocardium in the obese/insulin-resistantindividual shows the presence of mononuclear cell infiltrationin and around the sinoatrial node with fat deposition all alongthe conduction system. Lipomatous hypertrophy of the interatrialseptum has also been noted in these patients. All these changesmake the myocardium in the insulin-resistant hypertensive patientan ideal substrate for cardiac arrhythmia and sudden death (3).
Several metabolic, cardiovascular, and renal abnormalities contributeto the elevated CVD risk in patients with hyperinsulinemia andhypertension or the cardiometabolic syndrome (3,14,21,32). Hence,multitargeted-approaches, preferably population-based, to preventor control these derangements need to be implemented (21). Weightreduction is warranted with diet, lifestyle/behavior modificationand moderate physical activity of at least 30 min a day, 3 timesa week (3). However, most patients with the cardiometabolicsyndrome will benefit from tight glycemic control, antithrombotictherapy with ASA, cholesterol-lowering therapy with HMG-CoAreductase inhibitors (to an LDL-Cholesterol goal of less than100 mg/dl), and aggressive BP control, frequently more thantwo agents (ACE inhibitors, ARB, diuretics, CCB, - and -blockers)to a BP goal of <130/80 mmHg and ideally <115/75 mmHg(21).
RAAS blockade with ACE inhibitors and ARB seem to be particularlyhelpful in patients with the cardiometabolic syndrome. In patientswith DM, the role of these agents in improving the clinicaloutcomes and attenuating the progression of renal disease, boththrough BP-dependent as well as BP-independent effects has beenestablished (21). ARB significantly reduce the progression oftype 2 diabetic nephropathy (doubling of serum creatinine, ESRD,and death), both at early and late stage of renal disease withreduction in proteinuria, effects that go above and beyond BP-dependentbenefits (56). Similar effects of ACE inhibitors in patientswith type 1 diabetes have been confirmed, again with BP-dependentand BP-independent (21), while their renoprotective benefitsin patients with type 2 diabetes are still to be revealed. Onthe basis of these studies, the use of ACE inhibitors, ARB,or both is recommended as first-line therapy in patients withdiabetes and renal disease (59). Overt nephropathy is diagnosedat the onset of type 2 diabetes, and progressive renal diseaseis initiated in the prediabetic insulin-resistant state; itis therefore wise to extend these recommendations to includepatients with the cardiometabolic syndrome and renal disease.Whether RAAS blockade with ACE inhibitors or ARB reduces renalinjury better than other antihypertensive agents, especiallyin diabetic nephropathy, is still debatable. Studies reportedmixed results on this subject and invariably demonstrated slightlybetter control of BP in the groups of the active drug. Randomizeddouble-blinded head-to-head comparison trials with similar BPcontrol in active and control groups are needed to further clarifythis issue (60).
Further support for the importance of RAAS blockade in patientswith the cardiometabolic syndrome comes from completed trialssuggesting an insulin-sensitizing effect of ACE inhibitors (39)and ARB (40), with a potential of preventing the developmentof DM. Two ongoing trials, the Diabetes Reduction Assessmentwith Ramipril and Rosiglitazone Medications (DREAM) study, evaluatingan ACE inhibitor (ramipril), a thiazolidinedione (rosiglitazone),or a combination of both agents versus placebo, and the Nateglinideand Valsartan in Impaired Glucose Tolerance Outcomes Research(NAVIGATOR), evaluating an ARB (valsartan), a rapid on/off insulinsecretagogue (nateglinide), or both versus placebo, should leadto more definite important conclusions on the role of theseagents in the prevention of diabetes.
Detailed recommendations on the management of CVD and renaldisease risk factors in the cardiometabolic syndrome have beenelaborately discussed in our previous articles (3,14,21).
Hyperinsulinemia and hypertension are integral components ofthe cardiometabolic syndrome that frequently coexist with apossible common genetic predisposition. They contribute significantlyto progressive renal disease and elevated CVD morbidity andmortality associated with this syndrome. Resistance to the effectsof insulin on peripheral tissues and vasculature, as well ascentral actions of insulin stimulating the SNS activity andrenal effects enhancing renal sodium reabsorption, all contributeto the etiology of hypertension in the insulin-resistant state.Other mechanisms involved would include endothelial dysfunction,LVH, cardiac hyperreactivity, dyslipidemia, hyperglycemia, enhancedRAAS activity, altered renal structure and function with impairedpressure natriuresis leading to sodium retention, volume expansion,progressive renal disease, and eventually ESRD.
Other derangements in the cardiometabolic syndrome include hyperuricemia,an altered Kinin-Kinin system, a prothrombotic and proinflammatorystate, and microalbuminuria. Currently microalbuminuria is recognizedas not only a component of the cardiometabolic syndrome, butalso as an early marker of this syndrome and a reflection ofa generalized endothelial dysfunction, atherosclerosis, progressiverenal disease, and increased CVD morbidity and mortality.
In view of the complexity and diversity of the CVD and renalrisk factors associated with the cardiometabolic syndrome, multi-targetedapproaches to risk factor modification are recommended in patientswith this syndrome, with particular emphasis on RAAS blockadeand reduction of microalbuminuria. This would lessen the enormousburden of this syndrome, with rising prevalence and its complicationsfor healthcare systems.
Ford ES, Giles WH, Dietz WH: Prevalence of the Metabolic Syndrome among US adults: Findings from the Third National Health and Nutrition Examination Survey. JAMA 287: 356–359, 2002[Abstract/Free Full Text]
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Abstract
Introduction
(TNF-
3-adrenergic receptor, which regulates lipolysis in visceral fat, and the presence of two mutated genes on chromosome 7q, one that controls insulin levels and hypertension and the other, leptin, a peptide that regulates food intake (3,28). Deficiency in CD36, a known fatty acid transporter, is also believed to be involved in the predisposition to insulin resistance and hypertension in Asians (29). 
). 
- increase.