the metabolic syndrome—from insulin resistance to obesity and diabetes

8/13/2019 The Metabolic Syndromefrom Insulin Resistance to Obesity and Diabetes

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T h e M e t a b o l i cSyndromefrom

I n s u l i n R e s i s t a n c e t oO b e s i t y a n d D i a b e t e s

Emily Jane Gallagher, MRCPIa, Derek LeRoith, MD, PhDa,Eddy Karnieli, MDb,*

The growing prevalence of obesity worldwide is increasing concern surrounding therising rates of diabetes, coronary, and cerebrovascular disease with the consequenthealth and financial implications for the population.1 The metabolic syndromecomprises an assembly of risk factors for developing diabetes and cardiovasculardisease. Opinion varies with regard to the etiology of the metabolic syndrome and

whether it should be defined as a syndrome of insulin resistance, the metabolic conse-quences of obesity, or risk factors for cardiovascular disease.2 Some consider it nota to be a syndrome, but rather a collection of statistical correlations.3 This articlewill try to unveil some of the molecular and physiologic mechanisms underlying theentities of insulin resistance and the metabolic syndrome. It will focus on their clinicalrelevance for the care of overweight and/or obese patients with or without diabetes asdefined by the American Diabetes Association (ADA) criteria.4

HISTORIC OVERVIEW

The metabolic syndrome has undergone a host of incarnations in the medical literaturesince the clustering of metabolic risk factors for coronary artery disease, diabetes, andhypertension was described as Syndrome X by Reaven in 1988.5 The initial factorsdescribed by Reaven included impaired glucose tolerance (IGT), hyperinsulinemia,elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDLc).

A version of this article appeared in the 37:3 issue of theEndocrinology and Metabolism Clinicsof North America.a Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount

Sinai Medical Center, One Gustave L. Levy Place, Box 1055, New York, NY 10029-6574, USAb Institute of Endocrinology, Diabetes, and Metabolism, Rambam Medical Center and R.B.Rapaport Faculty of MedicineTechnion, 12 Halia Street, Haifa 31096, Israel* Corresponding author.E-mail address: [email protected]

KEYWORDS

Metabolic syndrome Insulin resistance Prediabetes Cardiometabolic risk factors Obesity

Med Clin N Am 95 (2011) 855873doi:10.1016/j.mcna.2011.06.001 medical.theclinics.com0025-7125/11/$ see front matter 2011 Elsevier Inc. All rights reserved.
mailto:[email protected]://dx.doi.org/10.1016/j.mcna.2011.06.001http://medical.theclinics.com/http://medical.theclinics.com/http://dx.doi.org/10.1016/j.mcna.2011.06.001mailto:[email protected]


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Subsequently, hyperuricemia and raised plasminogen activator inhibitor 1 (PAI-1)were suggested as components of the same syndrome.5,6 Obesity was not includedin Reavens definition of Syndrome X, as he suggested that insulin resistance, ratherthan obesity, was the unifying feature. The core components of what we now callthe metabolic syndrome: obesity, insulin resistance, dyslipidemia, and hypertensionhave remained since the World Health Organization (WHO) produced its definition in1998. WHO published criteria to define the metabolic syndrome in an attempt toharmonize reporting of prevalence through epidemiologic studies. The criteriaincluded a measure of insulin resistance, by a hyperinsulinemic euglycemic clamp,impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes, obesity(BMI >30 kg/m2), hypertension (140/90 mm Hg), and microalbuminuria.7 Critics ofthe WHO definition highlighted the impracticality of performing hyperinsulinemicclamp studies in epidemiologic research. They also pointed out that rather thanmeasuring the waist-to-hip ratio, waist circumference measurement was more conve-nient and had a comparable correlation to obesity. In addition, some believed thatmicroalbuminuria should not be included at all given the insufficient evidence of a closecorrelation with insulin resistance.3 These opinions lead to the second definition in1999, from the European Group for the Study of Insulin Resistance (EGIR). Theyrenamed the syndrome, insulin resistance syndrome and excluded subjects withdiabetes because of excessive complexities in measuring insulin resistance in theseindividuals. Insulin resistance remained an essential component, defined as a fastinginsulin level above the 75th percentile for the population. Two of these other elements(criteria associated with increased risk of coronary artery disease from the SecondJoint Task Force of European and other Societies on Coronary Prevention) were

also required: obesity defined as waist circumference 94 cm (37 inches) or more formen and 80 cm (32 inches) or more for women, hypertension remained defined as140/90 mm Hg or higher, and dyslipidemia with TG 180 mg/dL (2.0 mmol/L) ormore, and/or HDLc less than 39 mg/dL (1.01 mmol/L).3 In 2001, The National Choles-terol Education Program (NCEP) Adult Treatment Panel III (ATP III) changed the focusto cardiovascular risk factors and away from relying on measures of insulin resistanceand possible etiologies; therefore, the title The Metabolic Syndrome was reas-signed. The criteria were any three of the following: obesity (waist circumference102 cm [40 inches] in males and 88 cm [35 inches] in females, based on the1998 National Institutes of Health [NIH] obesity clinical guidelines), hypertension

(130/85 mm Hg based on Joint National Committee guidelines), fasting glucosemore than 110 mg/dL (6.1 mmol/L, including diabetes), TG 150 mg/dL (1.69 mmol/L)or more, and HDLc less than 40 mg/dL (1.03 mmol/L) in men or less than 50 mg/dL(1.3 mmol/L) in women.8 Waist circumference was not a required element as theNCEP/ATP III wished to include certain individuals and ethnic groups that have meta-bolic and blood pressure abnormalities associated with elevated cardiovascular risk,but do not meet the criteria for abdominal obesity. Subsequently, in 2003, the

American Association of Clinical Endocrinologists (AACE) modified the ATP III criteriaand renamed the disorder Insulin Resistance Syndrome. The AACE did not set outstringent criteria to define the syndrome, but described it as a group of abnormalities

associated with insulin resistance, including glucose intolerance (but not diabetes),abnormalities in uric acid metabolism, dyslipidemia (consistent with NCEP/ATP IIIcriteria), hemodynamic changes, prothrombotic factors, markers of inflammation,endothelial dysfunction and elevated blood pressure (as NCEP/ATP III). Thisconsensus also endeavored to identify individuals at increased risk of developingthe insulin resistance syndrome in the future: BMI greater than 25 kg/m2 (or waistcircumference >40 inches in men and 35 inches in women), known cardiovascular

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disease, hypertension, polycystic ovarian syndrome (PCOS), nonalcoholic fatty liverdisease (NAFLD), or acanthosis nigricans; family history of type 2 diabetes (T2DM),hypertension, or cardiovascular disease; history of gestational diabetes or glucoseintolerance; non-Caucasian ethnicity; sedentary lifestyle; and age older than 40 years.9

In parallel, the International Diabetes Federation (IDF) aimed to create a straightfor-ward, clinically useful definition, to provide worldwide conformity for epidemiologicstudies and identify those at greatest risk of developing diabetes and cardiovasculardisease. To this end, the IDF proposed a new consensus definition of the metabolicsyndrome in 2005. Obesity (BMI >30 kg/m2 or if30 kg/m2 by ethnic-specific waistcircumference measurements) was a prerequisite factor, as they felt it was a centraletiologic component of the syndrome. Two of four other factors were also required:TG 150 mg/dL or higher, HDLc less than 40 mg/dL in men or less than 50 mg/dL inwomen, systolic blood pressure 130 mm Hg or higher or diastolic blood pressure85 mm Hg or higher, fasting glucose more than 100 mg/dL (5.6 mmol/L, 2003 ADAdefinition of IFG10) including diabetes, and those with a previous diagnosis of or treat-ment for any of these conditions.11

DEFINITIONS

In thisClinics of North Americaseries, we follow the 2005 American Heart Association(AHA)/National Heart, Lung and Blood Institute (NHLBI) criteria as shown in Table 1.The revised definition is based on the ATP III criteria, requires three of the five factorslisted in Table 112 and primarily aims to diagnose those patients at increased risk oftype 2 diabetes and cardiovascular disease. When using these criteria, the reader

should take into account the updated differences relating to waist circumferencemeasures by ethnic origin (as suggested by the IDF) as well as the revised criterionfor impaired fasting glucose indicating those individuals at greater risk of developingthe metabolic syndrome.9,10,12

Table 1

Criteria for diagnosis of the metabolic syndrome (American Heart Association/National Heart,

Lung and Blood Institute) 2005

Any Three of the Following Criteria Parameter

Elevated waist circumference 102 cm (40 inches) in men88 cm (35 inches) in women

Elevated triglycerides 150 mg/dL (1.7 mmol/L)

Reduced HDLc


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Comparing the AHA/NHLBI to the IDF definition of the metabolic syndrome, bloodpressure, lipid, and glucose ranges are the same; however, in contrast to the IDF, the

AHA/NHLBI have not made obesity essential to the diagnosis but draw attention to theincreased risk of insulin resistance and the metabolic syndrome in certain ethnicgroups (ie, populations from South Asia, China, Japan, and other Asian countries)with only moderate increases in waist circumference. The IDF waist circumferencecut-off values that define obesity for Europoids are 8 cm less for both males andfemales than those measurements in the AHA/NHLBI criteria, which were based onthe National Health and Nutrition Examination Survey (NHANES).11,12 The waistcircumference cut-off measurements in the AHA/NHLBI definition approximatea BMI of 29.8 kg/m2 in males and 24.9 kg/m2 in females.12,13

It is likely that the definitions of the metabolic syndrome will continue to develop.Which definition is most useful will depend on its ability to predict cardiovascularoutcomes in prospective studies.

PREVALENCE

Reported rates of prevalence vary widely with the criteria used, age of the population,gender, ethnic group, prevalence of obesity in the background population, and envi-ronment. Based on the NHANES 19992002, it is estimated that 34.6% of the US pop-ulation meet the ATP III criteria for the metabolic syndrome. There is minimal genderdifference: 34.4% of males and 34.5% of females. An increased prevalence has beenshown with advancing age.1416

Worldwide, prevalence rates of the metabolic syndrome were found to be similar

irrespective of which set of criteria was applied, however different individuals wereidentified using different criteria.17 The ATP III and IDF criteria similarly classified92.9% of individuals in the NHANES. The IDF (with the lower waist circumferencecut-off points) increased the overall age-adjusted prevalence estimate to 39.1%(40.7% in males and 37.1% in females).18 However, concordance rates vary widelybetween studies. Both the Dallas Heart Study and the NHANES demonstrated thelowest concordance rate among Hispanic males. The PROCAM study from Germany,along with other European population studies, revealed low concordance rates.19

Other European population studies have shown large differences in estimatedprevalence.20,21 In a northern Mexican population study the IDF criteria classified

94.4% of females as having obesity by waist circumference measurements (80 cm),which may suggest the waist circumference cut-off levels are inappropriately low forthis population.22 Of particular interest, the IDF criteria underestimate the metabolicsyndrome prevalence in Asian populations, for example in Korea and China, as manyindividuals in these regions have metabolic risk factors without significant obesity.23,24

The NHANES study showed that with both the ATP III and IDF criteria, in males, thehighest prevalence of the metabolic syndrome is in whites at 35% (IDF 42.6%). Thelowest was in African American males, 21.6% (IDF 24.2%) despite the higher overallprevalence of hypertension and diabetes in this group. Mexican American womenhad the highest overall prevalence 37.8% (IDF 39.2%). White and African American

women had similar prevalence, 33.7% and 33.8% respectively (36.9% and 35.8%by IDF).18 The NHANES group had insufficient numbers of other ethnic groups tocalculate their prevalence rates. Apart from the Mexican American population, otherstudies have shown that American Indians, Hawaiian, Filipino, and Polynesian popu-lations have a higher incidence than those of European descent.15,2528

Rural populations tend to have lower prevalence rates than urban populations, whichhave been demonstrated in multiple ethnic groups and studies of migrations to western

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society.22,29 Western diet appears to bring with it increased risk of the metabolicsyndrome particularly in Chinese, Indian, and Middle Eastern populations.3032 Arabpopulations living in the United States have been shown to have higher prevalencethan those living in the Middle East.22,2933

Low cardiorespiratory fitness in some studies correlates significantly with incidenceof the metabolic syndrome in both men and women. In a Swedish study of healthyvolunteers over age 60, metabolic syndrome prevalence was 24% and 19% in menand women, respectively. The adjusted odds ratio for having the metabolic syndromein the high leisure-time physical activity group was 0.33, that of the low physicalactivity group.34A study of volunteers in Dallas, TX, with an age range of 2080 yearsyielded similar results, showing a hazard ratio of 0.47 in men and 0.37 in the physicallyactive women.35

PROGNOSIS

Equal to, if not exceeding, the importance of clinically practical definitions of the meta-bolic syndrome is having criteria that are pertinent for predicting the development oftype 2 diabetes and cardiovascular disease. In the United States in 2003, the preva-lence of cardiovascular disease was 34.2% and was a contributing or underlying causeof death in 37.3% of cases, which equates to 1 in every 2.7 deaths or 2500 deaths eachday and a cost of $403.1 billion.36 Data from the NHANES II show that combined, pre-existing cardiovascular disease and diabetes carry the greatest hazard for mortalityfrom coronary artery disease (hazard ratio [HR] 6.25) and cardiovascular disease(HR 5.26).37 Diabetes alone carries a HR of 2.87 for coronary artery disease mortality

and 2.42 for all cardiovascular disease mortality.37

Independent of the traditionalFramingham risk factors (age, smoking, total cholesterol, HDLc levels, and systolicblood pressure), some researchers have found that the metabolic syndrome is associ-ated with an increased probability of cardiovascular disease and conveys a higher riskthan the Framingham risk score of developing type 2 diabetes.3845 However, theFramingham investigators report little or no increase in the predictive power forcoronary heart disease by adding abdominal obesity, triglycerides, or fasting glucoseto their 10-year risk algorithm (Fig. 1).46,47 Debate surrounds which definition is thebest predictor of diabetes, cardiovascular disease, and mortality.24,48,49

Three recent meta-analyses of prospective studies investigating the metabolic

syndrome as a significant risk for cardiovascular disease and mortality showincreased relativerisk of both events.5052 One study demonstrated a relative risk ofdiabetes of 2.9950 and all three analyses revealed more moderate increases in riskfor cardiovascular events ranging from 1.53 to 2.7. All-cause mortality risk was esti-mated to be between 1.37 and 1.60 for those with the metabolic syndrome, dependingon the criteria employed.50,51 This greater probability of cardiovascular events andmortality has been shown to exist with the metabolic syndrome both in the presenceand absence of diabetes; however, as in the NHANES II, the presence of diabetes,along with the metabolic syndrome, significantly increases this risk (HR 1.56 withoutdiabetes, 1.82 with diabetes).37,39,53 The increased risk of cardiovascular disease

with the metabolic syndrome does not appear to be explained entirely by insulin resis-tance. In studies that calculate insulin resistance by the homeostasis model assess-ment of insulin resistance (HOMA-IR), the predictive power of the metabolicsyndrome for diabetes and cardiovascular disease development has been demon-strated to be independent of the HOMA-IR.3941 There is also conflict regardingwhether the metabolic syndrome as a whole confers a greater risk of cardiovasculardisease and diabetes than its individual components.49,5355 In the Atherosclerosis

The Metabolic Syndrome 859


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Risk in Communities (ARIC) study, hypertension and low HDLc were found to be thestrongest predictors of coronary heart disease; the metabolic syndrome as a wholewas not found to have a greater prediction power than these individual elements.53

PATHOGENESIS

Whether the metabolic syndrome is an assortment of unrelated risk factors or alliedtraits attributable to a common mechanism is a matter of ongoing debate.56,57

Although risk factors for the metabolic syndrome have been identified, the etiologyremains incompletely understood.9,12 As initially proposed by Reaven, it appearsthat insulin resistance is likely to be a significant link between the components of

Fig. 1. Four-step algorithm for management of modifiable aspects of the metabolicsyndrome. [WC, Waist Circumference >102 cm (men), >88 cm women; BMI, Body Mass Indexin kg/m2; [TG, Elevated triglycerides; [LDLc, Elevated low-density lipoprotein cholesterol(see text); [FPG, Elevated fasting plasma glucose (>100 mg/dL); Positive OGTT, Oral glucosetolerance test (75 g) with 2-hour glucose of 200 mg/dL; DM, diabetes mellitus; BP, bloodpressure: CVD, cardiovascular disease; 10YR, 10-year risk of CAD calculated by Framinghamrisk score. *Age >45 years (male), >55 years (female), cigarette smoking, dyslipidemia, hyper-tension, IFG, IGT, type 2 diabetes, family history of premature CVD in first-degree relative

(male


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the metabolic syndrome.5,58 Indeed, as mentioned previously, the metabolicsyndrome is also known as theinsulin resistance syndrome.3,9 Many lifestyle, molec-ular, and genetic contributors59 leading to the metabolic syndrome have beendescribed; these include obesity and disorders of adipose tissue; physical inactivity;diet; insulin receptor and signaling anomalies60,61; inflammatory cascades; mitochon-drial dysfunction62; molecules of immunologic, hepatic, or vascular origin (includingadiponectin, leptin, PAI-1, resistin, angiotensinogen); endocannabinoid receptors;nuclear receptors; hormones; and polygenic variability in individuals and ethnicgroups. Here, we will summarize how some of these factors contribute to the abnor-malities within the metabolic syndrome.

In response to glucose stimulation, pancreatic b cells release insulin, leading tosuppression of hepatic gluconeogenesis and increased glucose uptake and metabo-lism by the muscle and adipose tissue. Glucose transport into cells is mediated byglucose transporters (GLUT). One of the most important glucose transporters,GLUT4, is regulated by insulin. In response to insulin, GLUT4 is mobilized from intra-cellular storage vesicles and fuses to the cellular membrane to internalize glucose (seereview63). This is the major rate-controlling step in insulin mediated glucose uptakeand muscle glycogen synthesis.60,64,65 GLUT4 cellular concentration in adipocytesis decreased with advancing age, obesity, and type 2 diabetes.60 In skeletal muscleof obese and diabetic humans, GLUT4 is not decreased, but rather dysfunctional.66

Exercise and adiponectin appear to increase the expression of GLUT4, coincidentwith insulin sensitivity. With insulin resistance, there is an initial loss of the immediatepostprandial (first phase) response to insulin, leading to postprandial hyperglycemia.Subsequently, there is an exaggerated second-phase insulin response, which over

time causes chronic hyperinsulinemia.59

The resulting chronichyperinsulinemia leadsto resistance to the action of insulin (as further detailed).1,67,68

At a cellular level, insulin binds to the insulin receptor (IR) activating the tyrosinekinase pathway. This pathway stimulates the phosphorylation of receptor substratesand adaptor proteins, including insulin receptor substrates 1 and 2 (IRS1, IRS2),Gab1, Shc, and APS on selected tyrosine residues and these form docking sites forfurther downstream effectors.69,70 There are then two major pathways in insulin-mediated activities: one is initiated by phosphatidylinositol 3-kinase (PI3K) and is themajor channel of the metabolic effects of insulin; second is that downstream ofmitogen-activated protein (MAP) kinase signaling, mostly involved in growth and

mitogenesis.69

Within the PI3K pathway, tyrosine-phosphorylated IRSs recruit andinteract with the regulatory p85 subunit of PI3K, resulting in synthesis of phosphatidy-linositol 3,4,5 phosphate (PIP3). Downstream kinases PDK (phosphoinositide depen-dent kinase) and Akt, bind to PIP3 and this results in their activation. Akt is known tomediate the effects of insulin on glucose transport and storage, protein synthesis,and prevention of lipid degradation. Some of these metabolic effects are mediatedthrough Akt phosphorylation of FOXO (forkhead box class O) transcription factors.61,71

FOXO1 plays a key role in hepatic gluconeogenesis. When phosphorylated it is seques-tered in the cytoplasm and prevented from activating gluconeogenic genes.72,73 It hasalso been shown in vitro to repress the transcription of peroxisome proliferator

activated-receptor (PPAR)g promoter genes.73 PPARg is one of a family of nuclearreceptors, also including PPARa and PPARb/d, which are key transcription factorsinvolved in the regulation of glucose and lipid metabolism, along with insulin sensitivity.PPARg is found in insulin-responsive tissues, whereas PPARa is expressed in hepato-cytes, cardiac myocytes, and enterocytes, and PPARb/d is ubiquitous. While PPARgrepresses GLUT4 transcription,71,74 its thiazoledinedione synthetic ligands enhanceinsulin sensitivity, probably by dismissal of co-repressor complexes, switching them



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with co-activator complexes75,76 while concomitantly detaching PPARg/RXR dimerfrom its DNA binding site on the GLUT4 gene promoter.76 This, along with serine phos-phorylation of IRS (and prevention of tyrosine phosphorylation) by hyperinsulinemia,cytokines (ie, tumor necrosis factor alpha [TNFa]), decreased PI3K activity and geneticdefects (ie, Akt2)havebeen shown in vitro, in mouse models, and in humans to induceinsulin resistance.70,77 The result of deficits in the insulin-signaling pathway is increasednuclear activity of FOXO1 with greater expression of gluconeogenic genes, as well asinduction of lipogenic transcription factor sterol regulatory element binding protein 1c(SREBPIc) and elevated expression of lipogenic genes and a rise in VLDL secretion.60,78

Obesity has an important role in insulin resistance.2 Adipose tissue is not simplya storehouse for fat, but has been shown to be an endocrine organ producingmany factors, including interleukin (IL)-6, TNFa, resistin, lipoprotein lipase, acylationstimulation protein, cholesteryl-ester protein, retinol binding protein-4 (RBP4), estro-gens, leptin, angiotensinogen, adiponectin, insulin like growth factor-1 (IGF-1), andmonobutyrin.79 In this series of Clinics of North America, other articles will furtherdiscuss the adipose cell as an endocrine system as well as the mechanisms throughwhich adipose tissue leads to insulin resistance.

Visceral adiposity is independently associated with insulin resistance; lower HDLclevels; higher apolipoprotein B, RBP4, and triglyceride levels; smaller LDLc particles;aortic stiffness; coronary calcification; and hypertension.7981 Obesity has beenshown to contribute to the metabolic syndrome by increasing nonesterified fatty acids(NEFA) and production of inflammatory cytokines that result in insulin resistance, dys-lipidemia, hypertension, and production of prothrombotic factors.

NEFA are fatty acids derived from lipolysis of adipose tissue triglycerides that are

usually a source of energy in the fasting state. In obese subjects, NEFA levels areincreased despite higher levels of insulin. In skeletal muscle, excess NEFA contributeto insulin resistance by increasing levels of diacylglycerol (DAG), which lead to serinephosphorylation of IRS, thereby inhibiting normal insulin signaling. In the liver, NEFAcause insulin resistance in a similar manner, leading to increased gluconeogenesisand accentuation of hyperglycemia by increasing hepatic glucose output resulting innonalcoholic fatty liver disease (NAFLD). They also contribute to increased VLDLproduction and secretion by the liver, with increased triglycerides, apolipoprotein B(Apo-B), and small LDLc particles. In addition, NEFA lead to a decreased level ofHDLc by increasing the hepatic exchange of VLDL for HDL along with increasing

hepatic lipase, which degrades HDL. Other abnormalities associated with elevatedlevels of NEFA are endothelial dysfunction, beta cell apoptosis, and increasedPAI-1.2,60 In another article the role of fatty acids in obesity and insulin resistancewill be further described.

Inflammatory cytokines such as TNFa and IL-1b are produced by macrophagesin adipose tissue. They trigger proinflammatory cytokines c-jun N terminal kinase(JNK) and inhibitor ofkB kinase b/nuclear factor kB (IKKb/NF-kB) through classicalreceptor-mediated mechanisms. JNK leads to phosphorylation of c-jun compartmentof activator protein complex 1 (APC1) transcription factor, which leads to serine phos-phorylation of IRS, leading to impaired insulin signaling. JNK and IKKb/NF-kB also,

directly or indirectly, activateproinflammatory genes,leadingto a self-perpetuatingcycleof up-regulation of inflammatory cytokines and inadequate utilization of body energy.TNFahas also been shown to decreaseendothelialnitric oxide synthase (eNOS), causingdecreased expression of mitochondrial oxidative phosphorylation genes, leading toincreased oxidative cellular stress, with the accumulation of reactive oxygen species(ROS), as well as increased endoplasmic reticulum stress and decreased half-life of nitricoxide (NO). Decreased expression of PPARg co-activator 1a (PGC1a), an inducible

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co-regulator of nuclear receptors involved in the control of mitochondrial biogenesis andfunction, has also been found in subjects with insulin resistance and type 2 diabetes.These responses to cellular stress furtherincrease IKKb/NF-kB and thus the inflamma-tory process and well as PAI-1.2,60,62,69 A perceived energy deficit may occur withobesity, becauseof decreased hepaticATP, possibly because of impaired mitochondrialfunction, leading to central appetite stimulation. It is also associated with decreasedexercise capacity and increased fatigability, possibly because of mitochondrialdysfunction.82 The role of mitochondria in obesity and diabetes is also reviewed in thisissue of the journal.

Retinol binding protein 4 (RBP4) is the transporter for vitamin A (retinol) in the blood.Serum levels and expression of RBP4 in adipose tissue were found to be increased inmice with adipose-specific knockout for GLUT4.83 As mentioned above, decreasedGLUT4 expression is a common feature of obesity, insulin resistance, and type 2diabetes.60 These mice develop impaired insulin action in the muscle, liver, andadipose tissue.84 Injecting RBP4 into mice or transgenic overexpression of RBP4leading to increased concentrations caused impaired insulin signaling and increasedexpression of the gluconeogenic enzyme phosphoenolpyruvate carboxylase in theliver.83Analogous to this, RPB4 knockout mice developed increased insulin sensitivityand glucose tolerance.83 These findings led to interest in the possible causal role ofRBP4 in insulin resistance. In humans, higher levels of RBP4 are found with obesity,type 2 diabetes, impaired glucose tolerance, and those with a strong family historyof type 2 diabetes.85 RBP4 is correlated with insulin resistance and has been shownin some studies to correlate more specifically with insulin resistance than leptin, adi-ponectin, IL-6, or C-reactive protein (CRP).81,85As RBP4 is the main transport protein

for vitamin A, it has been postulated that the synthetic retinoid, fenretinide could lowerRBP4 levels and improve insulin sensitivity, although this has yet to be determined.85

Hypertension is about 6 times more frequent in obese than in lean subjects.According to the NHANES III, hypertension is present in 15% of males and femaleswith a BMI 25 kg/m2 or less, and 42% of males and 38% of females with a BMIgreater than 30 kg/m2.79,86 The mechanism behind hypertension is hypothesizedto be a combination of the direct hemodynamic effects of obesity on cardiac output,which is increased, and normal or increased peripheral vascular resistance (PVR).The increased PVR is thought to be a result of sympathetic overactivity, volumeexpansion from the antinatiuretic effects of insulin, and increased angiotensinogen

II and proinflammatory cytokine IL-6 with associated increased oxidative stress,leading to decreased NO and endothelial dysfunction.79,80,87 PPARghas been shownto be a major regulator of many of these components in adipocytes.87 Weight lossimproves hypertension in 50% of subjects.79 Further consideration on the relation-ship between obesity and hypertension is also detailed in this issue.

Other factors involved in the metabolic abnormalities associated with obesity andcardiovascular risk include leptin, adiponectin, resistin, and adipocyte fatty acidbinding protein (A-FABP). The absence of leptin leads to extreme obesity, asdemonstrated in the ob/ob mice and humans with congenital leptin deficiency.88,89

Most obese individuals will however have elevated leptin levels with resistance to its

appetite-suppressing effects.90 It is also linked to marked insulin resistance, but hasmixed consequences on other cardiovascular abnormalities.80 Leptin appears towork in adipocytes and augments the expression of PGC1a gene, which hasbeen shown to increase mitochondrial biogenesis and potentially increased mito-chondrial oxidation.62 Adiponectin is an anti-inflammatory adipokine produced byadipocytes. Its expression is affected by insulin, glucocorticoids, b-adrenergicagonists, and TNFa. It is decreased in obesity and increased in lean persons. It



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appears to have a direct anti-atherogenic affect via its anti-inflammatory properties(reducing production of proinflammatory and increasing anti-inflammatory cyto-kines) or via its insulin sensitizing action. Adiponectin receptors 1 and 2 (AdipoR1 and adipo R2) are expressed in macrophages and modulated by PPAR ligands;adipo R2 is a more predominant receptor and is induced by PPAR a and PPARg inprimary and THP-1 macrophages. There is some evidence that adiponectin may infact be a proinflammatory agent, but desensitizes macrophages to itself and otherinflammatory stimuli; there is ongoing investigation into its mechanism of action.91,92

Resistin, a hormone produced by adipocytes, appears to oppose the action ofinsulin; however, its functional significance in humans is not as yet known.2

A-FABP is a cytosolic protein present in mature adipocytes, macrophages, and inthe bloodstream. Elevated levels correspond with the features of the metabolicsyndrome. Recently, subjects from the Nurses Health study and Health Profes-sionals follow-up study93 have been found to carry a functional genetic variant of

A-FABP gene, resulting in decreased adipose tissue A-FABP expression, asso-ciated with reduced triglycerides and lower incidence of type 2 diabetes and coro-nary artery disease. Its proatherogenic activity is believed to be mediated by itsdirect affect in macrophages. A-FABP decreases PPARg activity and cholesterolefflux in macrophages, thus leading to the formation of foam cells. A-FABP corre-lates with CRP levels. Its levels are inversely related to those of adiponectin.94

Recently, the cannabinoid system has received much interest because of itseffects of cardiometabolic parameters and potential for pharmacologic manipula-tion. Two cannabinoid receptors (CB1 and CB2) have been identified to date.CB1 is found in the central nervous system (CNS), notably in the cerebral cortex,

hypothalamus, reward circuits (nucleus accumbens and amygdala), and anteriorpituitary.95 It is also found in white adipose tissue, enteric nervous system, hepa-tocytes, and skeletal muscle myocytes.96,97 The ligands for CB1 and CB2 areanandamide and 2-arachidonylglycerol (2-AG). The receptor is a G-protein coupledreceptor, the activation of which leads to activation of inward-rectifying potassium(Kir) channels in the CNS and inhibition of voltage-gated calcium channels. Theexpression of CB1 and CB2 is down-regulated by glucocorticoids, leptin, anddopamine and up-regulated by glutamate.96 Activation of CB1 receptors hasbeen shown to have central effects on appetite stimulation as well as increasinghepatic lipogenesis (via increase in lipoprotein lipase and SREBP1c), increasing

adipocyte tissue accumulation and decreasing muscle glucose uptake. Increasedactivation is also associated with decreased adiponectin levels. CB2 appears tobe more prevalent in the immune system.96,97 Antagonists of this endocannabinoidsystem have been shown to suppress appetite, induce weight loss, improve dys-lipidemia, and improve glucose utilization.98 At least one such drug (Rimonabant)has been approved for therapy in Europe.95,96

There appears to be a role of glucocorticoids, sex hormones, and growth hormone(GH) in the development of the metabolic syndrome. Adipocytes express the enzyme11b-hydroxysteroid dehydrogenase (11b-HSD), which converts inactive cortisone toactive cortisol, resulting in locally enhanced cellular glucocorticoid levels. The enzyme

is particularly elevated in visceral adipose tissue from obese individuals.99 Sexsteroids have been implicated in the regulation of adiponectin expression/secretion.Testosterone has been shown to selectively inhibit high molecular weight adiponectin,believed to be associated with the higher risk of insulin resistance in men than women.Low adiponectin levels have been associated with development of the metabolicsyndrome in postmenopausal women.80 Growth hormone deficiency has also beenrelated to an increased risk of metabolic syndrome.100

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CLINICAL APPROACH TO A PATIENT WITH THE METABOLIC SYNDROME

Aggressive intervention to reduce the risk of cardiovascular disease and type 2 dia-betes is recommended in individuals with the metabolic syndrome; therefore, long-term intervention and monitoring by their primary care physician is warranted. As an

underlying mechanism has yet to be elucidated, treating the individual componentsis necessary at this time.

Identifying patients of having metabolic abnormalities and thus at high risk for CVDand diabetes is important. Overall, the metabolic syndrome is highest among Mexican

American females14; however, it is worth noting that certain ethnic groups such asSouthern Asian groups may have metabolic abnormalities without abdominalobesity.29,30 It is recommended to monitor blood pressure, pulse rate, fasting glucoseand insulin levels, lipid profile, and liver and kidney function tests together with bodyweight, height, and waist circumference. In certain individuals, a glucose tolerancetest will be warranted as suggested by the ADA guidelines. Establishing a risk category

for coronary artery disease can be done using an online risk calculator based on theFramingham heart study (http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype5prof).101As the Framingham heart study was based on a middle-aged white population,with a minority of individuals with diabetes, it should be used with a degree of caution inother ethnic groups, who may have a higher population prevalence of coronary diseaseand in those with diabetes.

The primary management is a healthy lifestyle. The Diabetes Prevention Programshowed that lifestyle intervention reduced the incidence of metabolic syndrome by41% compared with placebo.102 Weight loss of the order of 7% to 10% body weightover 6 to 12 months is recommended.103 This should be achieved through moderate

calorie restriction (5001000 kcal/day deficit), physical activity of ideally 30 to60 minutes daily, supplemented by an increase in daily lifestyle activities. In the Dia-betes Prevention Program and Finnish Diabetes Prevention Study, weight losscontributed to a 58% reduction in the development of diabetes.104,105 Exercise isalso associated with improvement in dyslipidemia independent of weight loss.106

Exercise enhances the expression and translocation of GLUT4 and improves insulinsensitivity.107,108 The composition of the diet should be altered to contain less than200 mg/day of cholesterol, less than 7% saturated fat, with total fat of 25% to 35%of calories, low simple sugars, and increased intake of fruits, vegetables, and wholegrains.12 Smoking cessation should be implemented in all individuals with the meta-bolic syndrome. Low dose of aspirin is recommended in all cases of moderate tohigh risk of cardiovascular disease.12

For those in whom lifestyle change is not sufficient, pharmacotherapy is available fortreatment of obesity, dyslipidemia, and hyperglycemia. Pharmacologic treatment forobesity includes sibutramine, a serotonin norepinephrine reuptake inhibitor; orlistat,which is an inhibitor of intestinal lipase; rimonabant, which is an endocannabinoidreceptor-1 antagonist; and metformin, which reduces hepatic glucose production.Metformin was shown to induce weight loss and was associated with a 31%decreased incidence of diabetes when compared with placebo in the DiabetesPrevention Program.104,109 It is worthy to note that some of the above-mentioneddrugs have not yet been approved for the treatment of metabolic syndrome or preven-tion of diabetes. Individuals with morbid obesity (BMI >40 kg/m2 or >35 kg/m2 withmajor comorbidities) can be candidates for bariatric surgery or laparoscopic gastricbanding.110 The treatments of obesity are discussed in other chapters in this issue.

Drug therapy for dyslipidemia is very successful with the use of HMG Co-A reduc-tase inhibitors (statins), niacin, fibrates, ezetimibe (with statins), and fish oils. LDLc

http://hp2010.nhlbihin.net/atpiii/calculator.asp%3fusertype%3dprofhttp://hp2010.nhlbihin.net/atpiii/calculator.asp%3fusertype%3dprofhttp://hp2010.nhlbihin.net/atpiii/calculator.asp%3fusertype%3dprofhttp://hp2010.nhlbihin.net/atpiii/calculator.asp%3fusertype%3dprofhttp://hp2010.nhlbihin.net/atpiii/calculator.asp%3fusertype%3dprof


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lowering is the primary therapeutic target (


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4. American Diabetes Association. Standards of medical care in diabetes2008.

Diabetes Care 2008;31(Suppl 1):S1254.

5. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.

Diabetes 1988;37(12):1595607.

6. Reaven GM. Role of insulin resistance in human disease (syndrome X): an

expanded definition. Annu Rev Med 1993;44:12131.

7. Alberti K, Zimmet P. Definition, diagnosis and classification of diabetes mellitus

and its complications. Part 1: diagnosis and classification of diabetes mellitus.

Provisional report of a WHO consultation. Diabet Med 1998;15:53953.

8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol

in Adults. Executive summary of the third report of the National Cholesterol

Education Program (NCEP) expert panel on detection, evaluation, and treat-

ment of high blood cholesterol in adults (Adult Treatment Panel III). J Am Med

Assoc 2001;285(19):248697.

9. Einhorn D, Reaven GM, Cobin RH, et al. American college of endocrinology

position statement on the insulin resistance syndrome. Endocr Pract 2003;

9(3):23752.

10. Report of the expert committee on the diagnosis and classification of diabetes

mellitus. Diabetes Care 2003;26(Suppl 1):S520.

11. Alberti KG, Zimmet P, Shaw J. The metabolic syndromea new worldwide defi-

nition. Lancet 2005;366(9491):105962.

12. Grundy S, Cleeman J, Daniels S, et al. Diagnosis and management of the meta-

bolic syndrome: an American Heart Association/National Heart, Lung, and

Blood Institute scientific statement. Circulation 2005;112(17):273552.

13. Ford ES. The metabolic syndrome and mortality from cardiovascular diseaseand all-causes: findings from the National Health and Nutrition Examination

Survey II mortality study. Atherosclerosis 2004;173(2):30712.

14. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US

adults: findings from the third National Health and Nutrition Examination Survey.

J Am Med Assoc 2002;287(3):3569.

15. Maggi S, Noale M, Gallina P, et al. Metabolic syndrome, diabetes, and cardio-

vascular disease in an elderly Caucasian cohort: the Italian longitudinal study

on aging. J Gerontol A Biol Sci Med Sci 2006;61(5):50510.

16. Patel A, Huang KC, Janus ED, et al. Is a single definition of the metabolic

syndrome appropriate? A comparative study of the USA and Asia. Atheroscle-rosis 2006;184(1):22532.

17. Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in

worldwide populations. Endocrinol Metab Clin North Am 2004;33(2):35175,

table of contents.

18. Ford ES. Prevalence of the metabolic syndrome defined by the International Dia-

betes Federation among adults in the US. Diabetes Care 2005;28(11):27459.

19. Assmann G, Guerra R, Fox G, et al. Harmonizing the definition of the metabolic

syndrome: comparison of the criteria of the Adult Treatment Panel III and the

International Diabetes Federation in United States American and European pop-

ulations. Am J Cardiol 2007;99(4):5418.20. Adams RJ, Appleton S, Wilson DH, et al. Population comparison of two clinical

approaches to the metabolic syndrome: implications of the new International

Diabetes Federation consensus definition. Diabetes Care 2005;28(11):27779.

21. Athyros VG, Ganotakis ES, Elisaf M, et al. The prevalence of the metabolic

syndrome using the national cholesterol educational program and International

Diabetes Federation definitions. Curr Med Res Opin 2005;21(8):11579.



14/19

22. Lorenzo C, Serrano-Rios M, Martinez-Larrad MT, et al. Geographic variations of

the International Diabetes Federation and the National Cholesterol Education

Program-Adult Treatment Panel III definitions of the metabolic syndrome in

non diabetic subjects. Diabetes Care 2006;29(3):68591.

23. Yoon Y, Lee E, Park C, et al. The new definition of metabolic syndrome by the Inter-

national Diabetes Federation is less likely to identify metabolically abnormal but

non-obese individuals than the definition by the revised national cholesterol educa-

tion program: the Korea NHANES study. Int J Obes (Lond) 2007;31(3):52834.

24. Tong P, Kong A, So W, et al. The usefulness of the International Diabetes Feder-

ation and the National Cholesterol Education Programs Adult Treatment Panel III

definitions of the metabolic syndrome in predicting coronary heart disease in

subjects with type 2 diabetes. Diabetes Care 2007;30(5):120611.

25. Mancia G, Bombelli M, Corrao G, et al. Metabolic syndrome in the Pressioni Ar-

teriose Monitorate e Loro Associazioni (PAMELA) study: daily life blood pres-

sure, cardiac damage, and prognosis. Hypertension 2007;49(1):407.

26. Welty TK, Lee ET, Yeh J, et al. Cardiovascular disease risk factors among Amer-

ican Indians: the strong heart study. Am J Epidemiol 1995;142(3):26987.

27. Araneta MRG, Wingard DL, Barrett-Connor E. Type 2 diabetes and metabolic

syndrome in Filipina-American women: a high-risk nonobese population. Dia-

betes Care 2002;25(3):4949.

28. Simmons D, Thompson CF. Prevalence of the metabolic syndrome among adult

New Zealanders of Polynesian and European descent. Diabetes Care 2004;

27(12):30024.

29. Feng Y, Hong X, Li Z, et al. Prevalence of metabolic syndrome and its relation to

body composition in a chinese rural population. Obesity 2006;14(11):208998.30. Thomas GN, Ho SY, Janus ED, et al. The US National Cholesterol Education Pro-

gramme Adult Treatment Panel III (NCEP ATP III) prevalence of the metabolic

syndrome in a Chinese population. Diabetes Res Clin Pract 2005;67(3):2517.

31. McKeigue PM, Ferrie JE, Pierpoint T, et al. Association of early-onset coronary

heart disease in South Asian men with glucose intolerance and hyperinsuline-

mia. Circulation 1993;87(1):15261.

32. Whincup PH, Gilg JA, Papacosta O, et al. Early evidence of ethnic differences in

cardiovascular risk: cross sectional comparison of British South Asian and white

children. BMJ 2002;324(7338):63540.

33. Al-Lawati JA, Mohammed AJ, Al-Hinai HQ, et al. Prevalence of the metabolicsyndrome among Omani adults. Diabetes Care 2003;26(6):17815.

34. Halldina M, Rosella M, de Fairea U, et al. The metabolic syndrome: prevalence

and association to leisure-time and work-related physical activity in 60-year-old

men and women. Nutr Metab Cardiovasc Dis 2007;17(5):34957.

35. LaMonte MJ, Barlow CE, Jurca R, et al. Cardiorespiratory fitness is inversely

associated with the incidence of metabolic syndrome: a prospective study of

men and women. Circulation 2005;112(4):50512.

36. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics2006

update: a report from the American Heart Association Statistics Committee and

Stroke Statistics Subcommittee. Circulation 2006;113(6):e85151.37. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on

mortality from coronary heart disease, cardiovascular disease, and all causes

in United States adults. Circulation 2004;110(10):124550.

38. Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and risk of

major coronary events in the Scandinavian Simvastatin Survival Study (4S)

Gallagher et al868


15/19

and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/

TexCAPS). Am J Cardiol 2004;93(2):13641.

39. Saely CH, Aczel S, Marte T, et al. The metabolic syndrome, insulin resistance,

and cardiovascular risk in diabetic and nondiabetic patients. J Clin Endocrinol

Metab 2005;90(10):5698703.

40. Rutter MK, Meigs JB, Sullivan LM, et al. Insulin resistance, the metabolic

syndrome, and incident cardiovascular events in the Framingham offspring

study. Diabetes 2005;54(11):32527.

41. Jeppesen J, Hansen TW, Rasmussen S, et al. Insulin resistance, the metabolic

syndrome, and risk of incident cardiovascular disease: a population-based

study. J Am Coll Cardiol 2007;49(21):21129.

42. Eberly LE, Prineas R, Cohen JD, et al. Metabolic syndrome: risk factor distribu-

tion and 18-year mortality in the multiple risk factor intervention trial. Diabetes

Care 2006;29(1):12330.

43. de Simone G, Devereux RB, Chinali M, et al. Prognostic impact of metabolic

syndrome by different definitions in a population with high prevalence of obesity

and diabetes: the strong heart study. Diabetes Care 2007;30(7):18516.

44. Anderson KM, Wilson PW, Odell PM, et al. An updated coronary risk profile. A

statement for health professionals. Circulation 1991;83(1):35662.

45. Wannamethee SG, Shaper AG, Lennon L, et al. Metabolic syndrome vs Fra-

mingham risk score for prediction of coronary heart disease, stroke, and type

2 diabetes mellitus. Arch Intern Med 2005;165(22):264450.

46. Grundy SM, Brewer HB Jr, Cleeman JI, et al. For the conference p: definition of

metabolic syndrome: report of the National Heart, Lung, and Blood Institute/

American Heart Association conference on scientific issues related to definition.Circulation 2004;109(3):4338.

47. Wilson PW. Estimating cardiovascular disease risk and the metabolic syndrome:

a Framingham view. Endocrinol Metab Clin North Am 2004;33(3):46781, v.

48. Lorenzo C, Williams K, Hunt KJ, et al. The National Cholesterol Education

Program-Adult Treatment Panel III, International Diabetes Federation, and

World Health Organization definitions of the metabolic syndrome as predictors

of incident cardiovascular disease and diabetes. Diabetes Care 2007;30(1):

813.

49. Wang JJ, Ruotsalainen S, Moilanen L, et al. The metabolic syndrome predicts

cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns.Eur Heart J 2007;28(7):85764.

50. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes

associated with the metabolic syndrome: a summary of the evidence. Diabetes

Care 2005;28(7):176978.

51. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident

cardiovascular events and death: a systematic review and meta-analysis of

longitudinal studies. J Am Coll Cardiol 2007;49(4):40314.

52. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular

disease: a meta-analysis. Am J Med 2006;119(10):8129.

53. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in

Communities study. Diabetes Care 2005;28(2):38590.

54. Monami M, Lambertucci L, Ungar A, et al. Is the third component of metabolic

syndrome really predictive of outcomes in type 2 diabetic patients? Diabetes

Care 2006;29(11):25157.



16/19

55. Sundstrom J, Riserus U, Byberg L, et al. Clinical value of the metabolic

syndrome for long-term prediction of total and cardiovascular mortality:

prospective, population-based cohort study. BMJ 2006;332(7546):87882.

56. Kahn R, Buse J, Ferrannini E, et al. The metabolic syndrome: time for a critical

appraisal: joint statement from the American Diabetes Association and the Euro-

pean Association for the Study of Diabetes. Diabetes Care 2005;28:2289304.

57. Iribarren C, Go AS, Husson G, et al. Metabolic syndrome and early-onset coro-

nary artery disease: is the whole greater than its parts? J Am Coll Cardiol 2006;

48(9):18007.

58. Smith DO, LeRoith D. Insulin resistance syndrome, pre-diabetes, and the

prevention of type 2 diabetes mellitus. Clin Cornerstone 2004;6(2):716.

59. LeRoith D. Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of

metabolic and genetic abnormalities. Am J Med 2002;113(Suppl 6A):3S11S.

60. Armoni M, Harel C, Karnieli E. Transcriptional regulation of the GLUT4 gene:

from PPAR-gamma and FOXO1 to FFA and inflammation. Trends Endocrinol

Metab 2007;18(3):1007.

61. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways:

insights into insulin action. Nat Rev Mol Cell Biol 2006;7(2):8596.

62. Nisoli E, Clementi E, Carruba MO, et al. Defective mitochondrial biogenesis:

a hallmark of the high cardiovascular risk in the metabolic syndrome? Circ

Res 2007;100(6):795806.

63. Larance M, Ramm G, James DE. The GLUT4 code. Mol Endocrinol 2008;22:

22633.

64. Karnieli E, Armoni M. Transcriptional regulation of the insulin-responsive glucose

transporter GLUT4 gene: from physiology to pathology. Am J Physiol EndocrinolMetab 2008;295(1):E3845.

65. Charron MJ, Katz EB. Metabolic and therapeutic lessons from genetic manipu-

lation of GLUT4. Mol Cell Biochem 1998;182(12):14352.

66. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106(4):

47381.

67. Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycae-

mia. Diabetologia 2003;46(Suppl 1):M28.

68. Minokoshi Y, Kahn CR, Kahn BB. Tissue-specific ablation of the glut4 glucose

transporter or the insulin receptor challenges assumptions about insulin action

and glucose homeostasis. J Biol Chem 2003;278(36):3360912.69. Liang CP, Han S, Senokuchi T, et al. The macrophage at the crossroads of

insulin resistance and atherosclerosis. Circ Res 2007;100(11):154655.

70. Paz K, Hemi R, LeRoith D, et al. A molecular basis for insulin resistance.

Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their

binding to the juxtamembrane region of the insulin receptor and impairs their

ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 1997;

272(47):299118.

71. Armoni M, Harel C, Karni S, et al. FOXO1 represses peroxisome proliferator-

activated receptor-{gamma}1 and -{gamma}2 gene promoters in primary adipo-

cytes: a novel paradigm to increase insulin sensitivity. J Biol Chem 2006;281(29):1988191.

72. Nakae J, Biggs WH III, Kitamura T, et al. Regulation of insulin action and pancre-

atic beta-cell function by mutated alleles of the gene encoding forkhead tran-

scription factor FOXO1. Nat Genet 2002;32(2):24553.

73. Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogen-

esis through FOXO1-PGC-1alpha interaction. Nature 2003;423(6939):5505.

Gallagher et al870


17/19

74. Armoni M, Kritz N, Harel C, et al. Peroxisome proliferator-activated receptor-

gamma represses GLUT4 promoter activity in primary adipocytes, and rosiglita-

zone alleviates this effect. J Biol Chem 2003;278(33):3061423.

75. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351(11):110618.

76. Guan H-P, Ishizuka T, Chui PC, et al. Corepressors selectively control the tran-

scriptional activity of PPAR{gamma} in adipocytes. Genes Dev 2005;19(4):

45361.

77. George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance

and diabetes due to a mutation in AKT2. Science 2004;304(5675):13258.

78. Pegorier JP, Le May C, Girard J. Control of gene expression by fatty acids.

J Nutr 2004;134(9):2444S9S.

79. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: patho-

physiology, evaluation, and effect of weight loss: an update of the 1997 Amer-

ican Heart Association scientific statement on obesity and heart disease from

the Obesity Committee of the Council on Nutrition, Physical Activity, and Metab-

olism. Circulation 2006;113(6):898918.

80. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic

syndrome. Am J Med Sci 2005;330(6):2809.

81. Kloting N, Graham TE, Berndt J, et al. Serum retinol-binding protein is more

highly expressed in visceral than in subcutaneous adipose tissue and is

a marker of intra-abdominal fat mass. Cell Metab 2007;6(1):7987.

82. Khayat ZA, Patel N, Klip A. Exercise- and insulin-stimulated muscle glucose trans-

port: distinct mechanisms of regulation. Can J Appl Physiol 2002;27(2):12951.

83. Yang Q, Graham TE, Mody N, et al. Serum retinol binding protein 4 contributes

to insulin resistance in obesity and type 2 diabetes. Nature 2005;436(7049):35662.

84. Abel ED, Peroni O, Kim JK, et al. Adipose-selective targeting of the GLUT4 gene

impairs insulin action in muscle and liver. Nature 2001;409(6821):72933.

85. Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein 4 and insulin resis-

tance in lean, obese, and diabetic subjects. N Engl J Med 2006;354(24):

255263.

86. Brown CD, Higgins M, Donato KA, et al. Body mass index and the prevalence of

hypertension and dyslipidemia. Obes Res 2000;8(9):60519.

87. Sharma AM, Staels B. Review: peroxisome proliferator-activated receptor

gamma and adipose tissueunderstanding obesity-related changes in regula-tion of lipid and glucose metabolism. J Clin Endocrinol Metab 2007;92(2):

38695.

88. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene

and its human homologue. Nature 1994;372(6505):42532.

89. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in

a child with congenital leptin deficiency. N Engl J Med 1999;341(12):87984.

90. Maffei M, Fei H, Lee GH, et al. Increased expression in adipocytes of ob RNA in

mice with lesions of the hypothalamus and with mutations at the db locus. Proc

Natl Acad Sci U S A 1995;92(15):695760.

91. Kim C-H, Pennisi P, Zhao H, et al. MKR mice are resistant to the metabolicactions of both insulin and adiponectin: discordance between insulin resistance

and adiponectin responsiveness. Am J Physiol Endocrinol Metab 2006;291(2):

E298305.

92. Tsatsanis C, Zacharioudaki V, Androulidaki A, et al. Peripheral factors in the

metabolic syndrome: the pivotal role of adiponectin. Ann N Y Acad Sci 2006;

1083:18595.



18/19

93. Tuncman G, Erbay E, Hom X, et al. A genetic variant at the fatty acid-binding

protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes,

and cardiovascular disease. Proc Natl Acad Sci USA 2006;103:69705.

94. Xu A, Tso AW, Cheung BM, et al. Circulating adipocyte-fatty acid binding protein

levels predict the development of the metabolic syndrome: a 5-year prospective

study. Circulation 2007;115(12):153743.

95. Matias I, Vergoni AV, Petrosino S, et al. Regulation of hypothalamic endocanna-

binoid levels by neuropeptides and hormones involved in food intake and

metabolism: insulin and melanocortins. Neuropharmacology 2008;54(1):

20612.

96. Cota D. CB1 receptors: emerging evidence for central and peripheral mecha-

nisms that regulate energy balance, metabolism, and cardiovascular health.

Diabetes Metab Res Rev 2007;23(7):50717.

97. Woods SC. The endocannabinoid system: mechanisms behind metabolic

homeostasis and imbalance. Am J Med 2007;120(2 Suppl 1):S917 [discussion

S2932].

98. Kakafika AI, Mikhailidis DP, Karagiannis A, et al. The role of endocannabinoid

system blockade in the treatment of the metabolic syndrome. J Clin Pharmacol

2007;47(5):64252.

99. Walker BR, Andrew R. Tissue production of cortisol by 11beta-hydroxysteroid

dehydrogenase type 1 and metabolic disease. Ann N Y Acad Sci 2006;1083:

16584.

100. van der Klaauw AA, Biermasz NR, Feskens EJ, et al. The prevalence of the

metabolic syndrome is increased in patients with GH deficiency, irrespective

of long-term substitution with recombinant human GH. Eur J Endocrinol 2007;156(4):45562.

101. Wilson PW, DAgostino RB, Levy D, et al. Prediction of coronary heart disease

using risk factor categories. Circulation 1998;97(18):183747.

102. Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and inten-

sive lifestyle intervention on the metabolic syndrome: the diabetes prevention

program randomized trial. Ann Intern Med 2005;142(8):6119.

103. Expert Panel on the Identification, Evaluation and Treatment of Overweight in

Adults. Clinical guidelines on the identification, evaluation, and treatment of

overweight and obesity in adults: executive summary. Am J Clin Nutr 1998;

68(4):899917.104. Knowler W, Barrett-Connor E, Fowler S, et al. Reduction in the incidence of type

2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6):

393403.

105. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mel-

litus by changes in lifestyle among subjects with impaired glucose tolerance.

N Engl J Med 2001;344(18):134350.

106. Kraus WE, Houmard JA, Duscha BD, et al. Effects of the amount and intensity of

exercise on plasma lipoproteins. N Engl J Med 2002;347(19):148392.

107. Kim HJ, Lee JS, Kim CK. Effect of exercise training on muscle glucose trans-

porter 4 protein and intramuscular lipid content in elderly men with impairedglucose tolerance. Eur J Appl Physiol 2004;93(3):3538.

108. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu

Rev Med 1998;49(1):23561.

109. Pi-Sunyer FX. Use of lifestyle changes, treatment plans, and drug therapy

in controlling cardiovascular and metabolic risk factors. Obesity 2006;

14(Suppl 3):135S42S.

Gallagher et al872


19/19

110. Elder KA, Wolfe BM. Bariatric surgery: a review of procedures and outcomes.

Gastroenterology 2007;132(6):225371.

111. National Cholesterol Education Program (NCEP) Expert Panel on Detection,

Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment

Panel III). Third report of the National Cholesterol Education Program (NCEP)

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol

in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):

3143421.

112. Bottorff MB. Statin safety and drug interactions: clinical implications. The Amer-

ican Journal of Cardiology 2006;97(8 Suppl 1):S2731.

113. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure. Hypertension 2003;42(6):120652.

114. DREAM Trial Investigators, Gerstein HC, Yusuf S, et al. Effect of rosiglitazone on

the frequency of diabetes in patients with impaired glucose tolerance or impaired

fasting glucose: a randomised controlled trial. Lancet 2006;368(9541):1096105.

115. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction

and death from cardiovascular causes. N Engl J Med 2007;356(24):245771.


the metabolic syndrome—from insulin resistance to obesity and diabetes

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