腹型肥胖和代谢综合征

ISSN: 1524-4636 Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 1079-5642. Online 7272 Greenville Avenue, Dallas, TX 72514 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association. DOI: 10.1161/ATVBAHA.107.159228 20, 2008; 2008;28;1039-1049; originally published online MarArterioscler Thromb Vasc Biol Mathieu, Eric Larose, Josep Rodés-Cabau, Olivier F. Bertrand and Paul Poirier Jean-Pierre Després, Isabelle Lemieux, Jean Bergeron, Philippe Pibarot, Patrick Cardiometabolic Risk Abdominal Obesity and the Metabolic Syndrome: Contribution to Global http://atvb.ahajournals.org/cgi/content/full/28/7/e151 An erratum has been published regarding this article. Please see the attached page or: http://atvb.ahajournals.org/cgi/content/full/28/6/1039 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprints Reprints: Information about reprints can be found online at journalpermissions@lww.com 410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://atvb.ahajournals.org/subscriptions/ Biology is online at Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular by on April 9, 2011 atvb.ahajournals.orgDownloaded from ATVB In Focus Metabolic Syndrome and Atherosclerosis Series Editor: Marja-Riitta Taskinen Preview Brief Reviews in this Series: • Grundy, SM. Metabolic syndrome pandemic. Arteroscler Thromb Vasc Biol. 2008;28:629–636. • Barter PJ, Rye KA. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome. Arteroscler Thromb Vasc Biol. 2008;28:39–46. • Kotronen A, Yki-Ja¨rvinen. Fatty liver: a novel component of the metabolic syndrome. Arteroscler Thromb Vasc Biol. 2008;28:27–38. • Gustafson B, Hammarstedt A, Andersson CX, and Smith U. Inflamed adipose tissue: a culprit underlying the meta- bolic syndrome and atherosclerosis. Arteroscler Thromb Vasc Biol. 2007;27:2276–2283. Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk Jean-Pierre Despre´s, Isabelle Lemieux, Jean Bergeron, Philippe Pibarot, Patrick Mathieu, Eric Larose, Josep Rode´s-Cabau, Olivier F. Bertrand, Paul Poirier Abstract—There is currently substantial confusion between the conceptual definition of the metabolic syndrome and the clinical screening parameters and cut-off values proposed by various organizations (NCEP-ATP III, IDF, WHO, etc) to identify individuals with the metabolic syndrome. Although it is clear that in vivo insulin resistance is a key abnormality associated with an atherogenic, prothrombotic, and inflammatory profile which has been named by some the “metabolic syndrome” or by others “syndrome X” or “insulin resistance syndrome”, it is more and more recognized that the most prevalent form of this constellation of metabolic abnormalities linked to insulin resistance is found in patients with abdominal obesity, especially with an excess of intra-abdominal or visceral adipose tissue. We have previously proposed that visceral obesity may represent a clinical intermediate phenotype reflecting the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink for the clearance and storage of the extra energy derived from dietary triglycerides, leading to ectopic fat deposition in visceral adipose depots, skeletal muscle, liver, heart, etc. Thus, visceral obesity may partly be a marker of a dysmetabolic state and partly a cause of the metabolic syndrome. Although waist circumference is a better marker of abdominal fat accumulation than the body mass index, an elevated waistline alone is not sufficient to diagnose visceral obesity and we have proposed that an elevated fasting triglyceride concentration could represent, when waist circumference is increased, a simple clinical marker of excess visceral/ectopic fat. Finally, a clinical diagnosis of visceral obesity, insulin resistance, or of the metabolic syndrome is not sufficient to assess global risk of cardiovascular disease. To achieve this goal, physicians should first pay attention to the classical risk factors while also considering the additional risk resulting from the presence of abdominal obesity and the metabolic syndrome, such global risk being defined as cardiometabolic risk. (Arterioscler Thromb Vasc Biol 2008;28:1039-1049) Key Words: global cardiometabolic risk � insulin resistance � metabolic syndrome � visceral obesity � waist circumference Original received November 13, 2007; final version accepted March 6, 2008. From the Hoˆpital Laval Research Centre (J.-P.D., I.L., P. Pibarot, P.M., E.L., J.R.-C., O.F.B., P. Poirier); the Institut universitaire de cardiologie et de pneumologie (J.-P.D., P.M., E.L., J.R.-C., O.F.B., P. Poirier), Hoˆpital Laval; the Division of Kinesiology (J.-P.D.), Department of Social and Preventive Medicine, Universite´ Laval; the Lipid Research Centre (J.B.), CHUQ Research Centre; the Department of Medicine (P. Pibarot), Universite´ Laval; the Department of Surgery (P.M.), Universite´ Laval; the Faculty of Pharmacy (P. Poirier), Universite´ Laval, Québec City, QC, Canada. Correspondence to Jean-Pierre Despre´s, PhD, FAHA, Scientific Director, International Chair on Cardiometabolic Risk, Director of Research, Cardiology, Hoˆpital Laval Research Centre, 2725 chemin Ste-Foy, Pavilion Marguerite-D’Youville, 4th Floor, Québec City, QC, G1V 4G5, CANADA. E-mail jean-pierre.despres@crhl.ulaval.ca © 2008 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.107.159228 1039 by on April 9, 2011 atvb.ahajournals.orgDownloaded from The Pioneer In his seminal 1988 Banting award lecture, Reaven1 proposed that insulin resistance was a fundamental “disorder” associ- ated with a set of metabolic abnormalities which not only increased the risk of type 2 diabetes but also contributed to the development of cardiovascular disease (CVD) before the appearance of hyperglycemia. Reaven coined the term “syn- drome X” to describe the clustering abnormalities associated with insulin resistance but since another syndrome X had been documented in cardiology,2 the term insulin resistance syndrome became more frequently used to describe what should have been legitimately called the Reaven syndrome. It is also relevant to mention that as Reaven found insulin resistant individuals who were not obese, he did not include obesity as a feature of the insulin resistance syndrome. Since the introduction of the syndrome X concept, a plethora of studies3–7 have shown that insulin resistance assessed by various methods is indeed a key factor associated with clustering atherogenic abnormalities which include a typical atherogenic dyslipidemic state (high triglyceride and apolipoprotein B concentrations, an increased proportion of small dense LDL particles and a reduced concentration of HDL-cholesterol, HDL particles also being smaller in size), a prothrombotic profile, and a state of inflammation (Figure 1). Furthermore, insulin resistance could also contribute to an elevated blood pressure8–11 and to dysglycemia,6,12–14 even- tually leading, among genetically susceptible individuals, to systemic hypertension and type 2 diabetes. It is not the scope of this short review to deal with the question of whether or not it is insulin resistance or visceral obesity/ectopic fat which is the key primary culprit for the metabolic syndrome. Rather, the present article will propose that it is the mismanagement of energy under conditions of positive energy balance which leads to visceral/ectopic fat- insulin resistance and to features of the metabolic syndrome. From Pathophysiology to Clinical Assessment As most physicians cannot measure indices of insulin sensi- tivity in the context of their clinical practice, some organiza- tions such as the World Health Organization (WHO),15 the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III),16,17 the European Group for the study of Insulin Resistance (EGIR),18 the American Associ- ation of Clinical Endocrinologists (AACE),19 and more re- cently the International Diabetes Federation (IDF)20 have proposed to use simple clinical parameters with cut-off values to find individuals who would probably be insulin resistant and who would also show the atherogenic and diabetogenic abnormalities related to an impaired insulin action: the “metabolic syndrome” was born. However, it should be pointed out that there is no direct marker of insulin resista- nce in the NCEP-ATP III or IDF clinical criteria to diagnose the metabolic syndrome. Although patients diagnosed with the metabolic syndrome are likely to be more insulin resis- tant, there may be some discrepancies in the prevalence of insulin resistance depending on the metabolic syndrome clinical criteria used. Genetic and environmental determinants • Energy dense diet • Genetic variation • Age and Gender • Lack of physical activity • Smoking Impaired fibrinolysisInflammation Atherogenic dyslipidemia ↑↑ Blood pressure Dysglycemia • Stress • Neuroendocrine abnormalities • Steroid hormones • Susceptible endocannabinoid system • Drugs Based on key pathophysiological markers • Syndrome X (Reaven) • Insulin resistance syndrome ⇒ Based on clinical tools:• Metabolic syndrome (NCEP-ATP III or IDF) ⇒ • HDL-cholesterol • Glucose • Waist girth • Triglycerides • Blood pressure A B C Visceral obesity/ Ectopic fat Adipokines Insulin resistance/ ↑ Insulin Figure 1. Simplified model illustrating the possible correlates (A) of insulin resistance often found among individuals with excess viscer- al/ectopic fat. Panel B emphasizes the notion that the syndrome X/insulin resistance syndrome concept was based on pathophysiologi- cal considerations, whereas panel C highlights the fact that National Cholesterol Education Program-Adult Treatment Panel III (NCEP- ATP III) and International Diabetes Federation (IDF) metabolic syndrome is an entity identified in clinical practice by the presence of simple screening tools. 1040 Arterioscler Thromb Vasc Biol June 2008 by on April 9, 2011 atvb.ahajournals.orgDownloaded from With the use of these simple criteria, investigators found that a clinical diagnosis of the metabolic syndrome (either by NCEP-ATP III or IDF criteria) was associated with an increased relative risk of CVD.21–31 However, the fact that the 5 variables proposed in NCEP-ATP III and IDF are not used as continuous variables in a proper risk calculator but rather counted as “present” or “absent” likely makes these screening tools less than perfect for the optimal diagnosis of the metabolic syndrome (“presence” or “absence” of an abnor- mality may be too crude to assess an individual risk profile or response to therapy). Furthermore, there is a mosaic of combinations of 3 of the 5 criteria which makes it very unlikely that all these subgroups are similar entities from a pathophysiological standpoint and clinical prognosis.32 One classic example of this problem is the case of type 2 diabetic patients who are hyperglycemic (by definition as they have diabetes) and who are also most often obese and hyperten- sive. Because they have 3 criteria, these patients with type 2 diabetes are diagnosed as having the metabolic syndrome. However, these patients with diabetes are likely to be meta- bolically quite distinct from nondiabetic but high triglyceride, low HDL-cholesterol dyslipidemic abdominally obese pa- tients.33 Under the current metabolic syndrome diagnosis tools, they are considered as a homogeneous entity, which is very unlikely. For instance, it is clear that an elevated fasting blood glucose concentration, which is often referred to as a “prediabetic” state, is more useful to predict type 2 diabetes risk than the other markers of the metabolic syndrome.28,34,35 Additional work is needed to clarify this issue and a global metabolic syndrome calculator with variables treated as continuous variables would help address this problem. Inves- tigators have therefore raised the issue that better tools are needed to assess the clustering abnormalities of the metabolic syndrome and the severity of this condition and that only new metabolic syndrome calculators providing a continuous score will be able to address this question.36 Metabolic Syndrome: Putting Abdominal Obesity on the Front Line One key conceptual advance made, however, with the intro- duction of the metabolic syndrome as a clinically measurable (although imperfect) entity was the recognition of abdominal obesity as its most prevalent form,16,20,37,38 a notion still debated by Reaven nowadays.39,40 For instance, NCEP-ATP III made an index of abdominal adiposity (assessed by waist circumference) and not obesity (assessed by the body mass index [BMI]) as 1 of 5 criteria on which clinicians could diagnose the syndrome, the presence of 3 of the 5 criteria being required. However, the relationship of waist circumfer- ence to abdominal adiposity, especially visceral or intra- abdominal (the terms can be used interchangeably) obesity, is age- and gender- as well as ethnicity-dependent,41– 44 and these issues were not properly addressed in the initial NCEP- ATP III guidelines. For instance, waist circumferences of 102 cm and 88 cm were average values corresponding to a BMI of 30 kg/m2 in men and women, respectively.45 There is clearly a continuous relationship between waist circumfer- ence and clinical outcomes, and these cut-off values are currently difficult to justify, especially if we consider that women have, on average, more subcutaneous fat and less visceral fat than men.46,47 However, menopause is associated with a selective deposition of visceral fat, a phenomenon which again makes the single 88-cm value questionable.48–50 Regarding ethnicity, the IDF has recognized this problem and proposed to lower the waist circumference (which is a mandatory criterion in IDF) cut-offs for some ethnic groups.20 However, the ethnic-specific waist cut-off values that they proposed were not always validated against direct imaging data of visceral fat and clinical outcomes, and further work is needed to define what is high-risk abdominal obesity in various populations of the world. Abdominal Obesity and the Metabolic Syndrome: Too Much Visceral Adipose Tissue or a Marker of Ectopic Fat? There is substantial evidence supporting the notion that too much abdominal fat is predictive of insulin resistance and of the presence of related metabolic abnormalities commonly referred to as the metabolic syndrome.51–63 Despite the fact that abdominal obesity is a highly prevalent feature of the metabolic syndrome, the mechanisms by which abdominal obesity is causally related to the metabolic syndrome are not fully understood. Imaging studies using measurements of abdominal adiposity (MRI and computed tomography) have generally reached the conclusion that it is the excess of intraabdominal or visceral adipose tissue and not the amount of subcutaneous abdominal fat which is the key correlate of the metabolic abnormalities observed in overweight/obese patients.3,51,54,56,57,64–68 For instance, individuals perfectly matched for subcutaneous abdominal adiposity but with either a low versus a high accumulation of visceral adipose tissue have been shown to be markedly different in their levels of insulin resistance and glucose tolerance.51,54,56,57,69 However, after being matched for visceral adiposity, individ- uals with low or high levels of subcutaneous fat were not found to differ in insulin sensitivity.56,57 This finding provides evidence that despite the fact that numerous studies have shown that weight, BMI, subcutaneous fat, and visceral fat are all well correlated with insulin resistance and with alterations in indices of plasma glucose-insulin homeostasis, it is the subgroup of overweight/obese patients with an excess of visceral fat that shows the most severe insulin resistant state. However, we have to keep in mind that subcutaneous fat is not neutral although it may represent a “metabolic sink”. Evidence suggests that if hyperplasia goes on in expanding adipose tissue, patients may not develop features of the metabolic syndrome, whereas, if it becomes hypertrophic in response to positive energy balance with a limited ability to expand, then it may become insulin resistant and also con- tribute to the dysmetabolic state.70–73 However, these findings do not provide experimental evidence that visceral adiposity is causally related to insulin resistance. In a review article from our group37 3 scenarios have been proposed to explain the relation of visceral adiposity to the metabolic syndrome (Figure 2): (1) The hyperlipolytic state of the omental adipose tissue, which shows resistance to the action of insulin, contributes to expose (through the portal circulation) the liver to high Despre´s et al From Metabolic Syndrome to Global Cardiometabolic Risk 1041 by on April 9, 2011 atvb.ahajournals.orgDownloaded from concentrations of free fatty acids, impairing several hepatic metabolic processes leading to hyperinsulinemia (decreased insulin clearance), glucose intolerance (increased hepatic glucose production), and hypertriglyceridemia (increased VLDL-apolipoprotein B secretion); (2) The adipose tissue is a remarkable endocrine organ which is a source of adipokines like adiponectin and inflammatory cytokines such as inter- leukin (IL)-6 (IL-6) and tumor necrosis factor (TNF)-� (to only name a few) which contribute to the insulin resistant, proinflammatory, -thrombotic, and -hypertensive state of visceral obesity; (3) Excess visceral adiposity is only (or partly) a marker of the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink because of its inability to expand (lipodystrophy) or because it has become hypertrophied, dysfunctional and insulin resistant. Under this third scenario, sedentary individuals who cannot store their energy surplus in the subcutaneous adipose tissue would be characterized by accumulation of fat at undesired sites such as the liver, the heart, the skeletal muscle, and the pancreas. However, a more plausible explanation for the metabolic abnormalities of abdominal obesity is that all the above mechanisms are involved. An additional possibility is that a more primary neuroendocrine profile may channel excess energy both preferentially in the visceral depot and at undesired sites leading to visceral obesity, ectopic fat depo- sition, insulin resistance, and metabolic abnormalities.74 In this regard, the remarkable change in both body fat distribu- tion and metabolic profile of transsexual patients on hor- monal therapy75,76 provides spectacular evidence that a cer- tain neuroendocrine profile may represent a primary abnormality leading to the development of ectopic fat and the metabolic syndrome. Metabolic Syndrome Does Not Assess Global CVD Risk: The Notion of Cardiometabolic Risk One key criticism addressed to the metabolic syndrome is that although numerous studies have shown that its presence is associated with an approximately 2-fold increase in CVD risk,21,22 such an increase in relative risk cannot evaluate absolute risk. Furthermore, reported relative CVD risks associated with the metabolic syndrome have not always taken into account confounding variables which makes the study comparisons rather difficult. For that purpose, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) as well as the International Chair on Cardiometabolic Risk have empha- sized the critical impor