The Metabolic Syndrome at the Beginning of the XXI Century. A Genetic and Molecular Approach

469 Pages·2005·6.717 MB·469\469

by  Manuel Serrano Ríos, José F. Caro, Raffaele Carraro and José A. Gutiérrez Fuentes (Eds.)

Es una publicación
©2005 Elsevier España, S.A.
Génova, 17, 3.º
28004 Madrid, España
An Elsevier Imprint
Fotocopiar es un delito (Art. 270 C.P.)
Para que existan libros es necesario el trabajo de un importante colectivo
(autores, traductores, dibujantes, correctores, impresores, editores...).
El principal beneficiario de ese esfuerzo es el lector que aprovecha su contenido.
Quien fotocopia un libro, en las circunstancias previstas por la ley, delinque y
contribuye a la «no» existencia de nuevas ediciones. Además, a corto plazo,
encarece el precio de las ya existentes.
Este libro está legalmente protegido por los derechos de propiedad intelectual.
Cualquier uso fuera de los límites establecidos por la legislación vigente,
sin el consentimiento del editor, es ilegal. Esto se aplica en particular
a la reproducción, fotocopia, traducción, grabación o cualquier otro sistema
de recuperación de almacenaje de información.
Producción editorial: GEACONSULTORÍAEDITORIAL,S.L.L.
ISBN: 84-8174-892-7
Depósito legal: M-23.664-2005
Impreso en España por Gráficas Muriel, S.A.
Advertencia
La medicina es un área en constante evolución. Aunque deben seguirse unas precauciones de seguridad estándar,
a medida que aumenten nuestros conocimientos gracias a la investigación básica y clínica habrá que introducir
cambios en los tratamientos y en los fármacos. En consecuencia, se recomienda a los lectores que analicen los
últimos datos aportados por los fabricantes sobre cada fármaco para comprobar la dosis recomendada, lavía y
duración de la administración y las contraindicaciones. Es responsabilidad ineludible del médico determinar
las dosis y el tratamiento más indicado para cada paciente, en función de su experiencia y del conocimiento de
cada caso concreto. Ni los editores ni los directores asumen responsabilidad alguna por los daños que pudie-
ran generarse a personas o propiedades como consecuencia del contenido de esta obra.
El editor
List of Authors
The Editors 4 SYLVIE FRANCKHAUSER AND FÁTIMA BOSCH
CENTER OF ANIMAL BIOTECHNOLOGYAND GENE
MANUEL SERRANO RÍOS
THERAPYAND DEPARTMENT OF BIOCHEMISTRYAND
DEPARTMENT OF INTERNAL MEDICINE, HOSPITAL MOLECULAR BIOLOGY, SCHOOL OFVETERINARY
CLÍNICO SAN CARLOS, COMPLUTENSE UNIVERSITYOF MEDICINE, AUTONOMOUS UNIVERSITYOF BARCELONA,
MADRID, SPAIN BELLATERRA, SPAIN
JOSÉ F. CARO 5 ANTONIO RUIZ-TORRES
LILLYRESEARCH LABORATORIES, LILLYCORPORATE UNIVERSITYRESEARCHINSTITUTEOFAGEINGAND
CENTER, INDIANAPOLIS, USA METABOLISM, HOSPITALDELAPRINCESA, MADRID, SPAIN
RAFFAELE CARRARO
6 PETER M. NILSSON
DEPARTMENT OF ENDOCRINOLOGYAND NUTRITION,
DEPARTMENT OF MEDICINE, UNIVERSITYHOSPITAL,
HOSPITAL DE LAPRINCESA, AUTONOMOUS UNIVERSITY
MALMÖ, MALMÖ, SWEDEN
OF MADRID, SPAIN
7 CARLOS LORENZO1 AND MANUEL SERRANO
JOSÉ A. GUTIÉRREZ FUENTES RÍOS2
LILLYFOUNDATION, MADRID, SPAIN 1DEPARTMENT OF MEDICINE, UNIVERSITYOF TEXAS,
HEALTHSCIENCECENTERATSANANTONIO, TEXAS, USA
Background 2DEPARTMENTOFINTERNALMEDICINE, HOSPITALCLÍNICO
SAN CARLOS, MADRID, SPAIN
1 GAETANO CREPALDI
DEPARTMENT OF INTERNAL MEDICINE AND OF Genetics
GERONTOLOGYAND GERIATRICS,
UNIVERSITYOF PADUA, ITALIAN NATIONAL 8 VALERIYA LYSSENKO AND LEIF GROOP
RESEARCH COUNCIL (CNR) CENTER ON AGING, ITALY DEPARTMENT OF CLINICAL SCIENCES, DIABETES AND
ENDOCRINOLOGY, UNIVERSITYHOSPITAL, LUND
2 ANTONIO ZORZANO UNIVERSITY, MALMÖ, SWEDEN
DEPARTMENTOFBIOCHEMISTRYANDMOLECULARBIOLOGY,
FACULTYOF BIOLOGY, UNIVERSITYOF BARCELONA, AND 9 SOPHIE ROME AND HUBERT VIDAL
IRBB-BARCELONASCIENTIFIC PARK, BARCELONA, SPAIN MOLECULAR MECHANISMS OF DIABETES
LAËNNEC FACULTYOF MEDICINE, LYON, FRANCE
3 MARGARITA LORENZO1, ÁNGELA M.
VALVERDE2 AND MANUEL BENITO1 10 JOSÉ M. ORDOVÁS1 AND DOLORES CORELLA1,2
1DEPARTMENT OF BIOCHEMISTRYAND MOLECULAR 1NUTRITION AND GENOMICS LABORATORY, JEAN
BIOLOGYII, FACULTYOF PHARMACY, COMPLUTENSE MAYER–US DEPARTMENT OF AGRICULTURE HUMAN
UNIVERSITYOF MADRID, SPAIN NUTRITION RESEARCH CENTER ON AGING AT TUFTS
2INSTITUTE OF BIOCHEMISTRY(MIXED CSIC/UCM UNIVERSITY, BOSTON, MA. USA
CENTRE), FACULTYOF PHARMACY, COMPLUTENSE 2GENETICANDMOLECULAREPIDEMIOLOGYUNIT, SCHOOL
UNIVERSITYOF MADRID, SPAIN OFMEDICINE, UNIVERSITYOFVALENCIA, VALENCIA, SPAIN
•
iv List of Authors
Pathogenesis 17 MARÍA LUISA BONET, CATALINA PICÓ AND
ANDREU PALOU
11 STEFANO DEL PRATO
LABORATORYOF MOLECULAR BIOLOGY,
DEPARTMENT OF ENDOCRINOLOGYAND METABOLISM, NUTRITION AND BIOTECHNOLOGY, DEPARTMENT OF
SECTION OF METABOLIC DISEASES AND DIABETES, FUNDAMENTAL BIOLOGYAND HEALTH SCIENCES,
UNIVERSITYOF PISA, ITALY UNIVERSITYOF THE BALEARIC ISLANDS, SPAIN
12 WILLIAM A. BANKS1, NAOKO NONAKA1,2,3, 18 ENZO NISOLI1 AND SALVADOR MONCADA2
SEIJI SHIODA3, RYOTA NAKAOKE1,4 AND JOHN 1DEPARTMENT OF PRECLINICAL SCIENCES, HOSPITAL LITA
E. MORLEY1 VIALBA, LUIGI SACCO, SCHOOL OF MEDICINE,
1GRECC, VETERANS AFFAIRS MEDICAL CENTER-ST. UNIVERSITYOF MILAN, MILAN, ITALY
LOUIS AND SAINT LOUIS UNIVERSITYSCHOOL OF 2THE WOLFSON INSTITUTE FOR BIOMEDICAL RESEARCH,
MEDICINE, DIVISION OF GERIATRICS, DEPARTMENT OF UNIVERSITYCOLLEGE LONDON, LONDON, UK
INTERNAL MEDICINE, ST. LOUIS, MO, USA
2DEPARTMENT OF ORAL ANATOMY, SHOWAUNIVERSITY
SCHOOL OF DENTISTRY, TOKYO, JAPAN
3DEPARTMENT OF 1ST ANATOMY, SHOWAUNIVERSITY Related Diseases in the Metabolic
SCHOOL OF MEDICINE, TOKYO, JAPAN Syndrome
4DEPARTMENT OF PHARMACOLOGY, NAGASAKI
UNIVERSITYSCHOOL OF MEDICINE, NAGASAKI, JAPAN
19 ANGELO AVOGARO
DEPARTMENT OF CLINICAL AND EXPERIMENTAL
13 JOSÉ-MANUEL FERNÁNDEZ-REAL AND WIFREDO MEDICINE DIVISION OF METABOLIC DISEASES,
RICART SCHOOL OF MEDICINE,
SECTION OF DIABETES, ENDOCRINOLOGYAND UNIVERSITYOF PADOVA, PADOVA, ITALY
NUTRITION, UNIVERSITYHOSPITAL “DR. JOSEPTRUETA”
OF GIRONA, GIRONA, SPAIN
20 ANDREA NATALI AND ELE FERRANNINI
14 TOSHIMASA YAMAUCHI1,2,3 AND TAKASHI DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY
KADOWAKI1,2,3 OF PISA, PISA, ITALY
1DEPARTMENT OF METABOLIC DISEASES, GRADUATE
SCHOOL OF MEDICINE, UNIVERSITYOF TOKYO, TOKYO, 21 MARKOLF HANEFELD AND FRANK SCHAPER
JAPAN
CENTER OF CLINICAL STUDIES, TECHNICAL UNIVERSITY,
2DEPARTMENT OF INTEGRATED MOLECULAR SCIENCE ON
DRESDEN, GERMANY
METABOLIC DISEASES, GRADUATE SCHOOL OF
MEDICINE, UNIVERSITYOF TOKYO, TOKYO, JAPAN
3CORERESEARCHFOREVOLUTIONALSCIENCEAND 22 JUAN F. VILES-GONZÁLEZ, BRIAN G. CHOI
TECHNOLOGYOFJAPANSCIENCEANDTECHNOLOGY AND JUAN J. BADIMÓN
AGENCY, KAWAGUCHI, JAPAN
CARDIOVASCULAR BIOLOGYRESEARCH LABORATORY,
ZENAAND MICHAEL A. WIENER CARDIOVASCULAR
15 GEMA MEDINA-GÓMEZ, SARAH GRAY AND INSTITUTE, MOUNT SINAI SCHOOL OF MEDICINE,
ANTONIO VIDAL-PUIG NEWYORK, USA
DEPARTMENT OF CLINICAL BIOCHEMISTRYAND
MEDICINE, UNIVERSITYOFCAMBRIDGE, UK
23 MARKKU LAAKSO AND JOHANNA KUUSISTO
DEPARTMENT OF MEDICINE, UNIVERSITYOF KUOPIO,
16 GEORGE DIMITRIADIS1, ELENI BOUTATI1 KUOPIO, FINLAND
AND SOTIRIOS A. RAPTIS1,2
12ND DEPARTMENT OF INTERNAL MEDICINE, RESEARCH
INSTITUTE AND DIABETES CENTRE, ATHENS UNIVERSITY 24 NORBERT STEFAN AND HANS-ULRICH HÄRING
MEDICAL SCHOOL, ATHENS, GREECE DEPARTMENT OF INTERNAL MEDICINE, DIVISION OF
2HELLENIC NATIONAL CENTRE FOR RESEARCH, ENDOCRINOLOGY, METABOLISM AND
PREVENTION AND TREATMENT OF DIABETES, ATHENS, PATHOBIOCHEMISTRY, UNIVERSITYOF TÜBINGEN,
GREECE GERMANY
•
List of Authors v
25 JUAN JOSÉ ESPINÓS GÓMEZ AND JOAQUIM 27 SOTIRIOS K. KARATHANASIS AND RICK J.
CALAF I ALSINA SCHIEBINGER
REPRODUCTIVE MEDICINE UNIT, GYNECOLOGYAND LILLYRESEARCH LABORATORIES,
OBSTETRICS SERVICE, LILLYCORPORATE CENTER, INDIANAPOLIS, USA
HOSPITAL DE LASANTACREU I SANT PAU,
AUTONOMOUS UNIVERSITYOF BARCELONA, SPAIN
28 ADRIAN CAMERON, JONATHAN SHAW AND
PAUL ZIMMET
Prevention and Treatment
INTERNATIONAL DIABETES INSTITUTE, MELBOURNE,
26 MIGUEL A. RUBIO1,2, MARÍA D. BALLESTEROS AUSTRALIA
POMAR3 AND CARMEN MORENO2
1SCHOOL OF MEDICINE, COMPLUTENSE UNIVERSITYOF
MADRID, SPAIN
2NUTRITION UNIT. ENDOCRINOLOGYDEPARTMENT,
HOSPITAL CLÍNICO SAN CARLOS, MADRID, SPAIN
3ENDOCRINOLOGYAND NUTRITION DEPARTMENT,
HOSPITAL DE LEÓN, LEÓN, SPAIN
Introduction
The term «Metabolic Syndrome» (MetS) is generally used to the USAto be approximately 22.7% of the general population
indicate a clinical situation in which different degrees of hy- with important differences between ethnic groups within the
pertension, impaired glucose tolerance, atherogenic dyslipi- same socio-geographic areas1, whereas in Europe MetS preva-
demia, central fat accumulation, insulin resistance, as well lence results in 23% and 12% for male and female populations,
as prothrombotic and proinflammatory states, cluster to- respectively, with ample north-south and east-west geograph-
gether in the same individual. Such a concurrence of disor- ic variations2. To appreciate the whole impact of the problem
ders increases the probability of suffering from cardiovas- on population health, it must be considered that not only car-
cular disease or type 2 diabetes mellitus, possibly more than diovascular mortality but all–cause mortality are increased in
what the sum of the single risk factors would predict. people with the MetS3. And what is even a matter of greater
Sometimes, the «whole» really is greater than the «sum» of concern the prevalence of MetS in children and adolescence is
its parts. Such is the case with MetS. on the increase worldwide.
During the last decade, the MetS has progressively become This reality calls for an increasing effort on the part of the
a major public health problem both in wealthy societies and in scientific community to detect the etiopathogenic mecha-
developing countries. MetS is now approaching epidemic nisms and, consequently, to elaborate interventional initia-
proportions worldwide. Atotal of 115 million individuals suf- tives to counteract such escalating health crisis. This mount-
fer from this syndrome in the US, Japan, France, Germany, ing involvement of the biomedical community is well repre-
Italy, Spain and the UK, a number which is set to increase rap- sented by the exponential trend in the number of scientific
idly, fuelled by the rising obesity and diabetes epidemic. Its papers on «metabolic» and «insulin resistance» syndromes
spreading prevalence is strictly associated with the adoption published in the literature in the last three decades, as shown
of a «westernized» lifestyle, characterized by lack of physical in the graphic:
activity, excessive food intake, a combination of factors lead-
ing to overweight and obesity. In fact, obesity, particularly vis-
ceral obesity, seems to be a major determinant of insulin re-
Distribution of annual publications on «metabolic»
sistance, hence preparing the path to the clustering of meta- and «insulin resistance» syndromes
bolic and non-metabolic factors embraced under the
2004
descriptive term of MetS. Significant though it is, the MetS pa- 2003
2002
tient population remains poorly diagnosed. 2001
The prevalence of MetS depends on gender and several so- 2000
1999
cioeconomic, ethnic and geographic factors. It is estimated in 1998
1997
1996
1995
1994
1Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, 1993
Heymsfield SB. The Metabolic Syndrome: prevalence and associated 1992
risk factor findings in the US population from the Third National 1991
1990
Health and Nutrition Examination Survey, 1988-1994. Arch Intern
1989
Med. 2003;163:427-436. 1988
2The European Group for the Study of Insulin Resistance (EGIR). The 1987
Frequency of the WHO Metabolic Syndrome in European Cohorts, 1986
and an alternative definition of the insulin resistance syndrome. 1985
Diabet Metabolism ES 2002;28:364-76. 0 100 200 300 400 500 600 700 800 900 1000
3Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E,
Tuomilehto J, Salonen JT. JAMA. 2002 Dec 4;288(21):2709-16. Source: SCI
•
2 Introduction
Several scientific associations and public health organiza- such as obesity, insulin resistance, impaired glucose handling,
tions, such as WHO, EGIR, NECP, and AACE2,4-6, and, very re- dyslipidemia, hypertension, and of course, their relationships
cently, IDF7, have proposed their own definitions and diag- with CVD, but also on the newer aspects of MetS such as in-
nostic criteria of the MetS. However, this diversity of opinions flammation molecules, prothrombotic state, endothelial dys-
has generated terminology and conceptual confusion. function or non-alcoholic fatty liver disease, to mention just a
Therefore, at the beginning of a new millennium, the medical few of them.
and scientific community finds itself in the middle of a classic Moreover, several molecular and cellular pathways dis-
need-to-know/urge-to-act dilemma. cussed will provide more arguments to the debate on insulin
In such a context, we have conceived this book with an resistance and obesity as MetS pathogenic factors, as is the
open-minded attitude, trying to include the broadest concept case for the role of nitric oxide, PPARs nuclear transcription
of MetS possible, with the aim of offering the reader an up- factors, adipokines, thermogenesis, central actions of leptin
dated collection of expert viewpoints (from molecular patho- and insulin, as well as specific post-receptor pathway aspects
physiology to genetic epidemiology) on several key issues, in insulin-sensitive cells.
not only of the so-called «classic» components of the MetS To widen the ontogenic approach, different chapters have
been dedicated to addressing the MetS from such specialized
science contexts as the gerontologic, the evolutionistic or ex-
4World Health Organization Dept. of Noncommunicable Disease perimental modeling. Finally, a special effort has been made
Surveillance. Definition, diagnosis and classification of diabetes
to present a complete and updated overview, enriched with
mellitus and its complications: Report of a WHO consultation.
Geneva World Health Organization, 1999. several original contributions, in the field of therapeutics, nu-
5Executive Summary of The Third Report of The National Cholesterol
trition, and prevention measures for MetS.
Education Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High Blood Cholesterol In Adults (Adult Treatment For all the above reasons, we are confident that this book,
Panel III). Jama, 2001;285(19): 2486-97. thought to be a multidisciplinary compendium of expert con-
6Einhorn D, Reaven GM, Cobin RH, et al. American College of
tributions rather than a classic textbook, would successfully
Endocrinology position statement on the insulin resistance syndrome.
Endocr Pract 2003;9:237-252. contribute to the development of the intellectual discussion
7IDF Consensus Group «The IDF worlwide definition of the Metabolic
on MetS, one of the most intriguing and fascinating challenges
Syndrome». 1stIntl. Congress on «Prediabetes and the Metabolic
Syndrome». Berlin, 13-16 April 2005. to contemporary medicine.
THE EDITORS
M. SERRANO RÍOS; J. F. CARO; R. CARRARO;
J. A. GUTIÉRREZ FUENTES
1
Origin and Development
of the Metabolic Syndrome
GAETANO CREPALDI
DEPARTMENT OF INTERNAL MEDICINE AND OF GERONTOLOGYAND GERIATRICS,
UNIVERSITYOF PADUA, ITALIAN NATIONAL RESEARCH COUNCIL (CNR) CENTER ON AGING, ITALY
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Resumen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Historical development of the Metabolic Syndrome concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Pathophysiological issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ATPIII Diagnostic criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Main research challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
•
6 Background
Summary
Pietro Avogaro and myself in 1965 described a new syndrome characterized by an association of metabolic abnormalities and specifically
hyperlipidemia, obesity and diabetes. Interestingly we also pointed out the presence quite often of hypertension in association with these
metabolic abnormalities, as well as the high risk of coronary artery disease in carriers of this cluster of metabolic abnormalities. Over the
last 35 years the definition of plurimetabolic syndrome has evolved from the original description with the addition of a more detailed de-
finition of the typical abnormalities. The latest definition of Metabolic Syndromehas been given more recently by the ATP IIIpanel, which
defined it as the concurrent presence of three or more of the following abnormalities: intra-abdominal obesity, glucose intolerance or dia-
betes, hypertriglyceridemia, low HDL-C, hypertension.
Therefore, any patient with the Metabolic Syndrome has numerous reasons to be at high risk for atherosclerosis. Many emerging risk
factors that are not routinely measured are found to be associated with the Metabolic Syndrome:
• Insulin resistance
• Small, dense LDL
• Endothelial dysfunction
• Abnormal sympathetic nervous activity
• Prothrombotic markers—PAI-1, fibrinogen
• Proinflammatory markers such as CRP; VCAM
In conclusion, the data that have been accumulating over the past 40 years have contributed to defining the Metabolic Syndrome as a
complex clustering of many risk factors for cardiovascular disease. Recent data on the striking prevalence of the Metabolic Syndrome make
this disease the leading threat for cardiovascular health in our society.
Resumen
Pietro Avogaro y yo describimos en 1965 un síndrome nuevo caracterizado por una asociación de anomalías metabólicas y, más es-
pecíficamente, hiperlipidemia, obesidad y diabetes. Lo que resulta más interesante, también señalamos la presencia bastante frecuente
de hipertensión arterial asociada a estas anomalías metabólicas, así como el alto riesgo de arteriopatía coronaria en los portadores de
este conjunto de alteraciones. Durante los últimos 35 años, la definición del síndrome plurimetabólico ha evolucionado a partir de la
descripción original con la adición de una definición más detallada de las anomalías características. La última definición del síndro-
me metabólico la ha ofrecido recientemente el panelATPIIIy consiste en la presencia simultánea de tres o más de las anomalías si-
guientes: obesidad intraabdominal, intolerancia a la glucosa o diabetes, hipertrigliceridemia, C-HDLbajo e hipertensión arterial.
Por consiguiente, todo paciente con síndrome metabólico tiene numerosos motivos para presentar un riesgo elevado de ate-
rosclerosis. Se ha comprobado que muchos factores de riesgo vascular emergentes que no se determinan sistemáticamente se
asocian al síndrome metabólico:
• Resistencia a la insulina
• LDLdensas y pequeñas
• Disfunción endotelial
• Anomalías de la actividad nerviosa simpática
• Marcadores protrombóticos: PAI-1, fibrinógeno
• Marcadores proinflamatoios como PCR; VCAM
En conclusión, los datos que se han ido acumulando durante los últimos 40 años han contribuido a definir el síndrome me-
tabólico como un conjunto complejo de varios factores de riesgo de enfermedad cardiovascular. Los datos recientes sobre la pre-
valencia importante del síndrome metabólico hacen que esta enfermedad represente la principal amenaza para la salud cardio-
vascular en nuestra sociedad.
Introduction First of all it must be considered that the prevalence
rates and the interactions of these components are differ-
The Metabolic Syndrome (MetS) is a clinical entity of ent across sexes, age, and ethnic groups. Moreover, there
substantial heterogeneity, represented by the co-occur- are several problems related to the definition of the MetS:
rence of multiple metabolic and vascular disorders that
are risk factors for both type 2 diabetes mellitus and • the suggested components are continuous variables,
atherosclerotic cardiovascular diseases. Many studies implying that cut-off values are needed, but as yet no
have shown that four factors: obesity (especially central complete consensus exists for specific thresholds for
obesity), impaired glucose tolerance, atherogenic dys- establishing the diagnosis of each component;
lipidemia (high levels of triglycerides and low levels of • these variables are certainly interrelated, but the patho-
high density lipoprotein cholesterol) and hypertension physiology of their relation is not fully understood;
co-occur to a greater degree than expected by chance • inclusion of insulin resistance or diabetes as diagnos-
alone. tic components is also controversial.
•
Origin and Development of the Metabolic Syndrome 7
The main issue still debated is, however, if the MetS condition more often associated with “diabetes, athero-
arises from insulin resistance or from obesity. The little sclerosis, gout, and uric calculous disease”11,12.
consensus about the underlying unifying factor, if any, is The frequent simultaneous presence of obesity, hyper-
well illustrated by the long-standing debate about how lipidemia, diabetes and hypertension was first described
to define this syndrome: pluri-metabolic syndrome1 in 1965 by Avogaro et al1,13. In this work, we reported the
Metabolic syndrome2, syndrome X3, deadly quartet4, in- high risk of coronary artery disease in carriersof this clus-
sulin resistance syndrome5, dysmetabolic syndrome6. ter of metabolic and vascular abnormalities.
The association of these factors was subsequently de-
Historical development of the Metabolic scribed in 1977 by Haller et al, who first used the term
Syndrome concept “Metabolic Syndrome” and described the association
with atherosclerosis2.
Descriptions of the MetS and the attempts to develop In 1980 Vague suggested the concept that fat mass per
standardized diagnostic criteria have a long and inter- sehas little effect on the progression from obesity to dia-
esting story and, as anticipated, there are still so many betes, but it is the predominance of fat in the upper part
controversies that it will surely continue to be a highly of the body that leads to diabetes and atherosclerosis. As
debated issue. a matter of fact, insulin and cortisol secretion in obese
Nicolaes Tulp (1593-1674) was a prominent physician in patients are correlated with central obesity14.
Amsterdam and in 1991 a Dutch translation of his hand- In 1988 Reaven introduced the concept of Sindrome X
written work “Observationes”, was published7. On page as the clustering of disturbances in glucose and insulin
120 there is the very first case report of the hypertrigly- metabolism, dyslipidemia and hypertension. Reaven
ceridemia syndrome. Tulp made the connection between suggested that insulin resistance, with the consequent
hypertriglyceridemia and the ingestion of saturated fatty hyperinsulinemia, underlies this clustering and repre-
acids (“pure milk on the blood”), obesity and bleeding ten- sents an important cardiovascular disease risk factor per
dency. Not only that, he suggested a correct therapeutic se3. In his description, Reaven did not include over-
approach, mainly the reduction of the intake of saturated weight/obesity as a component of the syndrome.
fatty acids, and, finally, recognized the association be- In 1991, Ferrannini et al also suggested that this clus-
tween premature atherosclerosis and sudden death. tering was caused by insulin resistance and coined the
About 250 years ago, GB Morgagni described very term of “Insulin Resistance Syndrome”15.
clearly the association between visceral obesity, hyper- A working definition of the MetS was given by the
tension, hyperuricemia, atherosclerosis and obstructive “WHO Working Group on Diabetes” in 1998, modified in
sleep apnea syndrome, long before the MetS and the ob- 1999, with a list of criteria for the clinical diagnosis. In
structive sleep apnea syndrome were described8. particular, the WHO definitionstated that diabetes type
In 1923 Kylin described the co-occurrence of hyper- 2 or impaired glucose tolerance (IGT), together with at
tension, hyperglycemia and hyperuricemia9, while few least 2 of 4 other factors (hypertension, hyperlipidemia,
years later Marañón summarized the evidence of the as- obesity, and microalbuminuria), define the MetS. In case
sociation of hypertension, glucose metabolism distur- of normal glucose tolerance (NGT), the evidence of in-
bances and obesity. He also indicated that the first step sulin resistance is needed - defined as the lowest quartile
in the treatment of this pre-diabetic state is based on diet of measures of insulin sensitivity (e.g. insulin stimulated
and life style interventions10. glucose uptake during euglycemic clamp) or highest
Vague was the first to identify the importance of “an- quartile of fasting insulin or homeostasis model assess-
droid obesity”, meaning the upper body adiposity as the ment (HOMA) insulin resistance index. The definition of
Table 1-1. WHO definition of the Metabolic Syndrome
Diabetes, IFG, IGT, or HOMA insulin resistant and at least two of the following criteria
BMI >30 kg/m2 and/or Waist-to-hip ratio >0.90 in men or >0.85 in women
Serum triglycerides =>150 mg/dl (1.69 mmol/l) or HDL-C <35 mg/dl (<0.9 mmol/l) in men and <39
mg/dl (1.0 mmol/l) in women
Urinary albumin excretion rate >20 μg/min
Blood pressure =>140/90 mmHg
•
8 Background
obesity is based on either body mass index (BMI) or or on treatment for hypertension), and a fasting glucose
waist-to-hip ratio (WHR)16. (Table 1) =>110 mg/dL. (Table 2)
The WHO criteria present some weaknesses. For ex- Moreover, there are “optional measures” recom-
ample, it is well known that BMI is not a reliable meas- mended by the ATPIII panel, such as C-reactive protein,
ure of obesity in the elderly, due to the changes in as a marker of pro-inflammatory state, and fibrinogen, as
height with advancing age and to the different ratio of a marker of prothrombotic state.
lean and fat mass compared to younger adults. In ad- However, the five criteria and cut-off values proposed
dition, it has been shown that for any given BMI ter- by the NCEP-ATPIII panel have some problems as well
tile, subjects in the top waist tertile have a worse risk as the WHO criteria. First of all, they represent the con-
factor profile than individuals with the same BMI but sensus of experts and do not reflect an evidence-based
with lower waist circumference measures, due to the process. Data on their validity to provide a truly dis-
greater truncal adipose tissue, the real risk factor for criminant indication of individuals at risk for cardiovas-
MetS17. Therefore, BMI and waist circumference do not cular disease in different ethnic and age groups are
predict the risk of metabolic disturbances equally. needed. Moreover, the cut points for each component
Moreover, the frequency of microalbuminuria in non- are arbitrary and their applicability across groups (eth-
diabetic individuals is very low and, therefore, this cri- nic, age, sex) should be demonstrated.
terion is relevant only in the presence of diabetes. Finally, it is possible that, with more evidence about
Finally, the use of the euglycemic clamp technique, the the role of fibrinogen, C-reactive protein, etc., the criteria
gold standard for the measurement of insulin resist- will change and some of these optional measures might
ance, is not applicable in large epidemiologic studies. become main criteria.
As surrogate methods, the homeostasis model assess- A common feature of both WHO and ATP III defini-
ment (HOMA), fasting insulin or frequently-sampled tions is the fact that they include diabetic individuals,
intravenous glucose tolerance test have been used. while the definition of insulin resistance syndrome,
However, the different methods and cut-off values em- adopted by the American Association of Clinical
ployed in the studies conducted up to now might af- Endocrinologists (AACE), as well as the EGIR (European
fect the differences found in the prevalence rates of in- Group for the study of Insulin Resistance) definition,
sulin resistance18. aims to identify individuals with impaired glucose toler-
In 2001, the United States National Cholesterol ance, excluding those with diabetes. These criteria seem
Education Program’s Adult Treatment Panel III to be a mixture of the WHO and ATPIII criteria. However,
(ATPIII) report proposed a set of criteria similar to that no defined number of risk factors is specified and diag-
proposed by WHO, except for the fact that the key com- nosis depends on clinical judgement20. (Table 3)
ponent is visceral obesity instead of insulin resistance. In general, studies have demonstrated that the WHO
The ATPIII did not find enough evidence to recommend and ATP III definitions identify individuals with the
routine measurement of insulin sensitivity or the 2 hour MetS with a large overlap21.
post-challenge glucose determination, but included sim-
ply a fasting glucose determination19. Pathophysiological issues
This definition requires at least 3 of the following 5
factors: increased waist circumference (=>102 cm in men As already mentioned, today the MetS represents the
and =>88 cm in women), hypertriglyceridemia (=>150 confluence of two traits of thinking:
mg/dl), low HDL cholesterol (<40 mg/dl, in men and • One sees insulin resistance as the major underly-
<50 mg/dl in women), hypertension (=>130/85 mmHg ing risk factor for the MetS. The supporters of this line
Table 1-2. ATP III definition of the Metabolic Syndrome
At least three of the following criteria
Waist circumference >102 cm (>40 inches) in men and >88 cm (>35 inches) in women
Serum triglycerides =>150 mg/dl (1.69 mmol/l)
HDL-C <40 mg/dl (1.04 mmol/l) in men and <50 mg/dl (1.29 mmol/l) in women
Blood pressure =>130/85 mmHg
Serum glucose =>110 mg/dl (>6.1 mmol/l)