- Email: [email protected]
The metabolic syndrome revisited
International Congress Series 1253 (2003) 3 – 10
The metabolic syndrome revisited Pierre J. Lefe`bvre * Department of Medicine, University of Liege, CHU Sart Tilman (B35), B-4000 Liege 1, Belgium Received 23 October 2002; accepted 7 February 2003
Keywords: Metabolic syndrome; Syndrome X; Insulin resistance
1. Introduction The Banting Memorial Lecture at the June Meeting of the American Diabetes Association is a highlight of the international medical and scientific life in the field of diabetes. It recognizes the scientific and medical achievements of a long-standing career. In 1988, Dr. Gerald Reaven gave the Banting Lecture at the ADA Meeting in New Orleans [1]. His title was «The role of insulin resistance in human disease». In his lecture, Dr. Reaven made three major points: (1) he drew the attention on a clustering of signs and symptoms making a Syndrome that he called «Syndrome X». These signs and symptoms included: resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increased VLDL triglycerides, decreased HDL cholesterol and hypertension; (2) he suggested that, in this Syndrome, the common feature was insulin resistance and that the other components were secondary to the resistance to insulin; and (3) he concluded, rather provocatively, that «resistance to insulin-stimulated glucose uptake may play a crucial role in determining who will and who will not develop coronary artery disease. . .». The views expressed by Dr. Reaven generated an immense interest in the scientific community, interest but also debates and controversies. It has been said that the clustering of arterial hypertension, hyperglycemia and gout had been described in 1923 by Kilin [2]. Some said, correctly, that the syndrome was implicit in earlier works of Jean Vague in France or Per Bjorntorp in Sweden. Others said that the credit of emphasizing the role of hyperinsulinemia should go to Michaela Modan [3] and her coworkers who had published a less publicized but major paper in 1985. * Tel.: +32-4-365-43-23; fax: +32-4-366-70-68. E-mail address: pierre.Lefe`[email protected] (P.J. Lefe`bvre). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00141-9
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P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
The very name of Syndrome X was probably not very appropriate since it had previously been registered by the cardiologists to describe a particular form of «myocardial ischemia with reduced coronary perfusion reserve resulting from microvascular dysfunction». Quite amazingly, a later study showed that the patients having the «Cardiac Syndrome X» often exhibit also the «Reaven’s Syndrome X»! Surprisingly, obesity, probably the most well-known form of insulin resistance was not included in the original description of Syndrome X. In fact, Kaplan [4] isolated in 1989 what he called «the deadly quartet» in which upper-body obesity had been added to hypertension, diabetes and hypertriglyceridemia to constitute a syndrome associated with an increased risk of cardiovascular disease. In 1991, Zimmet [5] suggested to formally include central (or upper) obesity in the Syndrome and suggested to replace the name Syndrome X by the «Insulin Resistance Syndrome» or, better, the «Metabolic Syndrome». It has to be remembered that Hanefeld and Leonhardt [6] had mentioned the term «das metabolische syndrom» already in 1981. Subsequently, several other metabolic abnormalities have been associated with the syndrome including microalbuminuria, hyperuricemia, abnormalities in fibrinolysis and coagulation, such as increased levels of PAI-1 and further lipid abnormalities like the presence of small dense LDL particles or high Apo-B levels. In 1998, Alberti and Zimmet [7] submitted, in the name of the WHO consultation, the following working definition of the metabolic syndrome. The components of the Syndrome are: (1) impaired glucose regulation or diabetes; (2) insulin resistance; (3) arterial hypertension (antihypertensive treatment and/or BP z 160/90 mm Hg); (4) dyslipidemia with plasma triglycerides z 1.7 mmol/l and/or HDL cholesterol < 0.9 mmol/l in men and < 1.00 mmol/l in women; (5) central obesity (males: waist-to-hip ratio >0.90; females: waist-to-hip ratio >0.85) and/or BMI z 30 kg/m2; and (6) microalbuminuria (UAER z 20 mmg/min or albumin/creatinine ratio z 20 mgg 1). In the above, impaired glucose regulation includes impaired fasting glycemia (plasma fasting glucose values z 6.1 but < 7.0 mmol/l; whole blood fasting glucose z 5.6 to 6.1 mmol/ l). Insulin resistance is defined as «under hyperinsulinaemic euglycemic conditions, glucose uptake below lowest quartile for background population under investigation». This can be assumed to correspond to the highest quartile of the HOMAIR index. The metabolic syndrome is present if one of the two firsts and two of the last four criteria are present in a given individual. In this brief review, we will first survey some of the key epidemiological studies reported on the relevance of the metabolic syndrome over the last 10 years. Second, we will consider some studies suggesting that one can probably broaden the field of the metabolic syndrome to unexpected aspects of contemporary internal medicine. Third, we will briefly touch the various mechanistic hypotheses supporting the syndrome and, in conclusion, we will allude to possible therapeutic approaches.
2. Epidemiological studies A remarkable epidemiological study in support of the existence of the metabolic syndrome is the San Antonio Heart Study conducted by Stern et al. [8]. It has been
P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
5
performed on a random sample of the Mexican– American and of the non-Hispanic white population of San Antonio, TX. The population surveyed amounted to 2930 subjects. In this population, the total prevalence rates for obesity, Type 2 diabetes mellitus, impaired glucose tolerance, arterial hypertension, hypertriglyceridemia and hypercholesterolemia were 54.3%, 9.3%, 11.1%, 9.8%, 10.3% and 9.2%, respectively. However, the prevalence of each of these conditions in its isolated form (that is free of the other five) was only 29.0% for obesity, 1.3% for diabetes, 1.5% for arterial hypertension, 1.0% for hypertriglyceridemia and 1.7% for hypercholesterolemia. These large differences in prevalence between isolated and mixed forms indicated a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinemia (both fasting and 2 h after oral glucose); such hyperinsulinemia is indicative or suggestive of insulin resistance. In all the subjects who presented with one or another disorder (i.e. 1881 out of 2930 subjects or 64%), marked fasting and post-prandial hyperinsulinemia was associated with higher BMI, waist-to-hip ratio, fasting and post-glucose glycemia, systolic and diastolic blood pressure, serum triglyceride and serum cholesterol levels and lower HDL-cholesterol concentrations. All these associations were highly statistically significant. This study was the first unequivocal demonstration that there is, in some subjects, a cluster of abnormalities as described originally by Reaven to which one must add obesity and a high waist-to-hip ratio. Furthermore, the hypothesis that hyperinsulinemia is the key feature of the syndrome was confirmed. In a subsequent study, Haffner et al. [9] examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in an 8-year follow-up of the cohort initially studied between 1979 and 1982. The risk to develop hypertension was twofold in the subjects with the higher quartile of plasma insulin related to the one of the subjects with the lower quartile. The Relative Risks figures for hypertriglyceridemia, low HDL cholesterol and NIDDM were 3.5, 1.6 and 5.6, respectively. Baseline insulin concentrations were also higher in the subjects who subsequently developed multiple metabolic disorders. The metabolic syndrome concept was strongly supported by the results of that study, which showed, for the first time, that elevation of insulin concentrations precedes the development of numerous metabolic disorders. Another supportive study was the Paris Prospective Study [10]. That remarkable study included 6903 men aged 43 –54 years who were first examined between 1968 and 1973. Causes of death were ascertained after 15 years of mean follow-up. Significant independent predictors of coronary heart disease were: systolic blood pressure, number of cigarettes per day, plasma cholesterol level, and 2-h post-glucose load plasma insulin levels. Consequently, if we assume that hyperinsulinemia is a marker of insulin resistance, the results of the Paris Prospective Study are consistent with the hypothesis that insulin resistance is associated with a higher risk of coronary heart disease mortality. Another major study is the recent Botnia Study [11] in which a total of 4483 subjects aged 36 –70 years were included in the analysis of the cardiovascular risk associated with the metabolic syndrome. The salient features of that study is that the 1998 WHO definition of the metabolic syndrome was used to assess the prevalence of, and the cardiovascular
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P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
morbidity and mortality associated with, the syndrome. In women and men, respectively, the metabolic syndrome was seen in 10% and 15% of subjects with normal glucose tolerance, in 42% and 64% of those with impaired fasting glycemia or impaired glucose tolerance and in 78% and 84% of those with Type 2 diabetes. The risk of coronary heart disease and stroke was increased threefold in subjects with the syndrome. Overall cardiovascular mortality was five to six times greater in subjects with the metabolic syndrome compared to those who did not present it. Interestingly, of the individual components of the syndrome, one of the most disputed, namely microalbuminuria, conferred the strongest risk of cardiovascular death. Using a slightly different definition of the metabolic syndrome, the Third National Health and Nutrition Survey (NHANES III) performed in the USA [12] showed that the unadjusted and age-adjusted prevalence of the metabolic syndrome in that country were 21.8% and 23.7%, respectively. The prevalence increased over 40% in participants aged over 60 years. Using the 2000 census data, the study revealed that about 47 million US residents have the metabolic syndrome. These epidemiological studies performed over the last 10 years and selected among many others support the concept of insulin resistance being a major risk factor for cardiovascular morbidity and mortality. Furthermore, prevalence studies indicate that the problem affects a high percentage of the population, at least in the developed countries, and may have important implications for the public health sector. As emphasized by Alberti and Zimmet [7], the syndrome occurs commonly not only in Europids, Afro-Americans and Mexicans– Americans, as we have seen, but also in Asian Indians and Chinese, Australian and Alaskan Aborigines, Polynesians and Micronesians.
3. Widening the metabolic syndrome concept MARCEAU et al. [13] suggested and, like the Torino group [14], we confirmed that liver steatosis can be regarded as being part of the metabolic syndrome [15]. In a series of 528 liver biopsies performed in severely obese individuals, fatty acid deposition was seen in 391 (74%) of the biopsy specimens. Steatosis severity was positively associated with BMI ( p = 0.002), fasting hyperglycemia ( p = 0.007), hypertriglyceridemia ( p = 0.002) and hyperinsulinemia ( p = 0.003). Interestingly, we also observed a partial reversibility of the biological markers of both the metabolic syndrome and liver steatosis after gastroplastyinduced weight loss [16,17]. We agree with James and Day [18] that both the nonalcoholic steatohepatitis and the metabolic syndrome associated with severe obesity may be considered as common markers of a ‘‘disease of affluence’’. Interestingly, Greco et al. [19] recently reported that lipid malabsorption induced in massively obese subjects by biliopancreatic diversion induces not only a massive weight loss but also a reversal of intramyocellular fat accumulation and, in parallel, a full normalization of insulin sensitivity. Using the so-called ‘‘factor analysis’’ statistical method, Sakkinen et al. [20] have carefully studied the various ‘‘extensions’’ of the Syndrome that have been recently proposed. They have been able to confirm that elevated PAI-1 levels and impaired endothelial function are core features of the metabolic syndrome. Furthermore, they have
P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
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shown that inflammation was only weakly linked to insulin resistance, through association with obesity. Other diseases and conditions associated with the metabolic syndrome include the polycystic ovary syndrome [21], the prolonged QT syndrome [22], the adrenal incidentaloma [23] and even some psychiatric disorders like depression and schizophrenia [24]. For these last two, the question of cause or consequence and that of the effects of treatment must be asked.
4. Pathogenesis of the syndrome Theoretically, genetic and environmental factors should be considered. Until now, genetic abnormalities account only for a small number of rare syndromes in which insulin action is severely impaired and no one gene or group of genes has been identified as being the cause of the metabolic syndrome. The hypothesis that many gene abnormalities are clustering together to favor the occurrence of the syndrome is considered by numerous experts. The role of environmental factors is well established and includes overnutrition, sedentarity, accumulation of visceral fat and possibly fetal malnutrition. An argument in favor of environmental factors is the reversibility of various components of the syndrome with weight loss [25], including, at least in some individuals, complete normalization of insulin sensitivity [26]. Although not introduced in the original Syndrome X, abdominal obesity undoubtedly represents a key element of the metabolic syndrome [27]. For reasons that are still poorly understood, a positive energy balance, due to excess calorie intake and/or reduced energy expenditure, leads often to an excess of fat accumulation in the intraabdominal adipocytes. As reviewed by Lebovitz [28], an excess in visceral adipose tissue leads to an increase in the release of FFA, TNF-a, leptin and other products of adipose tissue metabolism. Indeed, in part due to their complement of adrenergic receptors, the visceral adipocytes have a high rate of lipolysis. These products drain through the portal vein directly into the liver, which sees an increase in FFA and triglycerides and starts accumulating fat (see above). This leads to an increase in hepatic insulin resistance, an increase in VLDL particle synthesis and a decreased in insulin clearance. The liver releases an increased amount of FFA into the peripheral circulation where they contribute to muscle insulin resistance either directly or indirectly through an increase in muscle triglycerides. Finally, it has been demonstrated that an increase in circulating VLDL particles can contribute to an increase in PAI-1 synthesis from the endothelial cells. Over the last 10 years, epidemiological studies, comforted by elegant mechanistic animal studies, have shown that fetal malnutrition increases the risk of subsequent metabolic syndrome and that postnatal overnutrition may aggravate the syndrome [29]. On this topic, also reviewed by Lebovitz [28], the following mechanisms may be operating. Fetal malnutrition would induce changes in the central nervous system regulation of metabolism to create more efficient metabolic pathways. This imprinting of the CNS would remain permanent into and throughout adult life. In the adult life, increased caloric intake and/or reduced physical activity, occurring in an individual with the modified imprinted metabolic pathways, would lead to obesity and the metabolic syndrome.
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5. Management of the metabolic syndrome and conclusions Treating a patient affected by the metabolic syndrome is at present not an easy task. Recommendations to modify lifestyle including modifications of dietary habits and suggestions to increase physical activity often fail despite the fact that recent wellconducted clinical trials have shown their efficacy [30]. Too often, the physician is left with the decision to treat the individual components of the syndrome including drugs to manage the abnormalities of glucose metabolism, the dyslipidemia, the arterial hypertension, the hyperuricemia, the abnormalities in coagulation and hemostasis. In practice, many of these patients receive 10 – 12 pills containing numerous drugs. If insulin resistance is really the mechanism underlying the syndrome, then drugs like metformin and the thiazolidinediones, which are effective in increasing insulin sensitivity, may represent a logical choice. Interestingly, new antihypertensive drugs also possess the ability to increase insulin sensitivity and may therefore be particularly interesting in the management of the metabolic syndrome. New drugs are in development, which have both PPARg and PPARa agonist activity, thus being able to simultaneously decrease insulin resistance and improve the dyslipidemia of the syndrome. As recently stated by Ford et al. [12] for the Participants of the Third National Health and Examination Survey in the United States, ‘‘because the root causes of the metabolic syndrome for the overwhelming majority of patients are improper nutrition and inadequate physical activity, the high prevalence of this syndrome underscores the urgent need to develop comprehensive efforts directed at controlling the obesity epidemic and improving physical activity levels. . .’’ In this fight against the metabolic syndrome, which is now seen in children and adolescents, all components of the Society, including the World Health Organization (WHO) and the International Diabetes Federation (IDF) [31] will have to counteract the dramatic lifestyle changes that our entire world has seen over the last 30 years by the aggressive promotion of cheap, easily available, high in calorie food and beverages combined to a mechanization of the Society and sedentary leisure activities like TV watching and the use of computers.
References [1] G.M. Reaven, Role of insulin resistance in human disease, Diabetes 37 (1988) 1595 – 1607. [2] E. Kilin, Studien ueber das Hypertonie – Hyperglyka¨mie – Hyperurika¨miesyndrom, Zent.bl. Inn. Med. 44 (1923) 105 – 127. [3] M. Modan, H. Halkin, S. Almog, A. Lusky, A. Eshkol, M. Shefi, A. Shitrit, Z. Fuchs, Hyperinsulinemia. A link between hypertension, obesity and glucose intolerance, J. Clin. Invest. 75 (1985) 809 – 817. [4] N.M. Kaplan, The deadly quartet. Upper-body obesity, glucose, intolerance, hypertriglyceridemia, and hypertension, Arch. Intern. Med. 149 (1989) 1514 – 1520. [5] P. Zimmet, Challenges in diabetes epidemiology. From West to the rest. Kelly West Lecture 1991, Diabetes Care 15 (1992) 232 – 252. [6] M. Hanefeld, W. Leonhardt, Das Metabolische Syndrom, Dt. Gesundh.wes. 36 (1981) 545 – 551. [7] K.G.M.M. Alberti, P.Z. Zimmet, for the WHO Consultation, Definition, diagnosis and classification of diabetes mellitus and its complications: Part 1. Diagnosis and classification of diabetes mellitus. Provision report of a WHO consultation, Diabet. Med. 15 (1998) 539 – 553.
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[8] E. Ferrannini, S.M. Haffner, B.D. Mitchell, M.P. Stern, Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome, Diabetologia 34 (1991) 416 – 422. [9] S.M. Haffner, R.A. Valdez, H.P. Hazuda, B.D. Mitchell, P.A. Morales, M.P. Stern, Prospective analysis of the insulin-resistance syndrome (Syndrome X), Diabetes 41 (1992) 715 – 722. [10] A. Fontbonne, M.A. Charles, N. Thibult, J.L. Richard, J.R. Claude, J.M. Warner, G.E. Rosselin, E. Eschwege, Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up, Diabetologia 34 (1991) 356 – 361. [11] B. Isomaa, P. Almgren, T. Tuomi, B. Forse´n, K. Lahti, M. Nissen, M.R. Taskinen, L. Groop, Cardiovascular morbidity and mortality associated with the metabolic syndrome, Diabetes Care 24 (2001) 683 – 689. [12] E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Examination Survey, JAMA 287 (2002) 356 – 359. [13] P. Marceau, S. Biron, F.-S. Hould, S. Marceau, S. Simard, S.N. Thung, J.K. Kral, Liver pathology and the metabolic syndrome X in severe obesity, J. Clin. Endocrinol. Metab. 84 (1999) 1513 – 1517. [14] G. Pagano, G. Pacini, G. Musso, R. Gabmino, F. Mecca, N. Depetris, M. Cassader, E. David, P. Cavallo-Perin, M. Rizzetto, Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association, Hepatology 35 (2002) 367 – 372. [15] F.H. Luyckx, A.J. Scheen, P.J. Lefe`bvre, Non-alcoholic steatohepatitis, Lancet 354 (1999) 1298 – 1299. [16] F.H. Luyckx, C. Desaive, A. Thiry, W. Dewe´, A.J. Scheen, J.E. Gielen, P.J. Lefe`bvre, Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty, Int. J. Obes. 22 (1998) 222 – 226. [17] F.H. Luyckx, A.J. Scheen, C. Desaive, A. Thiry, P.J. Lefe`bvre, Parallel reversibility of biological markers of the metabolic syndrome and liver steatosis after gastroplasty-induced weight loss in severe obesity, J. Clin. Endocrinol. Metab. 84 (1999) 4293. [18] O. James, C. Day, Nonalcoholic steatohepatitis: another disease of affluence, Lancet 353 (1999) 1634 – 1636. [19] A.V. Greco, G. Mingrone, A. Giancaterini, M. Manco, M. Morroni, S. Cinti, M. Granzotto, R. Vettor, S. Camastra, E. Ferranninni, Insulin resistance in morbid obesity. Reversal with intramyocellular fat depletion, Diabetes 51 (2002) 144 – 151. [20] P.A. Sakkinen, P. Wahl, M. Cushman, et al., Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome, Am. J. Epidemiol. 152 (2000) 897 – 907. [21] T. Sir-Petermann, B. Angel, M. Maliqueo, F. Carvajal, J.L. Santos, F. Pe´rez-Bravo, Prevalence of type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome, Diabetologia 45 (2002) 959 – 964. [22] G.M. Corbi, S. Carbone, P. Ziccardi, G. Giugliano, R. Marfella, F. Nappo, G. Paolisso, K. Esposito, D. Giugliano, FFAs and QT intervals in obese women with visceral adiposity: effects of sustained weight loss over 1 year, J. Clin. Endocrinol. Metab. 87 (2002) 2080 – 2083. [23] M. Terzolo, A. Pia, A. Ali, G. Osella, G. Reimondo, S. Bovio, F. Daffara, M. Procopio, P. Paccotti, G. Borretta, A. Angeli, Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87 (2002) 998 – 1003. [24] M.C.M. Ryan, J.H. Thakore, Physical consequences of schizophrenia and its treatment. The metabolic syndrome, Life Sci. 71 (2002) 239 – 257. [25] F.H. Luyckx, A.J. Scheen, C. Desaive, W. Dewe, J.E. Gielen, P.J. Lefe`bvre, Effects of gastroplasty on body weight and related biological abnormalities in morbid obesity, Diabetes Metab. (Paris) 24 (1998) 355 – 361. [26] M.R. Letiexhe, A.J. Scheen, P.L. Ge´rard, C. Desaive, P.J. Lefe`bvre, Postgastroplasty recovery of ideal body weight normalizes glucose and insulin metabolism in obese women, J. Clin. Endocrinol. Metab. 89 (1995) 393 – 399. [27] Y. Hong, T. Rice, J. Gagnon, J.-P. Despre´s, A. Nadeau, L. Pe´russe, C. Bouchard, A.S. Leon, J.S. Skinner, J.H. Wilmore, D.C. Rao, Familial clustering of insulin and abdominal visceral fat: the HERITAGE family study, J. Clin. Endocrinol. Metab. 83 (1998) 4239 – 4245. [28] H.E. Lebovitz, Insulin resistance: definition and consequences, Exp. Clin. Endocrinol. Diabetes 109 (Suppl. 2) (2001) S135 – S148.
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[29] D.J.P. Barker (Ed.), Type 2 Diabetes: The Thrifty Phenotype, Br. Med. Bull., vol. 60, 2001, pp. 1 – 204. [30] American Diabetes Association and National Institute of Diabetes, Digestive and kidney diseases. The prevention or delay of Type 2 diabetes, Diabetes Care 25 (2002) 742 – 748. [31] P. Zimmet, P. Lefe`bvre, The global NIDDM epidemic. Treating the disease and ignoring the symptom, Diabetologia 39 (1996) 1247 – 1248.
The metabolic syndrome revisited Pierre J. Lefe`bvre * Department of Medicine, University of Liege, CHU Sart Tilman (B35), B-4000 Liege 1, Belgium Received 23 October 2002; accepted 7 February 2003
Keywords: Metabolic syndrome; Syndrome X; Insulin resistance
1. Introduction The Banting Memorial Lecture at the June Meeting of the American Diabetes Association is a highlight of the international medical and scientific life in the field of diabetes. It recognizes the scientific and medical achievements of a long-standing career. In 1988, Dr. Gerald Reaven gave the Banting Lecture at the ADA Meeting in New Orleans [1]. His title was «The role of insulin resistance in human disease». In his lecture, Dr. Reaven made three major points: (1) he drew the attention on a clustering of signs and symptoms making a Syndrome that he called «Syndrome X». These signs and symptoms included: resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increased VLDL triglycerides, decreased HDL cholesterol and hypertension; (2) he suggested that, in this Syndrome, the common feature was insulin resistance and that the other components were secondary to the resistance to insulin; and (3) he concluded, rather provocatively, that «resistance to insulin-stimulated glucose uptake may play a crucial role in determining who will and who will not develop coronary artery disease. . .». The views expressed by Dr. Reaven generated an immense interest in the scientific community, interest but also debates and controversies. It has been said that the clustering of arterial hypertension, hyperglycemia and gout had been described in 1923 by Kilin [2]. Some said, correctly, that the syndrome was implicit in earlier works of Jean Vague in France or Per Bjorntorp in Sweden. Others said that the credit of emphasizing the role of hyperinsulinemia should go to Michaela Modan [3] and her coworkers who had published a less publicized but major paper in 1985. * Tel.: +32-4-365-43-23; fax: +32-4-366-70-68. E-mail address: pierre.Lefe`[email protected] (P.J. Lefe`bvre). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00141-9
4
P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
The very name of Syndrome X was probably not very appropriate since it had previously been registered by the cardiologists to describe a particular form of «myocardial ischemia with reduced coronary perfusion reserve resulting from microvascular dysfunction». Quite amazingly, a later study showed that the patients having the «Cardiac Syndrome X» often exhibit also the «Reaven’s Syndrome X»! Surprisingly, obesity, probably the most well-known form of insulin resistance was not included in the original description of Syndrome X. In fact, Kaplan [4] isolated in 1989 what he called «the deadly quartet» in which upper-body obesity had been added to hypertension, diabetes and hypertriglyceridemia to constitute a syndrome associated with an increased risk of cardiovascular disease. In 1991, Zimmet [5] suggested to formally include central (or upper) obesity in the Syndrome and suggested to replace the name Syndrome X by the «Insulin Resistance Syndrome» or, better, the «Metabolic Syndrome». It has to be remembered that Hanefeld and Leonhardt [6] had mentioned the term «das metabolische syndrom» already in 1981. Subsequently, several other metabolic abnormalities have been associated with the syndrome including microalbuminuria, hyperuricemia, abnormalities in fibrinolysis and coagulation, such as increased levels of PAI-1 and further lipid abnormalities like the presence of small dense LDL particles or high Apo-B levels. In 1998, Alberti and Zimmet [7] submitted, in the name of the WHO consultation, the following working definition of the metabolic syndrome. The components of the Syndrome are: (1) impaired glucose regulation or diabetes; (2) insulin resistance; (3) arterial hypertension (antihypertensive treatment and/or BP z 160/90 mm Hg); (4) dyslipidemia with plasma triglycerides z 1.7 mmol/l and/or HDL cholesterol < 0.9 mmol/l in men and < 1.00 mmol/l in women; (5) central obesity (males: waist-to-hip ratio >0.90; females: waist-to-hip ratio >0.85) and/or BMI z 30 kg/m2; and (6) microalbuminuria (UAER z 20 mmg/min or albumin/creatinine ratio z 20 mgg 1). In the above, impaired glucose regulation includes impaired fasting glycemia (plasma fasting glucose values z 6.1 but < 7.0 mmol/l; whole blood fasting glucose z 5.6 to 6.1 mmol/ l). Insulin resistance is defined as «under hyperinsulinaemic euglycemic conditions, glucose uptake below lowest quartile for background population under investigation». This can be assumed to correspond to the highest quartile of the HOMAIR index. The metabolic syndrome is present if one of the two firsts and two of the last four criteria are present in a given individual. In this brief review, we will first survey some of the key epidemiological studies reported on the relevance of the metabolic syndrome over the last 10 years. Second, we will consider some studies suggesting that one can probably broaden the field of the metabolic syndrome to unexpected aspects of contemporary internal medicine. Third, we will briefly touch the various mechanistic hypotheses supporting the syndrome and, in conclusion, we will allude to possible therapeutic approaches.
2. Epidemiological studies A remarkable epidemiological study in support of the existence of the metabolic syndrome is the San Antonio Heart Study conducted by Stern et al. [8]. It has been
P.J. Lefe`bvre / International Congress Series 1253 (2003) 3–10
5
performed on a random sample of the Mexican– American and of the non-Hispanic white population of San Antonio, TX. The population surveyed amounted to 2930 subjects. In this population, the total prevalence rates for obesity, Type 2 diabetes mellitus, impaired glucose tolerance, arterial hypertension, hypertriglyceridemia and hypercholesterolemia were 54.3%, 9.3%, 11.1%, 9.8%, 10.3% and 9.2%, respectively. However, the prevalence of each of these conditions in its isolated form (that is free of the other five) was only 29.0% for obesity, 1.3% for diabetes, 1.5% for arterial hypertension, 1.0% for hypertriglyceridemia and 1.7% for hypercholesterolemia. These large differences in prevalence between isolated and mixed forms indicated a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinemia (both fasting and 2 h after oral glucose); such hyperinsulinemia is indicative or suggestive of insulin resistance. In all the subjects who presented with one or another disorder (i.e. 1881 out of 2930 subjects or 64%), marked fasting and post-prandial hyperinsulinemia was associated with higher BMI, waist-to-hip ratio, fasting and post-glucose glycemia, systolic and diastolic blood pressure, serum triglyceride and serum cholesterol levels and lower HDL-cholesterol concentrations. All these associations were highly statistically significant. This study was the first unequivocal demonstration that there is, in some subjects, a cluster of abnormalities as described originally by Reaven to which one must add obesity and a high waist-to-hip ratio. Furthermore, the hypothesis that hyperinsulinemia is the key feature of the syndrome was confirmed. In a subsequent study, Haffner et al. [9] examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in an 8-year follow-up of the cohort initially studied between 1979 and 1982. The risk to develop hypertension was twofold in the subjects with the higher quartile of plasma insulin related to the one of the subjects with the lower quartile. The Relative Risks figures for hypertriglyceridemia, low HDL cholesterol and NIDDM were 3.5, 1.6 and 5.6, respectively. Baseline insulin concentrations were also higher in the subjects who subsequently developed multiple metabolic disorders. The metabolic syndrome concept was strongly supported by the results of that study, which showed, for the first time, that elevation of insulin concentrations precedes the development of numerous metabolic disorders. Another supportive study was the Paris Prospective Study [10]. That remarkable study included 6903 men aged 43 –54 years who were first examined between 1968 and 1973. Causes of death were ascertained after 15 years of mean follow-up. Significant independent predictors of coronary heart disease were: systolic blood pressure, number of cigarettes per day, plasma cholesterol level, and 2-h post-glucose load plasma insulin levels. Consequently, if we assume that hyperinsulinemia is a marker of insulin resistance, the results of the Paris Prospective Study are consistent with the hypothesis that insulin resistance is associated with a higher risk of coronary heart disease mortality. Another major study is the recent Botnia Study [11] in which a total of 4483 subjects aged 36 –70 years were included in the analysis of the cardiovascular risk associated with the metabolic syndrome. The salient features of that study is that the 1998 WHO definition of the metabolic syndrome was used to assess the prevalence of, and the cardiovascular
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morbidity and mortality associated with, the syndrome. In women and men, respectively, the metabolic syndrome was seen in 10% and 15% of subjects with normal glucose tolerance, in 42% and 64% of those with impaired fasting glycemia or impaired glucose tolerance and in 78% and 84% of those with Type 2 diabetes. The risk of coronary heart disease and stroke was increased threefold in subjects with the syndrome. Overall cardiovascular mortality was five to six times greater in subjects with the metabolic syndrome compared to those who did not present it. Interestingly, of the individual components of the syndrome, one of the most disputed, namely microalbuminuria, conferred the strongest risk of cardiovascular death. Using a slightly different definition of the metabolic syndrome, the Third National Health and Nutrition Survey (NHANES III) performed in the USA [12] showed that the unadjusted and age-adjusted prevalence of the metabolic syndrome in that country were 21.8% and 23.7%, respectively. The prevalence increased over 40% in participants aged over 60 years. Using the 2000 census data, the study revealed that about 47 million US residents have the metabolic syndrome. These epidemiological studies performed over the last 10 years and selected among many others support the concept of insulin resistance being a major risk factor for cardiovascular morbidity and mortality. Furthermore, prevalence studies indicate that the problem affects a high percentage of the population, at least in the developed countries, and may have important implications for the public health sector. As emphasized by Alberti and Zimmet [7], the syndrome occurs commonly not only in Europids, Afro-Americans and Mexicans– Americans, as we have seen, but also in Asian Indians and Chinese, Australian and Alaskan Aborigines, Polynesians and Micronesians.
3. Widening the metabolic syndrome concept MARCEAU et al. [13] suggested and, like the Torino group [14], we confirmed that liver steatosis can be regarded as being part of the metabolic syndrome [15]. In a series of 528 liver biopsies performed in severely obese individuals, fatty acid deposition was seen in 391 (74%) of the biopsy specimens. Steatosis severity was positively associated with BMI ( p = 0.002), fasting hyperglycemia ( p = 0.007), hypertriglyceridemia ( p = 0.002) and hyperinsulinemia ( p = 0.003). Interestingly, we also observed a partial reversibility of the biological markers of both the metabolic syndrome and liver steatosis after gastroplastyinduced weight loss [16,17]. We agree with James and Day [18] that both the nonalcoholic steatohepatitis and the metabolic syndrome associated with severe obesity may be considered as common markers of a ‘‘disease of affluence’’. Interestingly, Greco et al. [19] recently reported that lipid malabsorption induced in massively obese subjects by biliopancreatic diversion induces not only a massive weight loss but also a reversal of intramyocellular fat accumulation and, in parallel, a full normalization of insulin sensitivity. Using the so-called ‘‘factor analysis’’ statistical method, Sakkinen et al. [20] have carefully studied the various ‘‘extensions’’ of the Syndrome that have been recently proposed. They have been able to confirm that elevated PAI-1 levels and impaired endothelial function are core features of the metabolic syndrome. Furthermore, they have
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shown that inflammation was only weakly linked to insulin resistance, through association with obesity. Other diseases and conditions associated with the metabolic syndrome include the polycystic ovary syndrome [21], the prolonged QT syndrome [22], the adrenal incidentaloma [23] and even some psychiatric disorders like depression and schizophrenia [24]. For these last two, the question of cause or consequence and that of the effects of treatment must be asked.
4. Pathogenesis of the syndrome Theoretically, genetic and environmental factors should be considered. Until now, genetic abnormalities account only for a small number of rare syndromes in which insulin action is severely impaired and no one gene or group of genes has been identified as being the cause of the metabolic syndrome. The hypothesis that many gene abnormalities are clustering together to favor the occurrence of the syndrome is considered by numerous experts. The role of environmental factors is well established and includes overnutrition, sedentarity, accumulation of visceral fat and possibly fetal malnutrition. An argument in favor of environmental factors is the reversibility of various components of the syndrome with weight loss [25], including, at least in some individuals, complete normalization of insulin sensitivity [26]. Although not introduced in the original Syndrome X, abdominal obesity undoubtedly represents a key element of the metabolic syndrome [27]. For reasons that are still poorly understood, a positive energy balance, due to excess calorie intake and/or reduced energy expenditure, leads often to an excess of fat accumulation in the intraabdominal adipocytes. As reviewed by Lebovitz [28], an excess in visceral adipose tissue leads to an increase in the release of FFA, TNF-a, leptin and other products of adipose tissue metabolism. Indeed, in part due to their complement of adrenergic receptors, the visceral adipocytes have a high rate of lipolysis. These products drain through the portal vein directly into the liver, which sees an increase in FFA and triglycerides and starts accumulating fat (see above). This leads to an increase in hepatic insulin resistance, an increase in VLDL particle synthesis and a decreased in insulin clearance. The liver releases an increased amount of FFA into the peripheral circulation where they contribute to muscle insulin resistance either directly or indirectly through an increase in muscle triglycerides. Finally, it has been demonstrated that an increase in circulating VLDL particles can contribute to an increase in PAI-1 synthesis from the endothelial cells. Over the last 10 years, epidemiological studies, comforted by elegant mechanistic animal studies, have shown that fetal malnutrition increases the risk of subsequent metabolic syndrome and that postnatal overnutrition may aggravate the syndrome [29]. On this topic, also reviewed by Lebovitz [28], the following mechanisms may be operating. Fetal malnutrition would induce changes in the central nervous system regulation of metabolism to create more efficient metabolic pathways. This imprinting of the CNS would remain permanent into and throughout adult life. In the adult life, increased caloric intake and/or reduced physical activity, occurring in an individual with the modified imprinted metabolic pathways, would lead to obesity and the metabolic syndrome.
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5. Management of the metabolic syndrome and conclusions Treating a patient affected by the metabolic syndrome is at present not an easy task. Recommendations to modify lifestyle including modifications of dietary habits and suggestions to increase physical activity often fail despite the fact that recent wellconducted clinical trials have shown their efficacy [30]. Too often, the physician is left with the decision to treat the individual components of the syndrome including drugs to manage the abnormalities of glucose metabolism, the dyslipidemia, the arterial hypertension, the hyperuricemia, the abnormalities in coagulation and hemostasis. In practice, many of these patients receive 10 – 12 pills containing numerous drugs. If insulin resistance is really the mechanism underlying the syndrome, then drugs like metformin and the thiazolidinediones, which are effective in increasing insulin sensitivity, may represent a logical choice. Interestingly, new antihypertensive drugs also possess the ability to increase insulin sensitivity and may therefore be particularly interesting in the management of the metabolic syndrome. New drugs are in development, which have both PPARg and PPARa agonist activity, thus being able to simultaneously decrease insulin resistance and improve the dyslipidemia of the syndrome. As recently stated by Ford et al. [12] for the Participants of the Third National Health and Examination Survey in the United States, ‘‘because the root causes of the metabolic syndrome for the overwhelming majority of patients are improper nutrition and inadequate physical activity, the high prevalence of this syndrome underscores the urgent need to develop comprehensive efforts directed at controlling the obesity epidemic and improving physical activity levels. . .’’ In this fight against the metabolic syndrome, which is now seen in children and adolescents, all components of the Society, including the World Health Organization (WHO) and the International Diabetes Federation (IDF) [31] will have to counteract the dramatic lifestyle changes that our entire world has seen over the last 30 years by the aggressive promotion of cheap, easily available, high in calorie food and beverages combined to a mechanization of the Society and sedentary leisure activities like TV watching and the use of computers.
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[29] D.J.P. Barker (Ed.), Type 2 Diabetes: The Thrifty Phenotype, Br. Med. Bull., vol. 60, 2001, pp. 1 – 204. [30] American Diabetes Association and National Institute of Diabetes, Digestive and kidney diseases. The prevention or delay of Type 2 diabetes, Diabetes Care 25 (2002) 742 – 748. [31] P. Zimmet, P. Lefe`bvre, The global NIDDM epidemic. Treating the disease and ignoring the symptom, Diabetologia 39 (1996) 1247 – 1248.