Pharmacological Research 51 (2005) 387–389
Opinion
Reply to comment by Mart´ın-L´azaro and Becerra-Fern´andez Enzo Nisolia,∗ , Michele O. Carrubaa , Giovanni Federspilb a
Center for Study and Research on Obesity, University of Milan, Department of Preclinical Sciences, LITA Vialba, L. Sacco Hospital, 20157 Milan (Italy) and Istituto Auxologico Italiano, Milan 20149, Italy b Clinica Medica 3, Department of Medical and Surgical Sciences, University of Padua, Padua 35100, Italy Accepted 20 October 2004
Reaven suggested in 1988 the existence of a cluster of metabolic abnormalities with insulin resistance as the central pathophysiological feature [1], and labelled it “syndrome X”. The World Health Organization (WHO) and others have systematized this concept as “the metabolic syndrome”. The presence of the syndrome is suggested to increase the risk of developing diabetes and cardiovascular disease (CVD). In his description of the syndrome Reaven considered the following abnormalities: resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinaemia, increased triglycerides, decreased HDL-cholesterol, and hypertension. Since then several other metabolic abnormalities have been linked to insulin resistance including overall or abdominal obesity, microalbuminuria, hyperuricaemia and plasminogen activator inhibitor 1. In particular, a number of investigations show that visceral adiposity is a significant independent predictor of the insulin sensitivity [2,3], impaired glucose tolerance [4], elevated blood pressure [5,6], and dyslipidemia [7,8] seen in the metabolic syndrome. Furthermore, intraabdominal fat is metabolically active as a source of free fatty acids [9] and adipokines, such as adiponectin [10], tumour necrosis factor-␣ (TNF-␣) [11], and plasminogen activator inhibitor type 1 (PAI-1) [12]. To evaluate the differential effects of insulin resistance and central body fat distribution on the metabolic syndrome, a very recent study has examined the relation of insulin sensitivity and intra-abdominal adipose tissue and subcutaneous fat areas with the criteria for the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) (NCEP ATP III) metabolic syndrome [13] in a nondiabetic population [14]. The specific ∗
Corresponding author. Tel.: +39 02 50319682; fax: +39 02 50319683. E-mail address:
[email protected] (E. Nisoli).
1043-6618/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2004.10.006
aims were to: (1) examine whether insulin sensitivity and abdominal fat distribution, alone or together, were associated with the individual NCEP ATP III criteria, the number of criteria, and the metabolic syndrome; (2) evaluate the effect of sex and age on these relations; and (3) determine which NCEP ATP III criteria were the best correlates of insulin resistance and central body fat distribution. In this study of a large number of apparently healthy men and women of varying age, authors sought to evaluate the differential effects of insulin sensitivity and central body fat distribution on the features of the metabolic syndrome as defined by NCEP ATP III [13]. This study showed that both insulin resistance and central adiposity are significantly correlated with phenomena of the metabolic syndrome. Intra-abdominal fat area was independently associated with all of the metabolic syndrome features, whereas insulin sensitivity was independently associated with the criteria for HDL-cholesterol, triglyceride, and fasting plasma glucose levels. In contrast, subcutaneous fat area was independently correlated with only waist circumference after adjusting for visceral fat area and insulin sensitivity. The results of this study, therefore, suggest that accumulation of intra-abdominal adipose tissue is an important causal factor of the metabolic syndrome. Two very recent studies report on the prevalence of the metabolic syndrome in rural and urban areas in South Korea according to the definition suggested by the WHO and the NCEP ATP III [15,16]. In both studies a remarkably high prevalence is seen among women compared with men; however, among both men and women the syndrome occurs despite a low prevalence of overall and abdominal obesity. These results would suggest that genetic and/or behavioural factors associated with ethnicity may also contribute to CVD risk factors linked to metabolic changes. It is well established that the association between obesity and metabolic risk factors varies across populations [17–19], and the fact that Asian
388
E. Nisoli et al. / Pharmacological Research 51 (2005) 387–389
populations are experiencing high levels of CVD at much lower levels of obesity than European populations has led to reassessment of the ‘healthy range’ of body mass index and waist circumference for Asian populations by the WHO [18]. Based on the scientific methodology, changing the criteria for diagnostic evaluation of a disease can be defined as an “ad hoc strategy”. However, the cut-off values for abdominal and overall obesity included in the proposed definitions of the metabolic syndrome are based on studies of white Europeans, and its impact on metabolic factors should not uncritically be extrapolated to other ethnic groups. Maybe, we are in front of two different clinical situations: i.e. type 1 metabolic syndrome (in Caucasians) and type 2 metabolic syndrome (in South Koreans). But it is unlike this might solve the basic question: indeed, everyone knows that in science different things or concepts must not to be named similarly (i.e. defined with the same word). Thus, also supposed that metabolic syndrome is defined precisely in such a way and a general consensus on its diagnostic criteria exists, so that it would not be a “vague” (i.e. with confused limitations) concept, nevertheless it would remain an “ambiguous” (i.e. with different meanings) scientific concept, as stated in Logic treatises [20]. The last considerations oblige to put forward more general reflections on how we can operatively define with scientific rigour the metabolic syndrome, starting from the effects of insulin sensitivity and the central localization of fat on the characteristics of the syndrome itself. Indeed, as seen previously many studies show that both insulin resistance and visceral obesity are significantly associated to metabolic syndrome. Thus, a classic methodological and logic problem arises: the problem of “causation” (see [21–23]). How can we pass from “association” to “causation”? Most of the biomedical researches crosses easily from one to the other, but this is a really complex problem to be solved also on the theoretical basis. It is not so obvious to demonstrate a causal relationship when we are considering probabilistic phenomena, such as the biomedical ones. Some authors think that “if A is a true cause of B, then an opportune manipulation or a change of A ought to produce a change also in B” (this is defined as manipulation theory of causality). Others think that “A causes B if and only if the probability of B given A is major than the probability of B, given non-A” (probabilistic theory of causality), and so on [20–23]. Thus, substantial uncertainties and more general problems remain about the clinical definition of the metabolic syndrome and whether risk factor clusters collectively indicate a unifying underlying disorder or a single pathophysiological mechanism. Mart´ın-L´azaro and Becerra-Fern´andez, underlining that ATP III criteria detailed in our review article [24] are wrong, raise a wider problem on this issue: is one single, unambiguous definition possible for the so-called metabolic syndrome? Indeed, there are different types of definition: some of them have only a pragmatic relevance, others try to catch the nature of the thing, others are of causal type, etc. In the case we are discussing on, it would be necessary that the consensus on definition was preceded by a more general
consensus on the type of definition we would like for this case. For example, everybody are in accordance on definition of “cholera”, since there is a widely acccepted causal definition (Vibrio cholerae); for “type 1 diabetes mellitus” a general consensus on a pathophysiological definition exists; for “cancer” there is agreement for an essential definition (uncontrollable proliferation of cells). What type of definition is needed for metabolic syndrome? This is not a secondary or academic or only philosophical problem. Indeed, from such a definition may derive different therapeutic approaches. In particular this is relevant for drug therapy, either with insulin sensitizers or anti-obesity drugs for example.
References [1] Reaven GM. Banting lecture. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607. [2] Carey D, Jenkins A, Campbell L, Freund J, Chisholm D. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996;45:633–8. [3] Cnop M, Landchild M, Vidal J, Havel P, Knowles N, Carr D, et al. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes 2002;51:105–15. [4] Hayashi T, Boyko E, Leonetti D, McNeely M, Newell-Morris L, Kahn S, et al. Visceral adiposity and the risk of impaired glucose tolerance: a prospective study among Japanese Americans. Diabetes Care 2003;26:650–5. [5] Rattarasarn C, Leelawattana R, Soonthornpun S, Setasuban W, Thamprasit A, Lim A, et al. Regional abdominal fat distribution in lean and obese Thai type 2 diabetic women: relationships with insulin sensitivity and cardiovascular risk factors. Metabolism 2003;52:1444–7. [6] Kanai H, Tokunaga K, Fujioka S, Yamashita S, Kameda-Takemura K, Matsuzawa Y. Decrease in intra-abdominal visceral fat may reduce blood pressure in obese hypertensive women. Hypertension 1996;27:125–9. [7] Carr M, Hokanson J, Deeb S, Purnell J, Mitchell E, Brunzell J. A hepatic lipase gene promotor polymorphism attenuates the increase in hepatic lipase activity with increasing intra-abdominal fat in women. Arterioscler Thromb Vasc Biol 1999;19:2701–7. [8] Pascot A, Despres JP, Lemieux I, Bergeron J, Nadeau A, Prud’homme D, et al. Contribution of visceral obesity to the deterioration of the metabolic risk profile in men with impaired glucose tolerance. Diabetologia 2000;43:1126–35. [9] Lonnqvist F, Thome A, Nilsell K, Hoffstedt J, Arner P. A pathogenic role of visceral fat beta 3-adrenoreceptors in obesity. J Clin Invest 1995;95:1109–16. [10] Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 2003;52:1274–8. [11] Katsuki A, Sumida Y, Murashima S, Murata K, Takarada Y, Ito K, et al. Serum levels of tumor necrosis factor-␣ are increased in obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1998;83:859–62. [12] Alessi M, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997;46:860–7.
E. Nisoli et al. / Pharmacological Research 51 (2005) 387–389 [13] Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486–97. [14] Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, et al. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes 2004;53:2087–94. [15] Kim ES, Han S-M, Kim YI, Song K-H, Kim M-S, Kim WB, et al. Prevalence and clinical characteristics of metabolic syndrome in a rural population of South Korea. Diabet Med 2004;21:1141–3. [16] Song J, Kim E, Shin C, Kim S-S, Lee HK, Jung M, et al. Prevalence of the metabolic syndrome among South Korean adults: the Ansan study. Diabet Med 2004;21:1154–5. [17] Valdez R, Gonzalez-Villalpando C, Mitchell BD, Haffner SM, Stern MP. Differential impact of obesity in related populations. Obes Res 1995;3:223s–32s. [18] Lackland DT, Orchard TJ, Keil JE, Saunders DE, Wheeler FC, Adams-Campbell LL, et al. Are race differences in the prevalence of
[19]
[20] [21]
[22]
[23] [24]
389
hypertension explained by body mass and fat distribution? A survey in a biracial population. Int J Epidemiol 1992;21:236–45. Jorgensen ME, Glumer C, Bjerregaard P, Gyntelberg F, Jorgensen T, Borch-Johnsen K. Obesity and central fat pattern among Greenland Inuit and a general population of Denmark (Inter99): relationship to metabolic risk factors. Int J Obes Relat Metab Disord 2003;27:1507–15. Copi IM, Cohen C. Introduction to logic. New York: The Macmillan Company; 1994. Eells E, Skyrms B, Adams EW, Binmore K, Butterfield J, Diaconis P, et al. Probabilistic causality. Cambridge: Cambridge University Press; 1991. Price H. Causation in the special sciences: the case for pragmatism. In: Galavotti MC, Suppes P, Costantini D, editors. Stochastic causality. Stanford: CSLI Publications; 2001. Pearl J. Causality: models, reasoning and inference. Cambridge: Cambridge University Press; 2000. Nisoli E, Carruba MO. Emerging aspects of pharmacotherapy for obesity and metabolic syndrome. Pharmacol Res 2004;50:453–69.
