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Diabetes or IFG or IGT or IR (clamp)

Plus 2 of the following: BMI >30 or

WHR >0.9 (male); >0.85 (female) TG >1.7 mmol/l or

HDL <0.9 mmol/l (male) <1.0 mmol/l (female) Blood pressure >140/90 mm Hg

Albumin excretion >20 ^g/min

EGSIR ATP III

Fasting insulin: top 25% non-diabetics

Plus 2 of the following: Waist >94 cm (male) >80 cm (female)

HDL <1.0mmol/l

Blood pressure >140/90 mm Hg or antihypertensive medication FPG >6.1 mmol/l

3 or more of the following:

HDL <1.0mmol/l (male) <1.3 mmol/l (female) Blood pressure >140/90 mm Hg or antihypertensive medication FPG >6.1 mmol/l

ATP III = National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATP III); BMI = body mass index; EGSIR = European Group for the Study of Insulin Resistance; FPG = fasting plasma glucose concentration; IFG = impaired fasting plasma glucose; IGT = impaired glucose tolerance; IR = insulin resistance; TG = plasma triglyceride concentration; WHR = waist-hip ratio.

[1, 2]. Until 1998 an internationally recognized definition did not exist. In that year a WHO consultation proposed a set of criteria (diabetes mellitus or impaired fasting glycemia or insulin resistance plus 2 or more of obesity, dys-lipidemia, hypertension, or microalbuminuria). Subsequently, the National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATP III; 3 or more of obesity, dyslipidemia, hypertension or impaired fasting plasma glucose) and the European Group for the Study of Insulin Resistance (EGSIR; insulin resistance plus 2 or more of obesity, dyslipidemia, hypertension or impaired fasting plasma glucose) have formulated definitions. The WHO definition and that of EGSIR agree that they both include either glucose intolerance or insulin resistance as an essential component. However, for the NCEP:ATP III definition, this criterion is not included [1] (table 1). Despite these differences in definition, they also have major similarities. All include dyslipidemia, hypertension and a parameter for obesity.

Confusion about the relevance of considering the metabolic syndrome as a separate disease entity relates to differences in opinion regarding its definition. Opinions have varied as to whether the metabolic syndrome should be defined to indicate: (1) mainly insulin resistance; (2) the metabolic consequences of obesity; (3) the risk of CVD, or (4) simply as a collection of statistically related factors.

In 1988, it was proposed that individuals displaying the cluster of abnormalities associated with insulin resistance/compensatory hyperinsulinemia (glucose intolerance, hypertriglyceridemia, low high-density lipoprotein and essential hypertension) were at a significantly increased risk of CVD. Because the importance of insulin resistance and the associated abnormalities were not widely appreciated as CVD risk factors at that time, the cluster of associated abnormalities was subsumed under the rubric of syndrome X. Since the introduction of the concept of syndrome X considerable information has evolved relevant to the role of insulin resistance in human disease. This has resulted in two somewhat disparate approaches to thinking about the clinical implications of insulin resistance and its consequences. One view recognizes that the abnormalities related to insulin resistance have broadened considerably, and the adverse clinical outcomes extend beyond type-2 diabetes melli-tus and CVD. Because CVD is recognized to be just one of the multiple clinical syndromes, it seemed appropriate to replace the term syndrome X by the term 'insulin resistance syndrome'. The cardiologic community (ATP III) recognized the importance of a 'constellation of lipid and non-lipid risk factors of metabolic origin' to be important as CVD risk factors, added abdominal obesity to the abnormalities initially proposed to comprise syndrome X, designated this cluster as the metabolic syndrome and stated 'this syndrome is closely related to insulin resistance'. However, on the other hand, the stated purpose of ATP III was to provide criteria to make the clinical diagnosis of metabolic syndrome, not to provide a physiological construct to explain why insulin-resistant subjects are at increased CVD risk [3]. This divergent approach (simple criteria for the diagnosis of metabolic syndrome and emphasis on a physiological construct to explain why insulin-resistant subjects are at increased CVD risk) was greatly enhanced by their diagnostic criteria. As shown in table 1, only three of their criteria are necessary to diagnose the metabolic syndrome. This leaves the possibility that a lean glucose-tolerant subject can be labelled as being a patient with the metabolic syndrome. It is obvious that this divergent approach causes major problems for epidemiological studies and treatment.

Because of its ease for use, the NCEP:ATP III criteria are used most frequently. In those studies the prevalence varies in urban populations from 8% (India) to 24% (USA) in men, and from 7% (France) to 43% (Iran) in women. A very consistent finding is that the prevalence of the metabolic syndrome is highly age-dependent. This pattern is clear in Iran where the prevalence is <10% for both men and women in the 20- to 29-year age group, rising to 38 and 67%, respectively, in the 60- to 69-year age group. Similarly, in a French population, the prevalence rises from <5.6% in the 30- to 39-year age group to 17.5% in the 60- to 64-year age group. The prevalence data for the USA are comparable to those for Iran [1]. A recent study in 15,540 Chinese adults confirmed the rather high prevalence in developing countries [4]. The age-standardized prevalence was 9.8% in men and 17.8% in women. The age-related prevalence showed the same tendencies as anywhere else in the world, albeit less steep. It was 8.4% in men for the 35- to 44-year age group and 10.4% in the men aged 65-74 years. In women these figures were 9.4 and 28.6%, respectively [5].

Knowledge of the impact of the metabolic syndrome according to standard definitions on the cardiovascular and overall mortality in the general population is crucial for developing public health policy and clinical guidelines for its prevention and treatment [5]. However, comparisons of the published prevalence of the metabolic syndrome for different populations are difficult despite attempts to reach agreement on the definition of the metabolic syndrome. When different definitions are applied to the same study population, the prevalence can differ by ~60% [5]. It is even more troublesome that many studies compare prevalences using different criteria.

It can be stated that the ultimate importance of the recognition of the metabolic syndrome as a separate entity is that it helps to identify individuals at high risk of both type-2 diabetes and CVD. However, the different definitions are not equal in this respect. For Finland and Italy the WHO/EGSIR criteria are better than the NCEP:ATP III definition, while in the San Antonio study the reverse was found [6].

To promote consistency in epidemiological research related to the metabolic syndrome, the American Diabetes Association and the European Association for the Study of Diabetes analyzed the existing literature (mainly based on ATP III criteria) and concluded that the metabolic syndrome has been imprecisely defined and existing diagnostic criteria did not consider many other related CVD risk factors [2]. In 2005 the International Diabetes Federation (IDF) released a consensus clinical definition of the metabolic syndrome for worldwide use that included central obesity as a prerequisite. The IDF definition varied from the ATP III criteria with different criteria for glucose intolerance (table 2). A major additional difference was the inclusion of criteria for obesity in different ethnic groups, as the risk of type-2 diabetes is apparent at much lower levels of adiposity in Asian populations than in the European population [6].

This stricter definition can create additional problems. Comparison of the ATP III definition and the new IDF criteria in a representative sample of ~4,000 subjects in South Australia demonstrated that the IDF definition categorized 15-20% more people as having the metabolic syndrome. The IDF recommends 'aggressive and uncompromising' management of those classified to reduce CVD and diabetes. If this definition regains widespread acceptance, then substantially more people will receive management, including drug therapy [7]. Time will tell whether this increased cost in monetary and other terms is justified. Time will also tell whether these new criteria will resolve the discussion about the diagnostic criteria for the metabolic syndrome.

The Dysmetabolic Syndrome: Epidemiology and Etiology Table 2. Comparison of definitions of the metabolic syndrome by IDF and ATP III

Parameter IDF criterion

Obesity Waist circumference:

ethnic specificity Triglycerides TG >1.7mmol/l or specific treatment HDL Male: <1.0mmol/l female: <1.3mmol/l or specific treatment Hypertension Blood pressure: >130/85 mm Hg or specific treatment Glucose FPG: >5.6mmol/l or previously diagnosed diabetes mellitus

ATP III = National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATP III); FPG = fasting plasma glucose concentration; IDF = International Diabetes Federation; IGT = impaired glucose tolerance; TG = plasma triglyceride concentration.

Comparison to ATP III

Different

Same

Same

Same

More strict

Etiology

Medical science usually defines a syndrome as an 'aggregate of symptoms and signs associated with any morbid process, and constituting together the picture of disease'. The specific signs and symptoms are usually caused by a unifying underlying pathology, and their components confer a risk that is different from the sum of its parts. This definition does not seem to be applied in the discussions about the pathophysiology of the metabolic syndrome. In this discussion sometimes cause and effect are reversed, especially about the relation between free fatty acids (FFAs) and insulin sensitivity [1].

It has been stated that accumulating evidence strongly indicates that insulin resistance is the common pathogenetic factor for the individual components of the metabolic syndrome and explains the trait cluster [2, 8]. In many of the studies on the relation between insulin resistance and the occurrence of metabolic syndrome, surrogate measures of insulin resistance were used and these measures often loaded on more than one of the underlying factors. Few studies have examined the associations between the metabolic syndrome and direct measures of insulin sensitivity as the euglycemic-hyperinsulinemic clamp or the frequently sampled intravenous glucose tolerance test. Applying those techniques, still strong associations have been found between low insulin sensitivity and the metabolic syndrome in non-diabetic subjects. Subjects with ATP III- or WHO-defined metabolic syndrome had

5- to 10-fold increased risks of being in the lowest quartile of directly measured insulin sensitivity [9]. It has been concluded that these observations provide strong support for the notion that individuals with the metabolic syndrome are insulin-resistant and this disorder may be at the core of the cluster of metabolic abnormalities that characterizes the syndrome [9]. Although the conclusion that 'insulin resistance may be at the core of cluster of abnormalities' is carefully formulated and does not state that insulin resistance is the cause of the metabolic syndrome, the implicit suggestion is that it is. Is this conclusion justified? In other words, can the cluster of abnormalities together forming the metabolic syndrome be explained by diminished insulin action? A series of arguments will be provided to prove that this is not true.

In order to fulfill its role as a unifying underlying pathology, insulin resistance should not only be strongly related to the metabolic syndrome, but should also be present in every patient with the metabolic syndrome. This requirement is not fulfilled. In the definition proposed by WHO and EGSIR a central role is given to insulin resistance; however, according to the ATP III criteria, the existence of glucose intolerance or insulin resistance is not a prerequisite for diagnosis of the metabolic syndrome and ATP III criteria have a low sensitivity for identifying insulin resistance with dyslipidemia in non-diabetic individuals at increased risk for CVD [8]. This suggests that it could be possible that subjects diagnosed as having the metabolic syndrome do not have this abnormality which is considered to be essential for development of this syndrome. This suggestion proved to be true. In a study of 443 healthy volunteers in the USA, in whom insulin sensitivity was measured with the gold standard, it was shown that ~21% of the subjects evaluated met the ATP III criteria for identification of the metabolic syndrome. Approximately two thirds of these subjects were insulin-resistant. This shows a high correlation between the metabolic syndrome and insulin resistance, but more importantly it also shows that ~30% were insulin-sensitive [10]. A recent study, reported in the Annals of Internal Medicine on 258 obese non-diabetic subjects, showed that 78% of those with the metabolic syndrome were insulin-resistant and 48% with insulin resistance met the criteria of the metabolic syndrome, again values too low for insulin resistance to be a cause of the syndrome [11].

Another approach could be to show that treatment of insulin resistance alone will cure or improve the abnormalities of the metabolic syndrome. There are no data showing this. Treatment of the metabolic syndrome is treatment of its different components. There are no data showing that treatment of all its components adds something extra above this. There are also no data showing that treatment of one component 'cures' the other components [1]. It has been suggested that peroxisome proliferator-activated receptor-7 agonists could be ideal agents for managing the metabolic syndrome, as they reduce insulin resistance by influencing FFA flux. Systematic studies are lacking, but even if treatment with this agent alone improves or cures the metabolic syndrome, this cannot be used as an argument for insulin resistance being the core player in the development of the metabolic syndrome. These agents have pleiotropic effects far beyond improving insulin resistance [12].

The third approach to explore the role of insulin resistance in the development of the metabolic syndrome is to look at studies on long-term insulin administration and the development of the metabolic abnormalities of the metabolic syndrome. Insulin inhibits glucose production and stimulates glucose uptake - oxidation and glycogen synthesis in the insulin-sensitive tissues, muscle and adipose tissue. Suppression of production and stimulation of oxidation of glucose require less insulin than stimulation of uptake. In the traditionally glucocentric view of insulin resistance, a defect in insulin action requires more insulin than usual to maintain normal glucose fluxes [13]. In this glucocentric view it is ignored that insulin has many more regulatory tasks than those related to glucose metabolism. Another important function of insulin is suppression of lipolysis. Less insulin is required for suppression of lipolysis (suppression of FFA flux) than for regulation of glucose metabolism [14]. Numerous data have shown that lipids and especially high FFA levels will induce insulin resistance. There is now a growing appreciation that a chronic elevation in FFA levels is an early event that contributes to the development of insulin resistance [1, 15]. Insulin resistance will further increase FFA levels, and this can worsen insulin resistance again. In this way insulin resistance can worsen the metabolic abnormalities, but is never the primary contributor.

The relation between insulin resistance and hypertension seems to be well established [1]. Resistance to the metabolic effects of insulin and compensatory hyperinsulinemia have been postulated to mediate human essential hypertension, especially when associated with obesity. Evidence supporting this hypothesis has come mainly from epidemiological studies showing correlations between insulin resistance, hyperinsulinemia, and blood pressure, and from short-term studies suggesting that insulin has renal and sympathetic effects that could raise blood pressure if the effects were sustained. However, there have been no studies demonstrating a direct causal relationship between chronic hypertension and insulin resistance or hyperinsulinemia in humans. The few long-term studies that have been conducted in dogs and humans do not support the hypothesis that hyperinsulinemia causes hypertension or potentiates the hypertensive effects of other pressor agents such as angiotensin II or increased adrenergic tone. To the contrary, multiple studies in dogs and humans suggest that the vasodilator action of insulin tends to reduce blood pressure. Although resistance to insulin's metabolic effects has been suggested to be essential for hyperinsulinemia to cause hypertension, chronic increases in plasma insulin concentrations do not cause hypertension in dogs or humans, even in the presence of insulin resistance. Recent studies have further shown that the blood pressure-lowering effects of anti-hyperglycemic agents, initially believed to lower blood pressure by decreasing insulin resistance, may be unrelated to their effects on insulin sensitivity. Obesity appears to be a key factor in accounting for correlations between insulin resistance, hyperinsulinemia, and hypertension, but increased blood pressure in obesity does not appear to be mediated by insulin resistance and hyperinsulinemia [16]. Even in full-blown metabolic syndrome insulin resistance contributes only modestly to the increased prevalence of hypertension [17].

These data point to new upcoming pathophysiological findings about extra-adrenal cortisol production in adipose tissue. Within adipose tissue, the enzyme 11p-hydroxysteroid dehydrogenase type-1 interconverts inactive glucocorticoid cortisone and cortisol. In vivo, it is the reductase activity that is believed to predominate, generating cortisol in an autocrine/paracrine manner within the adipocyte microenvironment. An increasing amount of data shows that cortisol production by adipose tissue is increased in obesity and contributes to insulin resistance. Induction of weight loss reverses these changes [18]. These data suggest that insulin resistance is the consequence of abnormalities induced by local cortisol overproduction, a consequence of obesity. Based on these data, the suggestion crops up that insulin resistance is therefore not the main player in the pathophysiology of the metabolic syndrome, but a consequence of obesity.

An exception in this series of arguments against the primary role of insulin resistance in the pathogenesis of the components of the metabolic syndrome is hypertriglyceridemia. Literature data indicate that this abnormality is caused by overproduction and reduced clearance of very low-density lipopro-tein, both processes regulated by insulin. Overproduction of very low-density lipoprotein will lower high-density lipoprotein [19].

Conclusion

It is clear that more than one distinct pathophysiological process underlies the clinical expression of the metabolic syndrome, and insulin resistance can in some sense be related to them but seems to be less prominent than usually stated in literature. Adipose tissue is an active metabolic organ. An increase in the size of this organ with consequent changes in its metabolism can readily explain the features of the metabolic syndrome. Therefore, insulin resistance is not the main player in the metabolic syndrome, but central obesity is. FFA-induced insulin resistance is found and induced by central obesity. The same holds true for hypertension.

References

1 Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2005;365:1415-1428.

2 Kahn R, Buse J, Ferrannini E, Stern M: The metabolic syndrome: time for a critical appraisal.

Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-2304.

3 Reaven GM: The insulin resistance syndrome: definition and dietary approaches to treatment.

Annu Rev Nutr 2005;25:391-406.

4 Gu D, Reynolds K, Wu X, et al: Prevalence of the metabolic syndrome and overweight among adults in China. Lancet 2005;365:1398-1405.

5 Lakka HM, Laaksonen DE, Lakka TA, et al: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;228:2709-2716.

6 Alberti KGMM, Zimmet P, Shaw J: The metabolic syndrome-a new worldwide definition. Lancet 2005;366:1059-1062.

7 Adams RJ, Appleton S, Wilson DH, et al: Population comparison of two clinical approaches to the metabolic syndrome. Diabetes Care 2005;28:2777-2779.

8 Liao Y, Kwon S, Shaughnessy S, et al: Critical evaluation of adult treatment panel III in identifying insulin resistance with dyslipidemia. Diabetes Care 2004;27:978-983.

9 Hanley AJG, Wagenknecht LE, D'Agostino RB, et al: Identification of subjects with insulin resistance and p-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes 2003;52:2740-2747.

10 Cheal KL, Abbasi F, Lamendola C, et al: Relationship to insulin resistance of the adult treatment panel III diagnostic criteria for identification of the metabolic syndrome. Diabetes 2004;53:1195-1200.

11 McLaughlin T, Abbasi F, Cheal K, et al: Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med 2003;39:802-809.

12 Staels B, Fruchart JC: Therapeutic roles of peroxisome proliferators-activated receptor agonists. Diabetes 2005;54:2460-2470.

13 Rizza RA, Mandarino LJ, Gerich JE: Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 1981;240:E630-E639.

14 Nurjhan N, Campbell PJ, Kennedy FP, et al: Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 1986;35:1326-1331.

15 Boden G, Laakso M: Lipids and glucose in type 2 diabetes. What is cause and effect. Diabetes Care 2004;27:2253-2259.

16 Hall JE, Brands MW, Zappe DH, Alonso Galicia M: Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations? Proc Soc Exp Biol Med 1995;208:317-329.

17 Hanley AJG, Karter AJ, Festa A, et al: Factor analysis of metabolic syndrome using directly measured insulin sensitivity. The insulin resistance atherosclerosis study. Diabetes 2002;51: 2642-2647.

18 Tomlinson JW, Moore JS, Clark PMS, et al: Weight loss increases 11p-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J Clin Endocrinol Metab 2004;89: 2711-2716.

19 Taskinen MR: Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-749.

Discussion

Dr. Bantle: Could you say a little bit about the associations between the different definitions of metabolic syndrome and cardiovascular disease? It would seem to me that the definition to use is the one that is the best predictor of events.

Dr. Sauerwein: In my presentation I showed data that in Finland the European standards are better, but that in Holland, despite being close to Finland, the American ones are better predictors of cardiovascular disease, indicating that we need to redefine our diagnostic criteria. For reliable prediction and comparison of published data we need one definition. That is why the International Diabetes Federation (IDF) came up with a lot of new data, but they include so many things that we have to wait for proof of their validity.

Dr. Bantle: Is there any evidence that this definition works as a predictor of future events?

Dr. Sauerwein: It was just promoted. There is always a debate between the people who are in charge of one definition and those defending the other one.

Dr. Katsilambros: If I understood properly, you said that bariatric surgery does not improve hypertension. There is the so-called SHO study, a Scandinavian obesity study, which is perhaps the largest in the world and with a long follow-up, in which different kinds of operations were performed. After 2, 6 and 8 years the hypertension rate was lower when compared to the starting point before operation. However, after 10 years the rate again increased back to the beginning [1]. But even 10 years after the operation these people were still considerably obese and any benefit was not very lasting, and also, at least in this population, aging was another factor adding to the prevalence and incidence of obesity. So in my opinion at least, your statement about there being no relation to hypertension with regard to bariatric surgery is perhaps not the best way to express that, but I may be wrong.

Dr. Sauerwein: The data I showed are from that Swedish study. What the slide showed is that the incidence of hypertension has returned to baseline after 10 years. When insulin resistance is the common denominator, this dissociation cannot occur unless, as you suggested, a new mechanism for the induction of hypertension develops in this time period. This is a possibility, but pathophysiological data in favor of this are lacking. I think that other mechanisms like local cortisol production in abdominal fat deserve real consideration. Many people are considering insulin resistance and metabolic syndrome to be more or less synonymous. I am of the opinion that we need a more subtle approach.

Dr. Chiasson: I thought that your discussion was very interesting, and certainly Kahn et al. [2] have gone through this questioning of the metabolic syndrome. I think it is good that we raise questions about whether this is really a metabolic syndrome or just factors that are in parallel but totally independent, or whether they have a common background. So if I understand correctly, insulin resistance may not be the common denominator but you believe that the free fatty acids (FFAs) could be. FFA requires obesity to increase the plasma level. I was just wondering if the increase in FFA in obesity or under any other circumstances was not in fact due to insulin resistance, because otherwise you would expect the physiological level of insulin to be able to maintain inhibition on lipolysis. How do you explain this discrepancy that you are trying to propose?

Dr. Sauerwein: What I did not share with you is that fat in the diet has no influence on insulin resistance. I was part of a study were we consumed eucaloric diets with either 85% fat or 85% carbohydrate as the energy source for 14 days without hardly any induction of insulin resistance [3, 4]. The same holds true for diabetics [5]. So it is not just the fat or (FFA) fatty acids themselves, but the induction of obesity with excess fatty acids taken up by muscle, p-cells, etc., that induces insulin resistance. Induction of insulin resistance will induce a vicious cycle in which insulin resistance will stimulate FFA release, as you described. This will aggravate insulin resistance. However the starting point must be excess intake and obesity. Eucaloric fat intake is less of a problem.

Dr. Chiasson: I am not sure I understand correctly. I was under the impression that deposition of fat and triglyceride in the muscle and other tissues was related to insulin resistance and the increase in FFA in the circulation.

Dr. Sauerwein: This is true, but what I want to stress are the initial changes. Most of the studies are cross-sectional, ignoring the sequence of events. Confusion can also be ascribed to definition problems. A high fat diet is sometimes called a eucaloric diet with a high percentage of fat in it, but more frequently a hypercaloric diet has additional fat. This distinction is not always made, but is important as our data show.

Dr. Hill: You emphasized the importance of adipose tissue. We used to think that adipose tissue was pretty uninteresting and now we know it secretes many interesting products. Do you think products coming from fat cells will be found to be helpful in understanding the metabolic syndrome?

Dr. Sauerwein: This is a confusing area. You have to realize that morbid obesity is not always synonymous with major metabolic abnormalities. About 20% of the morbidly obese subjects are metabolically healthy [6]. I am not aware of any study focusing on the differences in expression of all those factors in morbidly obese subjects with and without major metabolic abnormalities, but I am convinced that the hormones produced by adipose tissue will have a major influence. However, I think it is too early now to make a statement about this.

Dr. Ditschuneit: Do you think that lipolysis and concentrations of FFAs may be a target for treating metabolic syndrome?

Dr. Sauerwein: Inhibition of lipolysis improves insulin resistance [7]. However suppression of lipolysis is only part of the story. The main problem is excess intake. With excess intake FFA will be stored in adipose tissue and muscle, inducing insulin resistance [8]. Even storage in adipose tissue, beyond a certain amount, induces insulin resistance, as adipose tissue increasing in size will attract macrophages [9]. This will induce a kind of local inflammation, increasing the degree of insulin resistance [10].

Dr. Slama: I think that there is ambiguity about the metabolic syndrome explaining the controversy, which is where we are now. The point is that the metabolic syndrome was first recognized by clinicians as a cluster of signs and symptoms associated with more complications in the future, all the complications we know. Then it was decided that the definition needs to have thresholds so that it is easier to recognize such a symptom. Now we ask, is that the best way to predict diabetes? Is that the best way to predict cardiovascular disease? Of course not. There is a very good equation, the Framingham equation, to predict cardiovascular complications; then there is a better equation, the score put forward by Hafner, to predict diabetes but it was not intended for that. The proposal that metabolic syndrome causes complications does not mean that the reverse is true. We don't want to say that the definition of metabolic syndrome is the universal way to diagnose or predict diabetes or cardiovascular disease; we say that a cluster of people or a subgroup of people affected by such and such signs will be at a higher risk of cardiovascular disease and diabetes. In other words, I think that in the natural history between a normal situation toward vascular complications or diabetes, there is something which is early on, which is a definition of the metabolic syndrome at the very beginning, then the disease progresses and then Framingham or other predictors are better indicators, but on the shorter run. On the long run perhaps when it is time to put preventive measures into action, it is the metabolic syndrome, and for Framingham and such this is the time not of prevention but of early treatment. What is your opinion?

Dr. Sauerwein: I completely agree with you. It is a cluster of abnormalities, nothing less, but definitely nothing more.

Dr. T. Wilkin: I think one of the difficulties is that we impose the problem upon ourselves. We apply categorization to what are continuous variables. If there are 4 or 5 continuous variables and we apply categorization then individuals are bound to have very different levels, some of which will satisfy the categories and others which won't. As long as we try to categorize what is continuous, we are going to have this problem.

Dr. Sauerwein: I agree.

Dr. Chieh Chou: I have a question related to the role of obesity in metabolic syndrome because in the case of diabetes with obesity, in patients with moderate weight loss, an improvement in the disease is often seen. So perhaps removing fat from the liver or muscle would really improve insulin resistance. What do you think?

Dr. Sauerwein: I agree. When people are storing their fat in the only place where it should be (in certain subcutaneous areas), they have no problems related to glucose intolerance. Translocation of fat by thiazolidediones to those areas improves glucose tolerance even despite the well-known increase in body weight [11]. Another problem is the unexplained relationship between abdominal obesity and insulin resistance. It was always thought that FFAs flowing from the intra-abdominal cavity to the liver would induce insulin resistance, but quantitatively the contribution of the intra-abdominal-based FFA to total FFA flux proved to be around 20% [12].

Dr. Mingdao Chen: The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) statement for 'metabolic syndrome' is quite different from that of the IDF. The ADA and EASD tried to say that the metabolic syndrome is only a cluster of a few factors or risks, it is not even a syndrome. However, a syndrome means several different signs and symptoms together, a situation surely suited to the metabolic syndrome. Which definition do you support?

Dr. Sauerwein: I think it is a cluster of a few factors, which have proven in the past to be predictors of cardiovascular disease. In that sense it is alright, but we should not draw pathophysiological conclusions from epidemiological data.

Dr. Mingdao Chen: Perhaps they just mean this is not a disease.

Dr. Sauerwein: Yes, that is what I tried to say.

Dr. Slama: One of the difficulties with the metabolic syndrome is blood pressure. The definition of metabolic syndrome gives a blood pressure of >130 mm Hg, but the situation is absolutely not the same if the blood pressure is 130 or 180 mm Hg. In both cases the definition is upheld, but 130 mm Hg would be normal for people other than those with a cluster, and 180 mm Hg is abnormal whether cluster or no cluster. So for me the real interest of the definition of the metabolic syndrome is those people who have all or most of the items of the cluster in the near normal range but become abnormal because they have a cluster. Of course if a patient has a blood pressure of 180 mm Hg, a blood glucose of 200, 5g triglyceride, he doesn't need to be labeled metabolic syndrome, he is badly sick. So the real interest of the metabolic syndrome is those who are just close to the thresholds and will not be considered as having a disease point by point, item by item, but are really affected because they have most of them.

Dr. Sauerwein: That is absolutely correct, but the problem is that this is being ignored in the literature.

References

1 Sjostrom L, Lindroos AK, Peltonen M, et al, Swedish Obese Subjects Study Scientific Group: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-2693.

2 Kahn R, Buse J, Ferrannini E, Stern M, American Diabetes Association, European Association for the Study of Diabetes: The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-2304.

3 Bisschop PH, Pereira Arias AM, Ackermans MT, et al: The effects of carbohydrate variation in isocaloric diets on glycogenolysis and gluconeogenesis in healthy men. J Clin Endocrinol Metab 2000;85:1963-1967.

4 Bisschop PH, de Metz J, Ackermans MT, et al: Dietary fat content alters insulin-mediated glucose metabolism in healthy men. Am J Clin Nutr 2001;73:554-559.

5 Allick G, Bisschop PH, Ackermans MT, et al: A low-carbohydrate/high-fat diet improves glucoregulation in type 2 diabetes mellitus by reducing postabsorptive glycogenolysis. J Clin Endocrinol Metab 2004;89:6193-6197.

6 Sims EA: Are there persons who are obese, but metabolically healthy? Metabolism 2001;50: 1499-1504.

7 Bajaj M, Suraamornkul S, Romanelli A, et al: Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients. Diabetes 2005;54:3148-3153.

8 Miles JM, Park YS, Walewicz D, et al: Systemic and forearm triglyceride metabolism: fate of lipoprotein lipase-generated glycerol and free fatty acids. Diabetes 2004;53:521-527.

9 Weisberg SP, McCann D, Desai M, et al: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-1808.

10 Xu H, Barnes GT, Yang Q, et al: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-1830.

11 Mayerson AB, Hundal RS, Dufour S, et al: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002;51:797-802.

12 Miles JM, Jensen MD: Counterpoint: visceral adiposity is not causally related to insulin resistance. Diabetes Care 2005;28:2326-2328.

Bantle JP, Slama G (eds): Nutritional Management of Diabetes Mellitus and Dysmetabolic Syndrome. Nestlé Nutr Workshop Ser Clin Perform Program, vol 11, pp 15-29, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2006.

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