• Some historical aspects on the Metabolic Syndrome
• Insulin resistance: the link between obesity and metabolic complications
• Defining the Metabolic Syndrome: an urgent need for an universal definition
• References

Some historical aspects on the Metabolic Syndrome

The contemporary definition of the Metabolic Syndrome refers to a cluster of metabolic abnormalities related to a state of insulin resistance which is often associated with a high-risk overweight/obesity phenotype. Because such cluster increases the risk of coronary heart disease (CHD) and type 2 diabetes, numerous consensus groups have attempted to provide recommendations to identify in clinical practice patients with these atherogenic/diabetogenic metabolic abnormalities. Although there has been an exponential proliferation of scientific papers and conferences on the Metabolic Syndrome, the concept of a cluster of abnormalities such as obesity, diabetes, dyslipidaemia and hypertension is not new and several physicians/investigators have contributed to the development of such concept through astute clinical observations or epidemiological/metabolic studies.

Insulin resistance: the link between obesity and metabolic complications

Obesity is obviously a prevalent cause of diabetes, dyslipidaemia and hypertension. However, because of its remarkable heterogeneity, it has been a puzzling condition which left physicians perplexed at times. Professor Jean Vague from the University of Marseille was the first to propose more than 40 years ago, that body fat topography was a better correlate of the complications of obesity (diabetes, hypertension, cardiovascular diseases) than excess fatness per se. 1 Vague used the term "android obesity" to define the pattern of fat distribution mostly characterized by an accumulation of adipose tissue over the trunk whereas he referred to the lower body fat pattern commonly found in women as "gynoid obesity" where adipose tissue accumulates mostly around the hips and thighs (Figure 1). He was really the first to suggest that lower body obesity was seldom associated with complications expected from an excess of body fat. However, it took a while before these remarkable clinical observations were confirmed by a series of studies conducted by several research groups over the last 20 years. Nevertheless, a few investigators had reported in the 60’s data suggesting a link between obesity, insulin resistance and related complications. For instance, Albrink and Meigs 2 reported an association between trunk fat and hypertriglyceridaemia. Avogaro and colleagues 3 documented the simultaneous presence of obesity, hyperinsulinaemia, hypertriglyceridaemia and hypertension. Welborn et al 4 should also receive credit for their early report on the links between hyperinsulinaemia, hypertension and peripheral vascular disease.

In the early 80’s, the late Per Björntörp from the University of Gothenburg in Sweden had come across Vague’s literature and he took advantage of the availability of anthropometric variables such as waist and hip circumferences to develop a simple index of body fat distribution, the waist to hip ratio (WHR). 5-8 Having access to two prospective studies of middle-aged men and women, the Swedish team found that the proportion of abdominal fat (as crudely appreciated by the WHR) was an independent risk factor for the development of cardiovascular diseases and diabetes over a follow-up period of more than a decade. 5,6 Simultaneously, in the United States, Ahmed Kissebah and his group9 had reported results emphasizing the importance of regional adipose tissue distribution as an important correlate of glucose intolerance, hyperinsulinaemia and hypertriglyceridaemia as these abnormalities were more frequently observed in the presence of upper than lower body obesity. These consistent results published in the early 80’s have generated a great deal of interest from the scientific and medical community. Therefore, a flourishing and abundant literature has been published on the topic since the mid-eighties.

For instance, Modan and colleagues proposed that hyperinsulinaemia could be the common element accounting for the relationship between obesity, type 2 diabetes and hypertension. Obesity and type 2 diabetes were also two conditions characterized by an insulin resistance state. 11 Ferrannini et al12 proposed that essential hypertension per se was an insulin resistance state. He proposed that insulin resistance involved glucose but not lipid or potassium metabolism that it was observed in peripheral tissues but not in the liver and that it was directly correlated with the degree of hypertension.

The concept of a constellation of abnormalities linked to insulin resistance as a key component was really pioneered, however, by Reaven 13 at the Banting lecture of the American Diabetes Association annual meeting in 1988. Reaven introduced the concept that an impaired in vivo insulin action was a central component of a cluster of metabolic abnormalities that did not necessarily include classical risk factors such as raised LDLcholesterol but rather comprised elevated triglyceride concentrations, low HDLcholesterol, fasting hyperinsulinaemia and elevated blood pressure (Figure 2). Obesity was not included as a feature of his “insulin resistance syndrome”, since Reaven argued that he could find insulin resistant subjects among nonobese individuals. Reaven referred to this agglomeration of metabolic complications as Syndrome X.

In another key lecture of the same meeting, DeFronzo 14 underlined the importance of a triumvirate of skeletal muscle, liver and beta-cell abnormalities in the aetiology of type 2 diabetes. He did emphasize that skeletal muscle insulin resistance was an essential element in the pathophysiology of type 2 diabetes. In addition, he indicated that an insulin resistant liver leading to increased hepatic glucose production would contribute to explain the glucose intolerance of these insulin resistant individuals. However, as insulin resistance can be frequently observed in nondiabetic individuals, DeFronzo also emphasized that a relative deficit in beta-cell insulin secretion capacity was essential to observe the conversion from an insulin resistant state to type 2 diabetes. Thus, if beta cell function was maintained, several insulin resistant individuals would never develop type 2 diabetes. Since then, DeFronzo has also included in his model the key role of adipose tissue-insulin resistance and related alterations in free fatty acid metabolism (Figure 3). 15

With the development of imaging techniques to precisely measure abdominal fat and to particularly distinguish intra-abdominal (visceral) from subcutaneous fat, several studies have shown that abdominal fat accumulation accompanied by an excess of visceral adipose tissue was predictive of the features of the Metabolic Syndrome irrespective of total adiposity indices, the most commonly used in clinical practice being the body mass index (BMI) (Figure 4). For instance, results from two pioneering groups in the world involved in the study of body fat distribution quantified by a sophisticated technique (computed tomography), have clearly established the critical contribution of visceral fat accumulation to the development of metabolic disorders including dyslipidaemia, impaired glucose-insulin homeostatis, a prothrombotic state and a proinflammatory profile. 16-19 Thus, an apparently normal weight individual with to much visceral fat would nevertheless be insulin resistant and show the features of the Metabolic Syndrome explaining why Reaven could find insulin resistant normal weight individuals.

Recently, there has been an even greater interest in the medical community since the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) identified the Metabolic Syndrome as a multiplex risk factor especially for cardiovascular diseases and type 2 diabetes which should deserve more clinical attention. 20,21 Moreover, the NCEP-ATP III identified six key components of the Metabolic Syndrome that are most closely related to cardiovascular diseases: abdominal obesity, atherogenic dyslipidaemia, hypertension, glucose intolerance/insulin resistance, proinflammatory state and prothrombotic state. 21 Among the clinical criteria proposed by the NCEP-ATP III to identify subjects with the Metabolic Syndrome, an elevated waist circumference as an index of abdominal obesity has been proposed rather than BMI as an indicator of overall obesity (Table). 20 Thus, the NCEP-ATP III criteria do recognize the importance of abdominal obesity as the form of obesity most strongly associated with the Metabolic Syndrome as well as a the driving force responsible for the epidemic proportions reached by the prevalence of the Metabolic Syndrome.

Some controversies remain around the role played by insulin resistance vs. abdominal obesity and organisations such as the International Diabetes Federation, the World Health Organisation, the American Association of Clinical Endocrinologists and the European Group for the study of Insulin Resistance have initially failed to align themselves to NCEP-ATP III as these organisations consider that insulin resistance was the key central component.

Defining the Metabolic Syndrome: an urgent need for an universal definition

In order to reduce the confusion in the medical community, universal agreement on the definition and clinical tools to assess the Metabolic Syndrome would be very helpful and efforts for additional international consensus activities have been made. Recent meetings have contribute to emphasize the notion that even if insulin resistance is indeed at the core of the Metabolic Syndrome, abdominal obesity is by far the most prevalent form of the Metabolic Syndrome. Therefore, to dissociate abdominal obesity/insulin resistance would be for the time being of little help. We should rather work on cut-off values proposed for the various clinical tools used to optimally discriminate for the presence of the Metabolic Syndrome in several population of the world.

References

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2. Albrink MJ, Meigs JW. The relationship between serum triglycerides and skinfold thickness in obese subjects. Ann N Y Acad Sci 1965;131:673-83.

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