1. Syndrome X: A Tribute to a Pioneer, Gerald M. Reaven
Most clinicians and health professionals have heard or read about metabolic syndrome.
For instance, as of October 2020, entering “metabolic syndrome” in a PubMed search
generated more than 57,000 publications since the introduction of the concept by Grundy
and colleagues in 2001 [1]. Although many health professionals are familiar with the
five criteria proposed by the National Cholesterol Education Program-Adult Treatment
Panel III for its diagnosis (waist circumference, triglycerides, high-density lipoprotein
(HDL) cholesterol, blood pressure and glucose), how these variables were selected
and the rationale used for the identification of cut-offs remain unclear for many
people. In addition, the conceptual definition of metabolic syndrome is often confused
with the tools (the five criteria) that have been proposed to make its diagnosis [2,3].
In the seminal paper of his American Diabetes Association 1988 Banting award lecture,
Reaven put forward the notion that insulin resistance was not only a fundamental defect
increasing the risk of type 2 diabetes, but he also proposed that it was a prevalent
cause of cardiovascular disease [4]. The latter point was a paradigm shift as cardiovascular
medicine had, at that time, a legitimate focus on cholesterol in risk assessment and
management. Reaven was therefore the first to propose that insulin resistance was
a central component of a cluster of abnormalities which included hyperinsulinemia,
dysglycemia, high triglycerides, low HDL cholesterol and elevated blood pressure.
Under his theory, this constellation of abnormalities would not only increase the
risk of type 2 diabetes but would also be a complex risk factor for cardiovascular
outcomes, even in the absence of type 2 diabetes. Reaven initially referred to this
condition as syndrome X. However, as there is also a syndrome X in cardiology [5,6]
and because insulin resistance is a core component of Reaven’s syndrome, insulin resistance
syndrome was a term that then gained popularity in the literature [7,8].
As measuring insulin resistance or circulating insulin levels was not considered as
feasible on a large scale in clinical practice, a group of experts then examined whether
it could be possible to identify insulin-resistant individuals with common clinical
tools widely used in primary care [1]. Because of the strong link between abdominal
obesity and insulin resistance, the panel thus agreed on the use of waist circumference
as a crude index of abdominal adiposity and then proposed sex-specific waist cut-off
values [1]. However, these waist circumference thresholds were based on the relationship
between waist circumference and body mass index (BMI) values defining obesity (men:
102 cm = 30 kg/m2 and women: 88 cm = 30 kg/m2) [9]. Thus, waist circumference thresholds
were simply determined from BMI values defining obesity and, most importantly, were
not based on clinical outcomes. In addition, because waist circumference and BMI are
correlated [10], an elevated waist girth, observed in isolation, cannot properly assess
abdominal fat accumulation [11]. For instance, a waist circumference of 104 cm in
a middle-aged man with a BMI of 26 kg/m2 is not the same adiposity phenotype as an
age-matched man with the same waist girth but with a BMI of 32 kg/m2. In this specific
example, the man with a BMI of 26 kg/m2 is clearly abdominally obese (high-risk form
of obesity) whereas the man with a BMI of 32 kg/m2 is mostly characterized by overall
obesity. This is why a recent consensus paper on the use of waist circumference in
clinical practice has proposed that waist circumference should not be measured as
a single adiposity index but rather interpreted along with the BMI in order to properly
discriminate abdominally obese (higher risk) from overall obese (lower risk) persons
[11].
Regarding simple metabolic markers of insulin resistance and other indices of metabolic
syndrome, triglycerides, HDL cholesterol levels and blood glucose are easily obtained
from routine clinical biochemistry laboratories, whereas blood pressure is measured
in primary care. On that basis, it was proposed that individuals showing any combination
of any three out of these five simple clinical criteria were likely to be characterized
by insulin resistance. Prospective analyses have also shown that any combination of
these factors was predictive of an increased risk of both type 2 diabetes and cardiovascular
disease [12,13,14,15,16,17].
As it had also been suggested that the waist cut-offs initially proposed were probably
too high, their values were thereafter lowered in harmonized criteria proposed by
other organizations [18]. Studies have shown that subgroups of individuals meeting
or not meeting the clinical criteria of metabolic syndrome (harmonized or not) were
quite distinct from each other in terms of risk of type 2 diabetes and cardiovascular
disease [12,13,14,15,16,17]. Of course, using different waist circumference cut-off
values generated different prevalence values but the subgroups identified were nevertheless
found to show different levels of risk.
2. From Syndrome X, Insulin Resistance/Metabolic Syndrome to Excess Visceral Adiposity
Because Reaven could find nonobese individuals with insulin resistance and individuals
with obesity who were insulin sensitive, he did not include obesity in his initial
definition of syndrome X. In that regard, early imaging studies measuring adiposity
with the use of computed tomography initially conducted by Matsuzawa and colleagues
and by ourselves suggested that there was a remarkable heterogeneity in abdominal
fat accumulation (visceral vs. subcutaneous) [19,20]. Additionally, subgroup analyses
revealed that there was substantial variation in glucose tolerance as well as in plasma
insulin and lipoprotein levels among equally overweight or obese individuals characterized
by low or high levels of visceral adipose tissue [21,22,23,24]. Since then, many large
cardiometabolic imaging studies have shown that an excess accumulation of visceral
adipose tissue (and not of subcutaneous fat) was a key correlate of the features of
insulin resistance, explaining why Reaven could not find a robust association between
total body fatness and his syndrome X: it was all about body fat distribution [2,3,25,26,27,28,29,30,31].
3. Liver Fat: A Key Partner in Crime in Visceral Obesity
More recently, with the availability of magnetic resonance spectroscopy, it has become
possible to noninvasively measure with great accuracy liver fat accumulation. With
the use of this technique, excess liver fat has been found to be associated with essentially
the same clustering metabolic abnormalities as those observed in visceral obesity
[32,33,34]. It is important, however, to point out that excess liver fat in isolation
(in the absence of excess visceral adipose tissue) is a relatively rare phenomenon
as its most frequent form is accompanied by high levels of visceral adipose tissue
[35,36,37]. Thus, it has recently become obvious that the most dangerous adiposity
phenotype includes excessive amounts of both visceral adipose tissue and liver fat,
which is by far the most prevalent form of insulin resistance or metabolic syndrome
[31]. On that basis, we have proposed that the clustering abnormalities of excess
visceral adiposity/liver fat for which insulin resistance is a key feature should
be called Reaven syndrome [3,38].
4. This Issue
Despite the progress made in our understanding of the constellation of atherogenic
and diabetogenic abnormalities found in the subgroup of individuals with excess levels
of visceral adipose tissue and liver fat, many questions remain regarding their etiology
and the most efficient approaches to prevent or to manage it.
Some of these questions are examined in this special issue of Nutrients. The reader
will find a mix of narrative reviews and communications written by well-published
investigators, top international experts in the field. We are very grateful to these
experts who have agreed to contribute to this issue [39,40,41,42,43,44,45,46,47,48,49].
Original papers that are relevant to our theme are also included [50,51,52,53,54,55,56,57,58,59].
As expected from the topics covered in Nutrients, this issue deals mostly with dietary
factors, although some other important lifestyle features, such as physical activity/exercise
and sleeping habits, are addressed. Both individual- and population-based solutions
are discussed. For instance, the link between dietary fat as well as dietary fructose
and sugar-sweetened beverages and some chronic diseases is reviewed. Considering the
importance of physical activity/exercise and cardiorespiratory fitness in the prevention
and treatment of features of metabolic syndrome, some papers review the literature
relevant to these topics. Moreover, other papers deal with the assessment of metabolic
syndrome in various age and ethnic groups. Finally, other highly relevant themes are
explored, such as sleep habits, sleep apnea and the development of metabolic syndrome
and lifestyle habits, the endocannabinoidome and features of metabolic syndrome.
5. The Future
Of course, it was not possible to cover all topics relevant to the assessment, prevention
and management of such a complex modifiable risk factor which results from the interaction
of genetic and environmental/lifestyle factors. The established relationship between
the presence of metabolic syndrome and the development of type 2 diabetes and cardiovascular
disease has been amply demonstrated, but the interest around metabolic syndrome and
visceral obesity is renewed as it has also been related to other chronic diseases,
such as brain health and some types of cancer [60,61]. Numerous studies are currently
under way to confirm these relationships, to elucidate the underlying mechanisms or
even to examine whether lifestyle intervention habits could prevent these diseases
and improve their treatment. As we are going through a major epidemic of chronic lifestyle
diseases, metabolic syndrome, although criticized as a concept, has been helpful as
a screening approach to better identify a subgroup of high-risk individuals who would
benefit from clinical and population-based approaches targeting their lifestyle habits.
Finally, with the relatively new concept of precision lifestyle medicine, which consists
of simultaneously taking into account the individual’s genetic profile as well as
his/her living environments and lifestyle habits [62], we propose that the multiplex
modifiable risk factor that represents metabolic syndrome will require concerted efforts
between clinical approaches and public health solutions if we want to reduce the burden
associated with this condition. We hope that the content of this Special Issue will
be found useful.