Editorial Current Vascular Pharmacology, 2014, Vol. 12, No. 4 549
Editorial
The Changing Face of Metabolic Syndrome and its
Components in the Light of Current Knowledge
Sibel Ertek
1and Maciej Banach
21
Department of Endocrinology and Metabolism, Ufuk University Medical Faculty, Ankara, Turkey;
2Department of
Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland
Keywords: Metabolic syndrome, cardiovascular
disease.
The metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular (CV) disease and diabetes [1]. However, the
contribution of each MetS component on the overall risk has been the subject of debate [2, 3]. Recently, new factors involved in
the pathophysiology of the MetS have been recognised. For example, chronic stress and dysregulation of the
hypothalamic-pituitary-adrenal axis including glucocorticoid actions and ‘’Omental Cushing’’, autonomic nervous system, cellular oxidative
stress, renin-angiotensin system activity and microRNAs [4-7]. The main components have also been re-evaluated in the light
of new findings.
Regarding dyslipidemia - we have learned more about the normal physiology and pathophysiology of lipoprotein
metabo-lism such as the importance of subgroups/subpopulations of low-density (LDL) and high-density lipoproteins (HDL) [8, 9] and
‘’HDL quality’’ (‘dysfunctional HDL’) [10, 11]. These advances have contributed to new treatment options as reviewed by
Filippatos et al. [12]. Besides drug combinations with known agents and apheresis, the use of viral vectors, microsomal
trans-port protein inhibitors, antisense oligonucleotides are on the way for hypertriglyceridemia treatment [12].
For all components of MetS, lifestyle modifications are the first-line management [13]. Due to cost-effectiveness issues,
drug side effects and other factors, alternative options also need to be considered for patients at “low” risk that do not qualify
for conventional pharmacological intervention [14]. In such patients, nutraceuticals are an option. Physicians should be aware
of these possibilities (preferably targeting more than one MetS component) and potential risks associated with their use [15].
Omega-3 fatty acids, cinnamon, berberine and psyllium are examples of such therapies with increasing clinical evidence [15].
Katsiki
et al. review several factors (other than the diagnostic criteria) associated with MetS [16]. These include waist to hip
ratio, HDL dysfunction, small dense LDL, postprandial hypertriglyceridemia, lipoprotein (a), uric acid, hepatic tests,
throm-botic factors, cytokines, adipokines, vitamin D, arterial stiffness, renal dysfunction, nephrolithiasis, polycystic ovary syndrome,
and obstructive sleep apnea. These factors interact with several MetS components [16-18].
The kidney is a target for damage due to hypertension and hyperglycemia. The kidney also interacts with non-diagnostic
MetS components such as uric acid metabolism [19]. Furthermore, the increasing population at risk for chronic kidney disease
(CKD) and the cost-effectiveness of CKD prevention suggests as that the pre-CKD stage should also be considered [14, 20].
Michalska
et al. discussed the evidence for diagnosis and treatment of pre-hypertension (pre-HT) (and high normal blood
pressure [BP]) [14]. BP increase is linearly related to increased mortality and CV morbidity [14] and pre-HT patients usually
have other MetS components and CV risk factors [21-23]. The available trials, including Trial of Preventing Hypertension
(TROPHY) and Prevention of Hypertension with the ACE inhibitor Ramipril in Patients with High Normal Blood Pressure
(PHARAO) [24, 25] have not provided enough evidence for pharmacological treatment of pre-HT. More and more evidence
suggests that the pre-HT definition should not have been introduced [14].
Similar to pre-HT, pre-diabetes is also discussed in this special issue. Recent studies have suggested the possible benefits of
early insulin treatment (EIT), including possible “remission” of diabetes [26]. However, the Outcome Reduction with an Initial
Glargine Intervention (ORIGIN) study did not show any benefit of insulin treatment for pre-diabetes [27]. There is still no large
comparative study on newly diagnosed diabetics, to test any benefit of insulin by early correction of glucotoxicity. In their
re-view, Ertek et al. discussed another interesting point - that after correction of glucotoxicity with insulin in selected patients,
treatment with oral antidiabetic drugs could be possible [26]. Although the patient selection criteria are still not clear, this
pos-sibility suggests that in the future the treatment of diabetes may vary for different groups of patients (i.e. more individualized)
[26].
Insulin resistance in patients with MetS is considered to exert important metabolic and peripheral effects [28, 29]. In fact,
insulin can influence nervous tissue and insulin resistance in the periphery may have some central implications. Some studies
on Alzheimer’s disease (AD) suggest the possible role of insulin resistance in the pathophysiology of AD, and even the term
“type 3 diabetes” was proposed for this neurodegenerative disease, selectively involving brain tissue [30]. Cetinkalp et al.
re-viewed the possible effects of insulin on the brain and possible therapeutic approaches for insulin resistance in brain tissue [31].
550 Current Vascular Pharmacology, 2014, Vol. 12, No. 4 Editorial
Pre-HT, pre-diabetes and dyslipidemia have many interrelationships and each new study on MetS might increase our
knowl-edge on the pathophysiology of MetS and its management. In the recent Italian Brisighella Study the authors showed the serum
LDL and apolipoprotein B levels were significantly related with BP in untreated sample of more than 2400 patients, and this
relationship was stronger in young people [32]. Same groups also reported a slight but significant beneficial effect of statins on
BP, depending on patient age, gender, pre-treatment lipid parameters and baseline BP [33-37]. However, a recent meta-analysis
has not confirmed that effect, suggesting that the reduction of CV events in hypertensive patients is not connected to a BP
reduction by statins [38]. Another possible link may exist between diabetes and hypertension. In the Anglo-Scandinavian
Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA), in which 19,257 patients were enrolled, systolic BP
was one of the main predictors of diabetes [39]. In another study the significance of high BP in predicting incident diabetes was
influenced by the baseline body mass index (BMI) and fasting glucose levels in the group of 14,054 non-diabetic Korean
sub-jects, suggesting the important role of obesity and insulin resistance [40]. Other trials [41, 42] showed that the reduced
inci-dence of diabetes with renin-angiotensin system blocking agents, possibly involves the renin-angiotensin-aldosterone system.
Adipocyte and endothelial dysfunction-related mechanisms, which have still not been not clearly defined, may also influence
the link between hypertension and diabetes [43].
The studies on associations between vitamin D, cytokines and adipokines with MetS were reviewed by Katsiki et al. [16].
Another interesting mechanism may be related to the pathophysiology of obesity, as discussed in the review by Cetinkalp et al.
where they described the intracerebral action of hyperinsulinemia on appetite [31]. Gut hormones and adipokines may also play
important roles on hypothalamic appetite centers and hypothalamic factors may even influence pancreatic beta-cell function
(possibly via corticotropin-releasing factor) [44]. Therefore, on the basis of the recent data MetS cannot be considered as a
sim-ple cluster of risk factors based on abdominal obesity with increased CV risk, but as a comsim-plex combination of pathologies
in-cluding metabolic-neurohormonal-endothelial and humoral systems (Fig. 1). Muscle tissues behave like an endocrine organ
during regular exercise and the exercise-induced cytokine cascade causes an increase of interleukins (IL) - IL-6, IL-1ra, IL-19
and soluble tumor necrosis factor receptor (sTNF-R), creating an anti-inflammatory environment [45-48]. Recent studies have
also suggested a paracrine role for periadventitial adipose tissue in the control of arterial vascular tone [49]. This regulation
depends on the anatomical integrity of the vessels and involves adipokines released from either periadventitial adipocytes or
perivascular adipose tissue, especially adipocyte-derived relaxing factor (ADRF) [49]. Therefore, “adipose and muscle tissue
cross-talk” via adipo- and myokines may become relevant in future treatment approaches for MetS. More updated information
on factors relevant to the pathogenesis of MetS may also be provided by expert panel overviews as published in this journal
[50-52].”
Fig. (1). New understanding of the pathophysiology of metabolic syndrome.
Recent studies have improved the current knowledge of MetS, which should no longer be considered as a simple cluster of
diagnostic characteristics (Fig. 1). We hope that this special issue of Current Vascular Pharmacology will contribute to a better
understanding of MetS. Enjoy reading this issue!
Adipocytes &
adipokines
Increased leptin and insulin, decreased adiponectin, increased resistin, changes in omentin, vaspin, visfatin,
adipocyte‐derived relaxing factor (ADRF) action on
blood vessels
Myocytes & myokines
IL‐6 increases hepatic glucose production during exercise and lipolysis in adipose tissue,
IL‐8 decrease adipose tissue mass, finally creation of
antiinflammatory environment, decreased resistin by physical activity
Pancreas & liver
Insulin resistance, central effects of insulin on neurons and apetite
centers, vitamin D‐related mechanisms, lipoprotein metabolism
with endothelial interaction
Brain and hypothalamo‐
hypophysial axis
Regulation of apetite, sympathetic nervous system
and hormonal actions
Cardiovascular system
Kidneys
Renin‐angiotensin‐ aldosteron system, sodium
Editorial Current Vascular Pharmacology, 2014, Vol. 12, No. 4 551
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
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