Pre-Metabolic Syndrome and Metabolic Syndrome: Biophysical-Semeiotic Viewpoint
Sergio Stagnaro MD. Biophysical Semeiotics Reaearch Laboratory, Via Erasmo Piaggio 23/8, 16039 Riva Trigoso (Genoa) Italy, Tel: (+39) 0185-42315, E-mail: firstname.lastname@example.org
Despite the alarming prevalence of the metabolic syndrome and the magnitude of risk it confers, defining the pathogenic links between the metabolic syndrome and cardiovascular disease, as all authors generally agree, has been difficult, and even the question of whether they are united by some common underlying patho-physiology remains a matter of intense debate.
I recently criticized  the Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes , underscoring some paramount points, always overlooked. As a matter of fact, because of my 53 years in clinical experience, I partially agree with the authors who have been researching in the field of metabolic syndrome. Some among them rightly underscore “that too much critically important information is missing to warrant its designation as a syndrome” .
In fact, now clinicians should evaluate and treat all CVD risk factors, without regard to whether a patient meets the criteria for diagnosis of the metabolic syndrome . The fact is that there are a growing number of physicians who are capable of early recognition of pre-metabolic syndrome, I discovered earlier, and after years or decades, identify the metabolic one, which always follows the former [14,15]. In addition, I have underlined that at the base alteration in all components of these syndromes, i.e., pre-metabolic and metabolic syndrome, there are both parenchymal and microvascular inherited alterations, bedside recognized in some biological systems since birth, which (i.e. the latter) parallel the former, according to my theory of angiobiopathy, which completes Tischendorf’s Angiobiotopy theory [16-29].
As a matter of fact, alterations of tissue-microvascular units, i.e. microcirculatory remodelling, characterized by newborn-pathological, type b), aspecific, endoarteriolar blocking devices [30-40], caused by local parenchimal gene mutations, account for the reason that great arterial vessels, and especially microvessels, including so-called vasa vasorum, show an impaired motility, that is, vasomotility of small artery and arterioles, and vasomotion of nutritional capillaries, according to Hammersen  (I also refer to personal web sites http://www.semeioticabiofisica.it, Biophysical-Semeiotic Constitutions) [4,8-12,14-19]. For further information on microvascular pathology, see http://www.semeioticabiofisica.it/microangiologia/common_eng.htm).
Clinical evidence demonstrates that neither all dyslipidemics, or all diabetics, or all hypertensive patients present metabolic syndrome, both classic and “variant,” I have described previously, conditio sine qua non of calcium depot in tissue, such as the artery wall.
On the contrary, patients involved by metabolic syndrome in some cases, but not in all, show overt type 2 diabetes and hypertension [16-18,22,23]). Really, these disorders may occur exclusively in people with the related constitution and inherited real risk
Interestingly, authors refer in a recent article that insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial, in my opinion, because inherited coronary real risk is overlooked. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a pro-atherogenic lipoprotein profile in blood. According to these authors, this is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1β (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Under an atherogenetic diet, LIRKO mice showed marked hypercholesterolemia and 100% of LIRKO mice, but 0% of controls, developed severe atherosclerosis. Thus, say the authors, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome . I sent a comment to the editors of Cell Metabolism stating that, as regards the paper conclusion, I cannot agree with authors as far as human is concerned, based on biophysical semeiotics data. Firstly, doctors are able now to bedside assess hepatic insulin resistance [25,26]. Secondly, the hepatic insulin resistance may be totally absent in patients with the pre-metabolic and metabolic syndrome, I described as “variant” form of both, that proved to be in my long clinical experience the conditio sine qua non of calcium deposit in tissues, including artery wall [18,20-32].
At this point, it is interesting to emphasize the presence, in all biological systems, including the entire vascular tree, of dual realms. In fact, I have recently demonstrated, besides the local realm, non-local realm in biology, highlighting a large number of biophysical-semeiotic reflex, manoeuvre, test patho-physiological mechanisms, not known until now [33-38]. Really interesting is Lory’s experiment, which parallels Aspect’s experiment, performed in sub-atomic world, acting on two entangled electrons: apart from their distance, twin biological systems react in identical way, under stimulation of precise trigger-points of only one of them .
Finally, the hepatic insulin receptor resistance is not associated in all cases with whatever metabolic disorder. It depends on dysfunction of PPARs in the liver, skeletal muscle, and adipose tissue, as I demonstrate later on. In ATS microcirculatory theory article , I explain the reason of the association between ATS and metabolic syndrome, that can occur exclusively in presence of biophysical-semeiotic ATS constitution [4,16,19-23].
As a matter of fact, microscopic and macroscopic worlds are continuously interacting in biology, so that the local realm prevails when cellular free energy is reduced due to impaired mitochondrial respiratory function, brought about by disorders. On the contrary, under physiological conditions, thanks to mitochondrion normal function, non-local realm is widespread in biological systems. Analogously, micro- and macro-vessels are strictly interacting, as my microvessel theory of ATS clearly demonstrates .
Certainly, interventions involving lower blood pressure, glycemia, serum cholesterol, and other risk factors (such as clinically diagnosed IIR) reduce the risk of cardiovascular disease (CVD) regardless of initial levels, and decrease the risk factors as much as possible. However, my personal lengthy clinical experience has taught me that we must go beyond the known risk factors, about 300, really too much. In fact, primary prevention of the most common and dangerous human pathologies, for example, CVD, depends especially upon easy and immediate bedside detection of individuals at inherited “real risk,” potentially from birth, that is, well-defined biophysical-semeiotic constitutions, assessed clinically in a quantitative way [4,15,18,20,28-41].
In order to clinically define a particular constitution and related inherited real risk, which does not exclude the presence of several constitutions, it is necessary to consider a present possibility of gathering unavoidable biophysical-semeiotic data at the bedside. This would include the necessary biological and molecular-biological information on the various human organs, tissues and biological systems, and at the same time reveal numerous types of biophysical-semeiotic constitutions, even from the quantitative point of view [14,15,17,19,26].
At this point, in the primary prevention of all components of metabolic syndrome, i.e. hyperinsulinemia-insulin resistance, IGT, and type 2 diabetes, obesity, and hypertension, first of all, doctors have to recognize on very large scale pre-metabolic syndrome, classic and variant. After that, physicians have to bed-side monitor pre-metabolic syndrome evolving to metabolic syndrome, since the well-known diabetes complications begin notoriously years or decades before diabetes onset. Among a lot of biophysical-semeiotic methods, different in technical difficulty, but all reliable and useful, peroxisome proliferator-activated receptors (PPARs) clinical evaluation proved to be really efficacious. Regarding such as assessment, I have been suggesting two clinical methods, based on melatonin and respectively thyroid hormone secretion, which allow doctors to evaluate at the bed-side the activity of these nuclear receptors in individuals involved by pre-metabolic syndrome [4,15,42-45]. In a few words, PPARs are members of the nuclear receptor family that regulates the expression of genes that control fatty acid synthesis, storage, catabolism, as well as glucose homeostasis and insulin sensitivity. PPARs, as heterodimers acting with another member of the nuclear receptor family, the retinoid X receptor (RXR-ROR), stimulated also by melatonin, hooking onto peroxisome proliferator response elements (PPREs), binding finally the P450 4A1 and 4A6 genes. In addition, recent data suggest that PPAR alpha and gamma activation decreases atherosclerosis progression not only by correcting metabolic disorders, but also through direct effects on the vascular wall [4,15,42-45]. PPARs modulate the recruitment of leukocytes to endothelial cells, control the inflammatory response and lipid homeostasis of monocytes/macrophages and regulate inflammatory cytokine production by smooth muscle cells. In conclusion, biophysical-semeiotic evaluating PPARs activity, described for the first time from clinical view-point, represents a paramount event in preventive medicine.
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