Biophysical-Semeiotic bed-side Evaluation of Adiponectin in classic and variant Pre-Metabolic and Metabolic Syndrome. (by Sergio Stagnaro) INTRODUCTION. ................................................................................................................................ 1 ADIPONECTIN ACTIONS IN INFLAMMATION AND ATS. ...................................................................... 1 ADIPONECTIN IN ATHEROGENESIS ..................................................................................................... 2 BIOPHYSICAL-SEMEIOTICS WORKING HYPOTHESIS : BED-SIDE EVALUATION OF ADIPONECTIN. ..... 3 REFERENCES. .................................................................................................................................... 4 Introduction. Notoriously obesity is associated with pre- metabolic syndrome late stage and metabolic syndrome as well as increasing risk for hypertension, dyslipidemia, type 2 diabetes, and atherosclerotic cardiovascular disease. In addition, adipose tissue (more than 10% of the body weight) is considered to be not only an energy reservoir but also an active endocrine tissue. Indeed, adipose tissue produces numerous proactive cytokines, the so-called “adipocytokines” (1). Among these, adiponectin, which is derived only from adipose tissue, circulates at concentrations ranging from 2 to 30 mg/L., showing a level 103 higher than the concentrations of other major hormones (e.g. leptin: See URL http://www.semeioticabiofisica.it/semeioticabiofisica/Do cumenti/Eng/Leptina%20Articolo%20eng doc), and 106 higher than those of most inflammatory cytokines (e.g. tumor necrosis factor -TNF- and interleukin, IL-6). it belongs to the soluble collagen superfamily, and has structural homology with collagen VIII, X, complement factor C1q, and TNF family (2). All authors agree with the fact that both C1q and TNF family play important roles in inflammation, immune system, and atherosclerosis. From the above remarks derives the importance of bed-side “quantitative” biophysical- semeiotic evaluation of adiponectin, possible for the first time thanks to Biophysical Semeiotics, in individuals involved either by pre- metabolic syndrome (in advanced stage) or metabolic syndrome. Adiponectin actions in inflammation and ATS. Adiponectin has been shown to have many anti- inflammatory and anti-atherogenic effects (3): 1) suppression of adhesion molecule expression of endothelial NF-kB signaling through the activation of cAMP protein kinase A, 2) suppression of foam cell formation through the inhibition of class A macrophage scavenger receptor (SR-A), 3) inhibition on the proliferation of myelomonocytic lineage cells, and on the function of matured macrophages, such as phagocytosis and TNF production, 4) suppression of the proliferation and migration of smooth muscle cells induced by platelet- derived growth factor (PDGF)-BB through binding with PDGF-BB directly, 5) inhibition of p42/44 extracellular signal-related kinase (ERK) phosphorylation in PDGF- BB-stimulated smooth muscle cells, 6) suppression of the expression of heparin-binding epidermal growth factor (EGF)- like growth factor (HB- EGF) in TNF induced activated endothelial cells and the proliferation and migration of smooth muscle cells stimulated by basic fibroblast growth factor (bFGF), PDGF, EGF, and HB-EGF. Particularly interesting for our purpose of “clinical” adiponectin biophysical-semeiotic assessement, is the 7) stimulation of nitric oxide (NO) production in endothelial cells through the pathway of phosphatidylinositol-3-kinase (PI3K) (3). Experimental animal models also showed the association between adiponectin and atherosclerotic disease, accumulation of adiponectin in the injured vessels but not in non- injured walls, acceleration of neointimal proliferation of smooth muscle cells in response to injury of adiponectin-deficient mice, improvement of neointimal proliferation supplemented with adenovirus expressing adiponectin, reduction of atherosclerotic lesions treated with adenovirus- mediated adiponectin in apolipoprotein E-deficient mice (apoE-KO), and suppression of VCAM-1, SR-A, and TNF in the aorta during the treatment with adenovirus expressing adiponectin (3). Adiponectin in atherogenesis Now-a-days there is a general agreement among the authors about the fact that vascular endothelial dysfunction plays an important role in pathogenesis of atherosclerosis, as I demonstrated clinically for the first time two decades ago, even in very young individual (4, 5, 6) (See www.semeioticabiofisica.it, Arteriosclerotic Constitution, and Microcirculatory Theory of Artheriosclerosis). A recent report showed that peak forearm blood flow (FBF) was correlated with adiponectin levels in healthy subjects (7). The intima- media thickness (IMT) of the carotid artery is associated with not only the prevalence of cardiovascular disease, but also an increased risk of cardiovascular events. Carotid IMT was significantly correlated with insulin resistance and adiponectin (8), suggesting that adiponectin might be a useful marker of identifying the early stage of atherosclerosis. Personal biophysical-semeiotic data have corroborated the results of a lot of studies, showing that plasma levels of adiponectin are significantly decreased in: 1) obese patients, 2) type 2 diabetic patients, 3) coronary artery disease (CAD) patients (9, 10, 11). Interestingly, in patients with type 2 diabetes, plasma adiponectin levels were shown to be lower in patients with CAD than in patients without CAD (10). A recent study reported that hypoadiponectinemia was significantly and independently correlated with CAD even after adjustment for several coronary risk factors (9), especially, male subjects with hypoadiponectinemia (< 4.0 mg/L) had a 2-fold increase in CAD prevalence, independent of other coronary risk factors (3). It was reported that plasma adiponectin levels were negatively correlated with the CRP levels in patients with CAD (10). This study also showed that not only was CRP mRNA expressed in human adipocyte, but also the levels of CRP mRNA in human adipose tissue were correlated negatively with the levels of adiponectin mRNA in that tissue (11). CRP is generally produced in the liver, however, a recent study showed the presence of CRP mRNA in atherosclerotic plaques (12). Therefore, the expression of CRP may be negatively regulated by adiponectin in adipose tissue. Indeed, the reciprocal relationship was found between adiponectin and TNF on their local production in adipose tissue. Unpublished biophysical-semeiotics results, gathered in individuals involved by CAD real risk (13, 14) corroborate a recent report, which showed that high plasma adiponectin are associated with lower risk of myocardial infarction in men without cardiovascular disease (15). This ist really intriguing bacause until now it has not been ascertained whether the decreased level of adiponectin in patients with CAD is the cause or the consequence of atherosclerosis, and this is an important question. The possible mechanisms are 1) decreased production in adipocyte, 2) increased consumption in blood stream, or 3) both (3). In my opinion, based on above-referred biophysical-semeiotic results, the first explanation is right. In anyway, body weight reduction increased plasma adiponectin levels in both diabetic and non-diabetic subjects (10), and in premenopausal obese women (16). In addition, the changes in plasma adiponectin levels were significantly correlated with the changes in BMI (16). However, regular exercise training without reduction of body weight did not alter the adiponectin levels in healthy subjects, although insulin sensitivity improved significantly (17). In my opinion, it seems really interesting that thiazolidinediones, which are synthetic ligands to peroxisome proliferator-activated receptor (PPAR), elevated plasma adiponectin levels in mildly obese subjects and increased adiponectin levels of both plasma and adipose mRNA expression, in addition to decreasing of TNF mRNA expression in mice (18). In a former p aper, I referred the paramount actions of Melatonin- Adenosine, according to Di Bella-Ferrari’s formula, in ameliorating both glucose metabolism and insulin sensitivity (19). These results suggest that the increasing adiponectin is not necessarily a simple consequence of improved insulin resistance in the clinical settings. It was reported that treatment of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist increased plasma adiponectin levels in insulin-resistant patients with essential hypertension (21). Several proposed mechanisms by which renin-angiotensin system (RAS) inhibition leads to an increase of adiponectin are 1) enhanced insulin sensitivity, 2) recruitment and differentiation of preadipocytes, and 3) increased transcription and/or translation of adiponectin (3). Indeed, RAS blockades have been reported to enhance insulin sensitivity, suppression of expression and secretion of TNF-alfa in adipocytes. Moreover, angiotensin II type 1 receptor (AT1) and type 2 receptor (AT2) in adipocyte are expressed during its differentiation (3). Biophysical-Semeiotics Working Hypothesis: Bed-Side Evaluation of Adiponectin. I hypothesized that, analogously to leptin (See in above- mentioned site, URL http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/Leptina%20Articolo%20eng doc), hand stimulation of adipose tissue, lasting about 20 sec., causes also adiponectin release from adipose tissue. Therefore, it could be possible to assess clinically vasodilation effects, induced by adiponectin-dependent stimulation and secretion of radical eNO (22, 23). The rationale for such as original evaluatio n is the immediate secretion of adiponectin by adipocytes (mammary gland, abdominal tissue, thigh, a.s.o.) in blood, and its binding to relative receptors, including endothelial receptors. Adiponectin acts consequently on endothelial cells, stimulating radical eNO production. From the above remarks derives the possibility of “clinical” evaluation of adiponectin with the aid of Biophysical Semeiotics in very different ways, among them in following only those of easy practical application will be described, to perform in individuals with pre-metabolic syndrome in both advanced stages and in overweight or obese people, involved by metabolic syndrome, classic and variant, the later I described in earlier papers (24-27). To assess plasma adiponectin levels, doctor can follow two diverse ways, both reliable, but different in difficulty, refinement and quantity of information: A) When subject to be examined is lying down in supine position, and psycho-physically relaxed with open eyes, doctor evaluates, firstly, basal finger-pulp microcirculation, i.e., local oxygenation (Fig.1) (4, 5, 26) by means of fingerpulp-gastric aspecific reflex latency time, which is in healthy, 8 sec. Then, soon thereafter, doctor stimulates adipose tissue of lateral abdomen or mamma regions or thigh, with the aid of manual pressure or by “large” pinch, to secrete among other substances the adiponectin for about 20 sec. (= interstitium appears large 1 cm., and microcirculation is activated, provoking a statistically significant increas ing of reflex latency time: 12 sec. (23). The difference between th two parameter values parallels plasma adiponectin level. In fact, in case of adiponectin deficiency (e.g., DM with obesity, ATS) the basal value is generally the same as the second one. Fig.1 Figure indicates the bell-piece right location and linees upon which auscultatory percussion, gently and directly, must be applied to ascertain the great curvature of stomach. B) An interesting method usefull in evaluating adiponenctin blood le vel is represented by assessing the basal arterial compliance (e.g., intensity of arterial- gastric aspecific or -ureteral “in toto” reflex) (23, 28), and soon therafter tha aboved-mentioned manoeuvre: in healthy, arterial dilation is statistically increased during the second evaluation, due to the production of eNO, induced by adiponectin. On the contrary, in case of adiponectin deficiency, arterial compliance is clearly impaired, in comparison with basal impaired parameter value. In conclusion, our interest it was to describe an original clinical method reliable in assessing adiponectin blood level, impaired in overweight and sedentary lifestyle, which is leading to a dramatic increase in the prevalence of metabolic syndrome. It has been clear, however, that cardiovascular and overall mortality increase in patients with metabolic syndrome, which is closely associated with obesity, and type 2 diabetes. Various in vitro, in vivo, and clinical studies so far have shown that adiponectin has anti-diabetic, anti- inflammatory, and anti-atherogenic properties (3). References. 1)Funahashi T, Nakamura T, Shimomura I, et al. Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 1999;38:202-6. 2) Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286-89. 3) Shimada K., Miyazaki T., Daida H. Adiponectin: a promising target in reducing mortality and morbidity of atherosclerotic disease. 2004-09-18: http://www.athero.org/comm- index1.asp 4) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio- venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989 5) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio- venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989 6) Stagnaro-Neri M., Stagnaro S., Modificazioni della viscosità ematica totale e della riserva funzionale microcircolatoria in individui a rischio di arteriosclerosi valutate con la percussione ascoltata durante lavoro muscolare isometrico. Acta Med. Medit. 6, 131-136, 1990 7) Shimabukuro M, Higa N, Asahi T, et al. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 2003;88:3236-40 8) Jansson PA, Pellme F, Hammarstedt A, et al. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J 2003;17:1434-40. 9) Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79-83. 10) Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000;20:1595-99. 11) Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999;100:2473-76. 12) Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 2003;107:671-74 13) Stagnaro Sergio. A clinical efficacious maneouvre, reliable in bed-side diagnosing coronary artery disease, even initial or silent, as well as "heart coronary risk". 3rd Virtual International Congress of Cardiology, FAC, http://www.fac.org.ar/tcvc/marcoesp/marcos.htm 14) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109 , 1997 15) Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004;291(14):1730-37. 16) Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose- derived anti- inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86:3815-19. 17) Hulver MW, Zheng D, Tanner CJ, et al. Adiponectin is not altered with exercise training despite enhanced insulin action. Am J Physiol Endocrinol Metab 2002;283:E861-65. 18) Maeda N, Takahashi M, Funahashi T, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001;50:2094-99. 19) Stagnaro-Neri M., Stagnaro S. La Melatonina nella Terapia del Terreno Oncologico. Edizioni Travel Factory, Roma, 2004 20) Stagnaro-Neri M., Stagnaro S. Le costituzioni Semeiotico-Biofisiche nella definizione della Single Patient Based Medicine. Edizioni Travel Factory, Roma (in press). 21) Furuhashi M, Ura N, Higashiura K, et al. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 2003;42:76-81. 22) Stagnaro S., Stagnaro-Neri M., Basi microcircolatorie della semeiotica biofisica. Atti del XVII Cong. Naz. Soc. Ital. Studio Microcircolazione, Firenze ott. 1995, Biblioteca Scient. Scuola Sanità Militare, 1995, 2, 94. 23) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Travel Factory, Roma, 2004. www.travelfactory.it 24) Stagnaro S. Pre- metabolic syndrome: the real initial stage of metabolic-syndrome, type 2 diabetes and arteroscleropathy. Cardiovascular Diabetology 2004, 3:1 http://www.cardiab.com/content/3/1/1/comments 25) Stagnaro S.-Neri M., Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabete mellito. Il Cuore. 6, 617, 1993. [Medline]. 26) Stagnaro-Neri M., Stagnaro S., La “Costituzione Colelitiasica”: ICAEM-, Sindrome di Reaven variante e Ipotonia-Ipocinesia delle vie biliari. Atti. XII Settim. It. Dietol. ed Epatol. 20, 239, 1993 27) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero-Marigo nella diagnosi clinica della iperinsulinemia-insulino resistenza. Acta Med. Medit. 13, 125,1997. 28) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione della compliance arteriosa e delle resistenze arteriose periferiche. Atti del XVII Cong. Naz. Soc. Ital. Studio Microcircolazione, Firenze Ott. 1995, Biblioteca Scient. Scuola Sanità Militare, 1995, 2, 93.
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