Cardiovascular Diabetology - Latest Comments

Correction

yumi yumi — 2010-02-22T00:00:00Z

I am Yumi Miyashita, the author of this article.

In the original report, the writing "A computer-assisted, least square　method..." is wrong. The correct writing is "A computer-assisted,
minimization...".

Carbohydrate-restricted Diet for The Therapeutic Paradigm

Robert Su — 2009-12-31T00:00:00Z

Robert Su, Pharm.B., M.D. Author, Carbohydrates Can Kill www.carbohydratescankill.com E-mail: carbohydratescankill@verizon.net

Congratulations to Doctors Node and Inoue on their excellent work to produce such an interesting and educational article.

In my literature review and personal experimentations, I have observed an axis of the excessive consumption of carbohydrates especially those high in glycemic indices and glycemic loads, the daily repeated postprandial hyperglycemia, the repeated postprandial inflammation with both acute and chronic pathological effects on cells, tissues, and organs. ^{[1., 2, 3]} The pathological role of hyperglycemia at least includes (1) inflammatory and pro-inflammatory, (2) vasoconstrictive (and hypertensive), (3) pro-thrombotic, (4) arteriosclerotic and atherosclerotic, and (5) glycosylative and pro-glycation. ^[4]

Inflammation by both acute and chronic or repeated postprandial hyperglycemia (during the period of hours immediately after the beginning of each meal) ^{[5, 6, 7]} illustrates why the readings of fasting blood glucose test and glucose tolerance test (at the end of the two-hour period), as well as hemoglobin A_1c are ineffective in predicting the risks of diseases including diabetes mellitus, arteriosclerosis and atherosclerosis, neurodegenerative diseases such as Alzheimer’s disease, cancers, and many others. The mass of the pancreatic beta cells starts to decrease, during an individual’s life regardless of his age, when the magnitude of hyperglycemia, on either the vertical or horizontal scale, or both, is so enormous that inflammation, as a consequence, permanently damages the beta cells (apoptosis.) Without halting the repeated postprandial hyperglycemia, the size of apoptosis would exceed the size of regeneration of the mass of the pancreatic beta cells. ^{[8, 9]} By the time when either or both the readings of fasting blood glucose and glucose tolerance test is abnormal, about 40-60% of the individual’s beta cells are already damaged or dead; and he is now diagnosed with diabetes mellitus. ^[10] During the same time, other tissues or organs are also assaulted by inflammation and have begun the pathological process. Studies have even shown atherosclerosis occurs in infancy. ^{[11., 12, 13]} The prognosis of his disease(s) will largely depend on the effectiveness of controlling his blood glucose level at all time not just on the readings of the fasting blood glucose and/or the two-hour post glucose tolerance test.

Hemoglobin A_1c is a result of glycation between blood glucose and the globin of hemoglobin. The higher the blood glucose level the greater the hemoglobin A_1c will be. Because of a lifespan of 60-90 day for hemoglobin, an individual’s hemoglobin A_1c largely reflects an averaged level of his blood glucose over a period, not an acute fluctuation of his blood glucose during a short period of hours. Having known the consequent inflammation of hyperglycemia, which is capable of triggering an acute vascular event or others, hemoglobin A_1c is ineffective as a predicting biomarker for acute heart attack or stroke.

I have emphasized that, regardless of an individual’s state of health, everyone needs an annual or semiannual series of blood glucose tests, started at the pre-prandial or fasting and continued for two or three hours of the postprandial at a 15-minute interval. These tests will help both assess the functions of his pancreatic beta cells, and evaluate the impacts of his foods on the blood glucose level. In my opinion when the readings are over 120 mg% (a red flag when over 150 mg%), ^{[14., 15, 16]} he should avoid the foods high in glycemic index and glycemic load for preventing his progression towards diabetes mellitus. The tests are beneficial for both preventive medicine and personal health education.

Having understood the relationships between the carbohydrate foods excluding the non-digestible fibers, the amount of monosaccharides in the small intestine for absorption, the level of blood sugars (mainly glucose here for illustration), ^[17] the level of inflammation as a result of hyperglycemia, ^{[18, 19, 20, 21, 22]} and the risks of diseases, we have employed many pharmacological products in both disease prevention and management. For examples, we have observed positive results, at least for a short period of time, with certain anti-inflammatory drugs, hypoglycemic agents for increasing insulin secretion or facilitating the peripheral glucose uptake, as well as insulin preparations in cases of insulin dependent diabetes mellitus.

During the recent years, we have also tried to reduce the amount of monosaccharides from being absorbed into the circulation, which directly boosts the blood glucose level. As cited in Doctors Node and Inoue’s article, we are using alpha-glucosidase inhibitors to reduce the postprandial blood sugar level. In addition, we have also discovered a benefit of the gastric by-pass surgery for lowering the diabetic patients’ blood glucose levels. ^[23] The alpha-glucosidase inhibitors block the release of the pancreatic amylase. The gastric by-pass surgery reroutes a majority of polysaccharides and disaccharides of the foods into a very short, last part of the small intestine for decreasing the contact time between the polysaccharides and disaccharides and the pancreatic enzymes, As a result, the surgery cuts the amount of polysaccharides and disaccharides to be converted into monosaccharides for absorption. ^[24] There might be some biochemical factors, which were possibly responsible for lowering the blood glucose level by both the alpha-glucosidase inhibitors and the gastric bypass surgery. However, both approaches restrict the amount of carbohydrates from being digested and absorbed, and consequently reduce the blood glucose level. Their success is also critically depending on the consumption of monosaccharides such as simple sugars in the individual’s foods, because neither approach can deter the absorption of monosaccharides. In short, they are either a biochemical or surgical form of restricting carbohydrate foods. However, their side effects and complications cannot be ignored.

Instead of letting the individual risk his health and life and take in many carbohydrate foods, andw sending a majority of polysaccharides and disaccharides into the colon for waste, it is logical for him to restrict carbohydrate foods daily in the first place, especially those high in glycemic indices and glycemic loads. As a result, he will have a stable, low normal range of blood glucose level at all time, sustain a very low level of inflammation, and improve his risks of vascular failure, diabetes mellitus, and many diseases.

References:

1 Su RK. “Carbohydrates Can Kill.” Carbohydrates Can Kill. Pages 328-332. http://www/carbohydratescankill.com
2 Su RK. “Inflammation, Inflammation & Inflammation!” Carbohydrates Can Kill. Pages 337-344. http://www/carbohydratescankill.com
3 Esposito K, et al. “ Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans Role of Oxidative Stress.” Circulation, Published online Volume 106, Number 16, Pages 2067-2072. September 30, 2002, http://circ.ahajournals.org/cgi/content/full/106/16/2067
4 Su RK. “Role of Hyperglycemia” Carbohydrates Can Kill. Pages 347-354. http://www/carbohydratescankill.com
5 Su RK. “Diabetes Mellitus and Insulin Resistance.” Carbohydrates Can Kill. Pages 50. http://www/carbohydratescankill.com
6 Su RK. “Everyone Needs Annual Blood Glucose Screening.” Carbohydrates Can Kill. Pages 364-367. http://www/carbohydratescankill.com
7 Koichi Node and Teruo Inoue, “Postprandial hyperglycemia as an etiological factor in vascular failure.” Cardiovascular Diabetology 2009, 8:23doi:10.1186/1475-2840-8-23 http://www.cardiab.com/content/8/1/23,
8 Eizirik DL, Korbutt GS, and Hellerström C. “Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function.” Journal of Clinical Investigation, Volume 90, Number 4, Pages 1263–1268. October 1992. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=443168 or “Video: If Diabetes Mellitus is Preventable.” http://www.carbohydratescankill.com
9 Akirav E. et al. “Beta-cell Mass and Type 1 Diabetes: Going, Going, Gone?” Diabetes. November 2008 vol. 57 no. 11 2883-2888 http://diabetes.diabetesjournals.org/content/57/11/2883.full.pdf+html
10 Leonardi O, et al. “Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus.” European Journal of Endocrinology. (2003) 149 99–102. http://www.eje-online.org/cgi/reprint/149/2/99.pdf
11 Tanaka K, Masuda J, Imamura T, Sueishi K, Nakashima T, Sakurai I, Shozawa T, Hosoda Y, Yoshida Y, Nishiyama Y, et al “A nation-wide study of atherosclerosis in infants, children and young adults in Japan.” Atherosclerosis. 1988 Aug;72(2-3):143-56 http://www.ncbi.nlm.nih.gov/pubmed/3214466?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed
12 Gerald S. Berenson, M.D., Sathanur R. Srinivasan, Ph.D., Weihang Bao, Ph.D., William P. Newman, M.D., Richard E. Tracy, M.D., Ph.D., Wendy A. Wattigney, M.S., for The Bogalusa Heart Study “Association between Multiple Cardiovascular Risk Factors and Atherosclerosis in Children and Young Adults.” New England Journal of Medicine, June 4, 1998, Number 23, Vol. 338:1650-1656 http://content.nejm.org/cgi/content/abstract/338/23/1650
13 osé Milei, MD PhD,1 Giulia Ottaviani, MD PhD,2 Anna Maria Lavezzi, MD,2 Daniel R Grana, VMD,1 Inés Stella, MD,1 and Luigi Matturri, MD PhD2 “Perinatal and infant early atherosclerotic coronary lesions.” Canadian Journal of Cardiology. 2008 February; 24(2): 137–141. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2644569
14 Williams LS, et al. “Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke.” Neurology Volume 59, Pages 67-71. 2002. http://www.neurology.org/cgi/content/abstract/59/1/67
15 Capes SE, et al. “Stress Hyperglycemia and Prognosis of Stroke in Nondiabetic and Diabetic Patients. A Systematic Overview.” Stroke. Volume 32, Pages 2426-2432. 2001. http://stroke.ahajournals.org/cgi/reprint/32/10/2426.pdf
16 Thomas MC, et al. “Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes.” Nephrology (BioMed Central). Volume 1, Number 1. 2000. Published online October 4, 2000. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=29098
17 Su RK. “The Digestion of Different Nutrients.” Carbohydrates Can Kill. Pages 9-12. http://www/carbohydratescankill.com
18 Seshadri P, et al. “A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity.” American Journal of Medicine, Volume 117, Issue 6, Pages 398-405. September 15, 2004. http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=Retrieve&list_uids=15380496
19 Thomas MC, et al. “Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes.” Nephrology (BioMed Central). Volume 1, Number 1. 2000. Published online October 4, 2000. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=29098
20 Yudkin JS, Stehouwer CDA, Emeis JJ and Coppack SW. “C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, and Endothelial Dysfunction. A Potential Role for Cytokines Originating From Adipose Tissue.” Arteriosclerosis, Thrombosis, and Vascular Biology, (the American Heart Association, Inc.) Volume 19, Number 4, Pages 972-978. 1999. http://atvb.ahajournals.org/cgi/content/full/19/4/972?ijkey=bc7ff94a637764853fbee0ded041fcffb04b0cff
21 Esposito K, et al. “ Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans Role of Oxidative Stress.” Circulation, Published online Volume 106, Number 16, Pages 2067-2072. September 30, 2002, http://circ.ahajournals.org/cgi/content/full/106/16/2067
22 Liu S, et al. “Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women.” American Journal Clinical Nutrition. Volume 75, Number 3, Pages 492–8. 2002. http://www.ajcn.org/cgi/content/abstract/75/3/492
23 Cummings DE, et al. “Role of the bypassed proximal intestine in the anti-diabetic effects of bariatric surgery.” Surgery for Obesity and Related Diseases. 2007; 3(2): 109–115. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702249/pdf/nihms%2D21334.pdf/?tool=pmcentrez
24 Su RK. “Speaking of Diabetic Diet.” Carbohydrates Can Kill. Pages 332-337. http://www/carbohydratescankill.com

Correction

Enrique Fisman — 2009-12-17T00:00:00Z

TO THE READERS:
After the publication of this manuscript, the authors discovered a mistake in the figure legends. In both legends the correct reference number should be 52 instead of 45.

Arterial Hypertension is under control if hepatic PPARs are well functioning.

Sergio Stagnaro — 2009-12-09T00:00:00Z

Sirs,
from the clinical view-point, I agree with the data of this fascinating study. In fact, only when the lipid and glucose metabolism is under control, blood pressure can be in normal range. Now-a-days, the best method in assessing lipid and glucose metabolism is the bedside evaluation of liver PPARs (1-7). Accordingly, low caloric diet and regular physical exercise induced significant improvement in blood pressure, body mass index, waist-to-hip- circumference,without any change on drug prescription, but it brings about other paramount benifits (1). Let us consider, for instance, that one of the most active areas of metabolic research into potential treatments surrounds the role of nuclear receptors as a treatment target for both glucose and lipid metabolism. In addition, agonists of the peroxisome proliferator-activated receptor (PPAR) offer unique potential in several respects (See www.semeioticabiofisica.it; Practical Applications: PPARS). PPAR agonists (such as fibrates, thiazolidinediones, coniugated-melatonin, according to Di Bella-Ferrari) have been shown to lower triglyceride and increase HDL-c, with a variable effect upon LDL-c blood levels. PPARs agonists have variable effects on the lipid profile, in addition to improving insulin sensitivity and blood glucose levels in patients with type 2 diabetes. Pre-clinical studies suggest that both PPARs and PPARs agonists have direct anti-atherogenic effects (1). Therefore, single agents that promote both PPARs and PPARs agonism could theoretically offer significant benefits in improving dyslipidaemia and reducing hyperglycaemia, and thus reduce these cardiovascular risk factors associated with type 2 diabetes and metabolic syndrome. Interestingly, PPAR physiological functioning proved to be useful and reliable to indicate clinically a normal glyco-lipidaemic metabolism, in agreement with other authors (2). Among a lot of biophysical-semeiotic methods (See above-mentioned website; Practical Applications), different in technical difficulty, but similarly reliable and useful in assessing peroxisome proliferator-activated receptors (PPARs) (3), I suggest two methods, based on melatonin and thyroide hormone secretion, which allow doctor to bed-side evaluate the activity of such nuclear receptors in individuals with Pre-Metabolic Syndrome (3-6). 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, e.g., in the liver. PPARs bind as heterodimers with another member of the nuclear receptor family, the retinoid X receptor (RXR- ROR), stimulated also by melatonin (3-6), to peroxisome proliferator response elements (PPREs) in 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 (1-7). 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.

REFERENCES
1) Stagnaro Sergio. Bedside biophysical-semeiotic PPARs evaluation in glucose-lipid metabosism monitoring. Annals of Family Medicine 2007; 5: 14-20. http://www.annfammed.org/cgi/eletters/5/1/14
2) Stagnaro Sergio. Reale Rischio Semeiotico Biofisico. I Dispositivi Endoarteriolari di Blocco neoformati, patologici, tipo I, sottotipo a) oncologico, e b) aspecifico. Ediz. Travel Factory, www.travelfactory.it, Roma, Luglio 2009.
3) Stagnaro Sergio. Pre-Metabolic Syndrome and Metabolic Syndrome: Biophysical-Semeiotic Viewpoint. www.athero.org, 29 April, 2009. http://www.athero.org/commentaries/comm904.asp
4) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico". Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm
5) Stagnaro S., Stagnaro-Neri M., La Melatonina nella Terapia del Terreno Oncologico e del "Reale Rischio" Oncologico. Ediz. Travel Factory, Roma, 2004.
6) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm
7) Stagnaro Sergio Biophysical-Semeiotic Bed-Side Evaluating PPARs Activity in Metabolic Syndrome. Cardiovascular Diabetology. (19 September 2005) http://www.cardiab.com/content/4/1/14/comments#211488

Hypercoagulability, a physiological reaction to increased blood viscosity due to hypovolaemia

Simon Thornton — 2009-05-14T00:00:00Z

Dear Sir,

I was very interested to read the recent article by Jax et al., (1) in the journal Cardiovascular Diabetology (2009; 8 (1): 24) entitled “Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2” where the authors clearly show an increased thrombogenic state in diabetes associated with an increase in blood viscosity. Similar risk factors have been reported with hypertension and when this disease state is associated with diabetes the risk is even further increased (2). It is important to note that plasma viscosity correlates to the progression of coronary and peripheral artery diseases (3). Now the question could be asked whether the hypercoagulability is a symptom of the two disease states or a reaction to the problem of viscosity ?

I have already published a letter on a common link between hypertension and diabetes and that being the hormone angiotensin (4), released in physiological response to a hypovolaemic state associated with these problems. This could suggest that with hypovolaemia not only blood perfusion could become a serious problem but also red blood cell volume, and thus the heart would need to work more to pump thickening blood around the body thus affecting tissue perfusion (5). A further adaptation to a reduced blood volume that would allow easier blood flow is a decrease in the number of red blood cells, which would induce also a state of mild hypoxia (6). But what about the increase in coagulability; I would like to suggest that this is a normal physiological reaction simply to aid the fluidity of the blood.

Furthermore, it has been shown that anti-hypertensive treatments, especially antagonists of the renin-angiotensin system, can have a positive effect on these haemorheological disturbances (2). With colleagues I have a letter (7) concerning the use of antagonists of the renin angiotensin system and obesity where we comment on the decreases in body weight seen in obese animals. We suggest that this is due to the increased drinking observed in these animals with the use of the antagonists. This would tend to reinforce the idea that it is the correction of the hypovolaemia that leads to correction of the haemorheological disturbances.

In the future then it would appear important to suggest that fluid, especially water, consumption be monitored, if not encouraged, in all human studies on haemostatic risk factors in patients with diabetes and/or hypertension.

References

1. Jax TW, Peters AJ, Plehn G, Schoebel FC. Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2. Cardiovasc Diabetol. 2009; 8 (1): 24.
2. Kearney-Schwartz A, Virion JM, Stoltz JF, Drouin P, Zannad F. Haemorheological disturbances in hypertensive type 2 diabetic patients--influence of antihypertensive therapy. Fundam Clin Pharmacol. 2007; 21 (4): 387-396.
3. Késmárky G, Kenyeres P, Rábai M, Tóth K. Plasma viscosity: a forgotten variable. Clin Hemorheol Microcirc. 2008; 39 (1-4): 243-246.
4. Thornton SN. Angiotensin, the hypovolaemia hormone, aggravates hypertension, obesity, diabetes and cancer. J Intern Med. 2009; 265(5):616-7.
5. Baskurt OK, Meiselman HJ. Blood rheology and hemodynamics. Semin Thromb Hemost. 2003; 29 (5): 435-450.
6. Thornton SN. Hypovolaemia-induced mild hypoxia produces subchronic metabolic dysfunction. Int J Obes (Lond). 2009; 33 (5): 605.
7. Thornton SN, Even PC, van Dijk G. Hydration increases cell metabolism. Int J Obes (Lond). 2009; 33 (3): 385.

Biophysical-Semeiotic Bedside Evaluation of Leptin.

Sergio Stagnaro — 2007-11-29T00:00:00Z

Sirs,

Leptin receptors are highly expressed in areas of the hypothalamus known to be important in regulating body weight, as well as in T lymphocytes and vascular endothelial cells (See Practical Applications in www.semeioticabiofisica.it).

Such as physiological events represent the rationale of biophysical-semeiotic bedside evaluation of leptin concentrations, augmented in metabolic syndrome and often in advanced stages of pre-metabolic syndrome, classic and variant. Thus, the possibility of recognizing, for the first time clinically, leptin increase constitutes a diagnostic tool of essential importance, applicable on very large scale.

Recent studies with obese and non-obese humans demonstrated a strong positive correlation of serum leptin concentrations with percentage of body fat, and also that there was a higher concentration of ob mRNA in fat from obese compared to thin subjects. Genetically obese mices with inactivating mutations in the ob gene or the gene encoding the leptin receptor (db gene) have been known for many years and were instrumental in the initial cloning of the ob gene 2, 5, 6).

It appears that as adipocytes increase in size due to accumulation of triglyceride, they synthesize more and more leptin. In essence, leptin provides the body with an index of nutritional status. Leptin's effects on body weight are mediated through effects on hypothalamic centers that control feeding behavior and hunger, body temperature and energy expenditure.

Decreased hunger and food consumption, mediated at least in part by inhibition of neuropeptide Y synthesis. Neuropeptide Y is a very potent stimulator of feeding behavior.

Increased energy expenditure, measured as increased oxygen consumption, higher body temperature and loss of adipose tissue mass.

The mechanisms by which leptin exerts its effects on metabolism are largely unknown and are likely quite complex. In contrast to dieting, which results in loss of both fat and lean mass, treatment with leptin promotes lipolysis in adipose tissue, but has no apparent effect on lean tissue.

Recent studies in obese and non-obese humans demonstrated positive correlation between serum leptin concetration and percentage of body adipose tissue and highest presence of ob-m-RNA in adipose tissue than that observed in lean individuals (7). These data were corroborated clinically by Biophysycal Semeiotics (8).

Bibliografia.

1) Cherhab FF, Mounzih K, Lu R, Lim ME: Early onset of reproductive function in normal female mice treated with leptin. Science 275:88, 1997.

2) Clement K, Vaisse C, Lahlou N, et al: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398, 1998.

3) Considine RV, Sinha MK, Heiman ML etc: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Eng J Med 334:292, 1996.

4) Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 395:763, 1998.

5) Halaas JL, Gajiwala KS, Maffel M, etc: Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543, 1995.

6) Montague CT, Faroozi IS, Whitehead JP, etc: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903, 1997.

7) Pelleymounter MA, Cullen MJ, Baker MB, etc: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540, 1995.

8) 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

Hypertensive Constitution accounts for the exsistence of diabetics with and without Hypertension.

Sergio Stagnaro — 2006-10-21T00:00:00Z

Sirs.

Interestingly,“clinical” biophysical semeiotic evidence demonstrates that natriuretic peptides (NP) act acutely to reduce plasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular permeability (1, 2, 3, 4). Fortunately, all these actions can nowadays be evaluated quantitatively, for the first time, at the bed-side by means of Biophysical-Semeiotics (See http://www.semeioticabiofisica.it, Practical Applications) (2). Firstly, we can assess the basal vasodilation of whatever artery, e.g., of brachial artery, and, secondly, the NP-dependent artery dilation, according to methods described also in above-cited site (2, 3). At this point, from both diagnostic and prognostic view-point, it is really usefull the precise “clinical” biophysical-semeiotic evaluation of renal and artery NP acute effects, observed during and soon therefater stretch-ischaemia test, in detail described formerly (ibidem). In healthy, doctor may observe these known renal and artery effects, brought about by NP (during intense, obstructive digital pressure upon the precordium for about 20 sec.), which cause both vasodilation, by relaxing vascular smooth muscle (in a “similar” way as acetyl-choline does) (1), and an acute increase in vascular permeability via receptors on the microvascular endothelium, clinically evaluated by artery compliance test (2) as well as Bilancini-Lucchi’s sign (3). These mechanisms, infact, also decrease blood volume by favoring redistribution of plasma protein and fluid from the vascular space to the interstitial space.

To summarize, my clinical biophysical data enlighten the hypertension problem, i. e., they account for the reason that some, but not all, diabetic patients are hypertensive, providing new data to support the hypothesis of hypertensive constitution, by investigating the regulation of plasma volume due to NP. For the first time, in an ongoing clinical research (book in press), biophysical-semeiotic methods were utilized in 25 young “healthy” individuals, but involved by hypertensive constitution (4) and “white cloth” hypertension, aiming to assess NP-dependent vasodilation and modulation of vascular permeability, confronting them with data observed in controls without hypertensive constitution.

In fact, soon after the discovery of the natriuretic peptides, authors recognized the importance of changes in vascular permeability in regulating the distribution of water between the plasma space and the interstitial space , now-a-days fortunately assessed clinically (1, 4, 5, 6)

Although preliminary, these data of my study are very promising, allowing to recognize individuals with hypertensive biophysical-semeiotic Constitution, apparently “healthy, but evolving slowly and symptomless to artery hypertension (Pre-Metabolic Syndrome worsening to Metabolic Syndrome) (4,5).

References.

1) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico”. Travel Factory SRL., Roma, 2004.

http://www.travelfactory.it/semeiotica_biofisica.htm

2) Stagnaro-Neri M., Stagnaro S., Stadio pre-ipertensivo e monitoraggio terapeutico della ipertensione arteriosa. Omnia Medica Therapeutica. Archivio, 1-13, 1989-90, 19904)

3) Stagnaro-Neri M., Stagnaro S., Il Segno di Bilancini-Lucchi nella diagnosi clinica del diabete mellito. The Pract. Ed. It. 176, 30, 1993

4) Sabrane, K. et al. 2005. Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J. Clin. Invest. 115:1666-1674. doi:10.1172/JCI23360

5) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm

6) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory SRL., Roma, 2005. http://www.travelfactory.it/semeiotica_biofisica.htm

"Bedside assessing ANS, RAAS, and IIR: a complex relation to type 2 diabetes".

Sergio Stagnaro — 2005-11-15T00:00:00Z

I can't agree with the paper's conclusions "In frequency domain, the analysis of sympathetic (LF) and parasympathetic (HF) component evidenced an association between the offspring of type 2 diabetic subjects and a sympathetic overactivity. A global reduction and alteration of circadian rhythm of autonomic activity are present in offspring of type 2 diabetic patients with and without insulin resistance. The data of our study suggested that an autonomic impairment is associated with the familiarity for type 2 diabetes independently to insulin resistance and that an impairment of autonomic system activity could precede the insulin resistance..." In my opinion, such statements are not completely true as well as misleading, as allows me to state a 48-year-long clinical experience . Firstly, nowadays doctors can fortunately "quantitatively" assess both autonomous nervous system (ANS) activity and renin-angiotensin-aldosterone-system (RAAS), circulating and tissural, in every biological system, although too much authors overlook this knowledge (1, 2, 3). As a matter of fact, the method used in their research in not right at all: for instance, it is well known that during physical exercise there is sympathetic overactivity in central adipose tissue and heart, but parasympathetic overactivity in muscles! Secondly, sympathetic overactivity appears always in the course of developing type 2 diabetes, but its CAEMH-dependent relation to IIR is quit complex (See http://www.semeioticabiofisica.it, my article "Beyond Hyperinsulinemia-Insulin Resistance in the War against Arteriosclerosis and type 2 Diabetes Mellitus" at the URL http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/Beyond%20Hyperinsulinemia%20engl.doc. Finally, physicians knowing Biophysical Semeiotics are able to evaluate at bedside, first, even AT BIRTH, "Diabetic AND Dyslipidaemic" constitutions, like Pre-Metabolic Syndrome and hyperinsulinaemia-insulinresistence, differentiating easily individuals with or without "diabetic" constitution; the latter will never become diabetic, of course (3,4,5) ,and finally type 2 diabetes, starting from its initial stage, by means of a lot of clinical tools, among them "pancreatic acute pick test of GH-RH secretion" (described in the above cited website, URL http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/Test%20del%20GH-RH%20DM%20eng..doc.

In conclusion, new ideas are difficult to be accepted; I thank for this reason... Cardiovascular Diabetology (6), even if they maybe highlightening old theories.

1) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione clinica del picco precoce della secrezione insulinica di base e dopo stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo attivazione del sistema renina-angiotesina circolante e tessutale – Acta Med. Medit. 13, 99 1997

2) Stagnaro-Neri M, Stagnaro S., Valutazione clinica percusso-ascoltatoria del sistema nervoso vegetativo e del sistema renina-angiotensina, circolatorio e tessutale. Arch. Med. Int. XLIV, 17378. 1992

3) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm 2004

4) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/libro_costituzionisemeiotiche.htm 2004

5) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory, Roma, 2005. http://www.travelfactory.it/libro_singlepatientbased.htm 2005

6) Stagnaro Sergio. Biophysical Semeiotic Constitutions, Genomics, and Cardio-Vascular Diseases. BMC Cardiovascular Disorders http://www.biomedcentral.com/1471-2261/4/20/comments#95454 2004

Biophysical-Semeiotic Bed-Side Evaluating PPARs Activity in Metabolic Syndrome.

Sergio Stagnaro — 2005-09-19T00:00:00Z

Sirs,

in my 48-year-long clinical experience, the primary prevention of all components of metabolic syndrome, as IIR, IGT and type 2 diabetes, dyslipidaemia, is principally based on recognizing on very large scale Pre-Metabolic syndrome, classic and “variant” (See web site www.semeioticabiofisica.it/microangiologia.it, Pre-Metabolic Syndrome, URL http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%), and its early evolution to metabolic syndrome, since the well-known diabetes and dyslipidaemia complications begin years or decades before disorder onset.

Dyslipidaemia is a major risk factor for atherosclerotic coronary heart disease, which in turn is the commonest cause of mortality in type 2 diabetes, caused by dyslipidaemia-dependent insulin-resistance. Management is typically multifactorial and includes dietary recommendations, routine physical exercise, aggressive control of other lifestyle risk factors, and for many patients drug intervention. Future drug treatments will improve other facets of diabetic dyslipidaemia, atherogenesis and vascular risk.

One of the most active areas of metabolic research into potential treatments surrounds the role of nuclear receptors as a treatment target for both glucose and lipid metabolism. For example, agonists of the peroxisome proliferator-activated receptor (PPAR) offer unique potential in several respects. PPAR agonists (such as fibrates) have been shown to lower triglyceride and increase HDL-c, with a variable effect upon LDL-c blood levels. PPARγ agonists (such as the thiazolidinediones) have variable effects on the lipid profile, in addition to improving insulin sensitivity and blood glucose levels in patients with type 2 diabetes. Pre-clinical studies suggest that both PPARα and PPARγ agonists have direct anti-atherogenic effects (1).

Therefore, single agents that promote both PPARα and PPARγ agonism could theoretically offer significant benefits in improving dyslipidaemia and reducing hyperglycaemia, and thus reduce these cardiovascular risk factors associated with type 2 diabetes and metabolic syndrome.

In addition, PPAR physiological functioning indicates clearly a normal glyco-lipidaemic metabolism (2).

Among a lot of biophysical-semeiotic methods, different in technical difficulty, but similarly reliable and useful in assessing peroxisome proliferator-activated receptors (PPARs) (3), I suggest two methods, based on melatonin and thyroide hormone secretion, which allows doctor to bed-side evaluate the activity of such nuclear receptors in individuals with Pre-Metabolic Syndrome (3-6). 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, e.g., in the liver. PPARs bind as heterodimers with another member of the nuclear receptor family, the retinoid X receptor (RXR- ROR), stimulated also by melatonin (3-6), to peroxisome proliferator response elements (PPREs) in 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 (ibidem). 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.

1) Camejo G, Rosengren B, Hallberg C, Wallin B. PPAR agonists vascular effects contributing to their apparent anti-atherogenic action. Presented at the 2nd International Symposium on PPARs: from basic science to clinical applications. March, 2003.

2) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.

3) Stagnaro Sergio. Bed-Side Biophysical-Semeiotic Evaluation of PPARs Activity.

http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/PPARs%20BS%20Evaluation%

4) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico”. Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm

5) Stagnaro S., Stagnaro-Neri M., La Melatonina nella Terapia del Terreno Oncologico e del “Reale Rischio” Oncologico. Ediz. Travel Factory, Roma, 2004.

6) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm

Newer antioxidants should include the old antioxidant: sodium thiosulfate

Melvin Hayden — 2005-06-27T00:00:00Z

First, congratulations on an excellent article in this exciting area of research.

Sodium thiosulfate is emerging as a treatment for calciphylaxis. It is capable of donating its two unpaired electrons, is a scavenger of reactive oxygen - nitrogen species, and may generate glutathione. Additionally, it is an excellent chelator of calcium, which is a problem in diabetes resulting in medial vascular ossification – calcification.

The peripheral arteriolopathy associated with diabetes and skin ulcerations are all too frequently recalcitrant to standard therapy and result in untold complications with eventual limb loss. It is entirely possible that therapy with sodium thiosulfate could promote healing of these ulcers and prevent limb loss by accelerating healing of these peripheral diabetic ulcers just as it has been so helpful in the recent months in promoting healing of the skin ulcerations associated with calciphylaxis.

Leitago DJ, Blakley BW: Quantification of sodium thiosulphate protection of cicplatin-induced toxicities. J Otolaryngol. 2004; 32(3): 146-150

Cicone JS, Petronis JB, Embert CD, Spector DA: Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis. 2004; 43(6): 1104-1108

Giselle Guerra, Ronak C. Shah, and Edward A. Ross: Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrology Dialysis Transplantation 2005; 20(6): 1260 - 1262

Karageuzyan KG: Oxidative stress in the molecular mechanism of pathogenesis at different diseased states of organism in clinics and experiment. Curr Drug Targets Inflamm Allergy 2005; 4(1): 85-98