Wednesday, February 20, 2013

Sugar Disease: Atherosclerosis

Scientific literature describes with great detail an involvement of B12, B9 and Vitamin D deficiencies, as well as, an impact of sugar consumption on our body's healing mechanism.

All these deficiencies are prevalent on a diet deprived of animal protein & fat, also known as a vegan diet. B12, B9 and vitamin D are found in adequate amounts in a human being's evolutionary diet of an omnivore origin. Due to probiotic bacteria's abilities to synthesis B12 and B9, as well as, synthesis of vitamin D on the skin following exposure to UVB light, a meatless diet is debatable. Yet, there are other factors in meat, that make it necessary for DNA repair and other healing processes.

The goal of this article is to describe what is known, via presentation of references to clinical studies as well as references to sources of literature, that can expand the investigators confidence in the knowledge presented.

Links in the body of the article will send you to Wikipedia articles, or other sources.
Study references can be found throughout the article, and the list is found at the end of the article.

Sugar Disease: Atherosclerosis

Hardening of the arteries is accomplished by a few contributing factors.
These factors include;
The Homocysteine Connection

B12** and B9*** are essential in converting Homocysteine into a stable compound[1]*.
Homocysteine irritates the blood vessels walls, causing injury to the cell membrane[2].
Cell membrane injury accompanies an inflammatory response.
This response sends signals to brain.
The brain, in turn, tells Liver to create cholesterol and ship it to injured site.
The molecular machine that ships cholesterol from Liver to injured site is LDL.

On a high sugar diet, glucose is toxic.
It has been observed to accelerate oxidation of LDL particles[3].

Insulin innate role

Insulin defends the whole system by accomplishing a few tasks;
  • Shutdown of Liver's mechanism of converting amino acids into glucose[4][5][6][7],
  • Shuttling all glucose present in the bloodstream into cells[7],
  • Shuttling remaining glucose into fat cells (glucose converted into fatty acids for storage)[7].
The Liver is capable of creating glucose (for energy) by converting amino acids into glucose[8].
Clearly, the mechanism of shutting down glucose production in the liver by insulin is an innate mechanism in place for taking care of existing high glucose levels from the diet.

Glucose toxicity has been linked to pancreas beta-cell degradation[9][10].
Clearly, sugar is harming insulin creating cells, leading to development of Diabetes type 1.
Type 1 Diabetics MUST inject insulin when they eat sugar, otherwise heavy damage occurs.

When cells can't accept anymore glucose, insulin shuttles them into fat cells, where they are converted into fatty acids. Also, Insulin reduces the breakdown of fats into fatty acids, thus preventing the usage of stored energy for energy usage.
Consequently, fat cells become fatter, because of sugar.

LDL particles and their cholesterol are oxidized due to the unstable nature of the bloodstream; promoted by Homocysteine levels and sugar levels.

Note: LDL particles have an armor; antioxidants like CoQ10 and Vitamin E[11][12]. Both are fat soluble, so they require fat to embed themselves in the LDL outer layer.

Macrophage Connection

As a defense mechanism accompanying the inflammatory response, white blood cells are sent to the area of inflammation in order to deal with any potential microbial/viral/fungal threat, neutralize it and clean the area up.

Monocytes, that come to the area, turn into Macrophages[13][14].
Macrophages are like garbage trucks, they can grab the oxidized cholesterol and collect it.

The mechanism of transporting cholesterol back to the liver, for recycling, is accomplished by HDL.
This particle has developed a mechanism with Macrophages called "Reverse Cholesterol Transport".
This mechanism describes a transfer from macrophages to HDL particles[15].
Essentially, this is how the Macrophages get rid of the accumulating cholesterol they grab and store.

Impairment of this mechanism causes Macrophages to self-destruct (Apoptosis),
and the accumulated cholesterol hardens and forms Foam cells.

Vitamin D Connection

Macrophages require Vitamin D to function properly.
This includes cholesterol metabolism[16] by preventing cholesterol uptake by macrophages[17].

Vitamin D's role has to do with relieving stress on the Macrophage. When stress increases the macrophage changes expression and overeats oxidized cholesterol LDL's, which leads to foam cell formation[18]. Supplementation with vitamin D2 (1,25(OH)(2)D) has clinically been observed to improve suppression of foam cell formation by increasing cholesterol efflux from stressed Macrophages.

Vitamin D has an important role in managing the cholesterol uptake and egress in Macrophages.
This vitamin suppresses foam cell formation, thus suppressing plaque formation in the arteries.

Cause and Effect Chart
Deficiency in B9 and B12 >>> Increase in Homocysteine
Homocysteine >>> Inflammatory response
Inflammation >>> Cholesterol transport to site
High sugar in diet >>> Cholesterol oxidation
Deficiency in Vitmain D >>> Impaired Immune cell clean up of cholesterol
Macrophages accumulate cholesterol >>> Formation of Foam cells

*Some studies imply that B6 is necessary to reduce homocysteine. However, one study[19] has found not such effect. B6 contribution can be associated with the cells requirements of that vitamin in order to synthesis Coenzyme Q10[20]. CoQ10 can protect against homocysteine-induced toxicity.
**B12 deficiency can be a result of imbalance in the microbial population in the gastrointestinal tract. Pathogenic bacteria destroy specialized cells, that produce Intrinsic Factor - an enzyme that carries B12 across the gut lining into the bloodstream[21][22]. Probiotic supplementation resolves this issue[23].
***Infection by Helicobactor Pylori not only inhibits B12 absorption but also B9[24]. This also found an increase in Homocysteine.

[1] Lancet. 1995 Jul 8;346(8967):85-9. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J. Source  Department of Geriatric Medicine, University Witten-Heddecke, Velbert, Germany.
[2] Atherosclerosis. 2011 Jun;216(2):461-6. doi: 10.1016/j.atherosclerosis.2011.02.027. Epub 2011 Feb 24. Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study. Kloppenborg RP, Nederkoorn PJ, van der Graaf Y, Geerlings MI. Source  Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands.
[3] Free Radic Res. 2002 May;36(5):521-9. Glucose accelerates copper- and ceruloplasmin-induced oxidation of low-density lipoprotein and whole serum. Leoni V, Albertini R, Passi A, Abuja PM, Borroni P, D'Eril GM, De Luca G. Source  Department of Experimental and Clinical Biomedical Sciences, Varese, Italy.
[4] Ann Surg. 1994 Jun;219(6):679-86; discussion 686-7. Insulin regulation of hepatic glucose transporter protein is impaired in chronic pancreatitis. Andersen DK, Ruiz CL, Burant CF. Source  Department of Surgery, University of Chicago, Illinois.
[5] Science. 2003 Jun 6;300(5625):1574-7. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Du K, Herzig S, Kulkarni RN, Montminy M. Source  Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.
[6] Cell Metab. 2009 May;9(5):417-27. doi: 10.1016/j.cmet.2009.03.013. APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney G, Zhu W, Vanhoutte PM, Kraegen EW, Xu A. Source  Department of Medicine, The University of Hong Kong, Hong Kong.
[7] Insulin | Wikipedia
[8] Glucogenic amino acid | Wikipedia
[9] J Clin Invest. 2002 Sep;110(6):851-60. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY. Source  Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland.
[10] Diabetes. 2003 Mar;52(3):581-7. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Source  Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
[11] Ann Med. 1991 Dec;23(6):649-56. Coenzyme Q10, alpha-tocopherol and free cholesterol in HDL and LDL fractions. Johansen K, Theorell H, Karlsson J, Diamant B, Folkers K. Source  Department of Analytical Chemistry, Kabi-Pharma AB, Stockholm, Sweden.
[12] Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9388-91. The roles of coenzyme Q10 and vitamin E on the peroxidation of human low density lipoprotein subfractions. Alleva R, Tomasetti M, Battino M, Curatola G, Littarru GP, Folkers K. Source  Institute of Biochemistry, Faculty of Medicine, University of Ancona, Italy.
[13] Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11529-30. Epub 2004 Aug 3. The in and out of monocytes in atherosclerotic plaques: Balancing inflammation through migration. Ludewig B, Laman JD. Source  Research Department, Kantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland.
[14] Curr Opin Lipidol. 2009 October; 20(5): 370–378. doi:  10.1097/MOL.0b013e3283309848 Macrophage heterogeneity in atherosclerotic plaques Jason L. Johnson and Andrew C. Newby
[15] Macrophage Reverse Cholesterol Transport. Key to the Regression of Atherosclerosis? Marina Cuchel, MD, PhD; Daniel J. Rader, MD Circulation. 2006; 113: 2548-2555 doi: 10.1161/​CIRCULATIONAHA.104.475715
[16] J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):430-3. doi: 10.1016/j.jsbmb.2010.03.018. Epub 2010 Mar 23. Vitamin D regulates macrophage cholesterol metabolism in diabetes. Riek AE, Oh J, Bernal-Mizrachi C. Source  Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, United States.
[17] Circulation. 2009 Aug 25;120(8):687-98. doi: 10.1161/CIRCULATIONAHA.109.856070. Epub 2009 Aug 10. 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, Petty M, Chen Z, Schechtman KB, Bernal-Mizrachi L, Bernal-Mizrachi C. Source  Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
[18] J Steroid Biochem Mol Biol. 2013 Jan 17. pii: S0960-0760(13)00010-1. doi: 10.1016/j.jsbmb.2012.12.019. [Epub ahead of print] 1,25(OH)(2) vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients. Riek AE, Oh J, Bernal-Mizrachi C. Source  Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Avenue, Campus Box 8127, St. Louis, MO 63110, USA.
[19] Am J Clin Nutr. 2005 Mar;81(3):648-55. Dietary vitamin B-6 restriction does not alter rates of homocysteine remethylation or synthesis in healthy young women and men. Davis SR, Scheer JB, Quinlivan EP, Coats BS, Stacpoole PW, Gregory JF 3rd. Source  Food Science & Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville 32611-0370, USA.
[20] Biofactors. 1999;9(2-4):359-63. Clinical implications of the correlation between coenzyme Q10 and vitamin B6 status. Willis R, Anthony M, Sun L, Honse Y, Qiao G. Source  Institute for Biomedical Research, University of Texas at Austin 78712, USA.
[21] Arch Intern Med. 2000 May 8;160(9):1349-53. Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency? Kaptan K, Beyan C, Ural AU, Cetin T, Avcu F, Gülşen M, Finci R, Yalçín A. Source  Department of Hematology, Gülhane Military Medical Academy, Ankara, Turkey.
[22] J Clin Gastroenterol. 2003 Feb;36(2):130-3. An association between Helicobacter pylori infection and serum vitamin B12 levels in healthy adults. Shuval-Sudai O, Granot E. Source  Internal Medicine Services, Kupat Holim Leumit, Hadassah University Hospital, Jerusalem, Israel.
[23] J Nutr. 2007 Mar;137(3 Suppl 2):812S-8S. Helicobacter pylori and probiotics. Lesbros-Pantoflickova D, Corthésy-Theulaz I, Blum AL. Source  Department of Internal Medicine, Clinique Genolier, 1272 Genolier, Switzerland.
[24] Am J Gastroenterol. 2002 Apr;97(4):861-6. Relation of Helicobacter pylori infection to plasma vitamin B12, folic acid, and homocysteine levels in patients who underwent diagnostic coronary arteriography. Tamura A, Fujioka T, Nasu M. Source  Second Department of Internal Medicine, Oita Medical University, Hasama, Japan.

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