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Glycosylation: What is it, how it affects patients with diabetes

Glycosylation refers to the covalent bonding of blood glucose to the red blood cells. Normally, only a small percentage of blood glucose, usually between 4.5%- 6%, is covalently linked to the red blood cells in hemoglobin of the non diabetes population.

This value is commonly referred to as glycosylated hemoglobin or more specifically hemoglobin A1c.[i] The quantification for hemoglobin A1c is based on the total accumulation and reaction between glucose and red blood cells over their life span of 90-120 days. Apparently, short term or hourly elevations in blood sugar levels do not seem to acutely affect the total hemoglobin A1c value. This may be due possibly to the suspected slow rate in which glucose and hemoglobin combine.

Nevertheless, the increased amount and duration of glucose in the blood allows more glycosylation to occur, not only with hemoglobin, but with proteins and this can have systemic ramifications.[ii] The excessive cleavage of glucose, especially with important protein amino groups, can affect cell function and structure and create an inbalance which leads to cell destabilization.[iii] [iv]

This condition seems to target organs and tissues that are not dependent on insulin for their absorption of glucose. Kidneys, blood vessels, peripheral nerves and lenses of the eye are more susceptible to damage from periods of hyperglycemia than other organs due to their lack of insulin dependence.

There appears to be a particular enzyme implicated in the corruption of these cell structures. It is called aldose reductase. Aldose reductase is responsible for converting sugars to their corresponding alcohols namely sorbitol. Since a diabetes patient has higher than normal serum glucose levels, susceptible cells exposed to aldose reductase accumulate larger amounts of these converted alcohols. It is known as the polyol pathway.[v]

This process creates an imbalance within the cell, causing a loss of electrolytes and other minerals and ultimately leading to the collapse of its architecture. There has been continuing research in developing aldose reductase inhibitors that will reduce this enzyme’s affects and hopefully the complications associated with it. Unfortunately, every drug developed so far as an inhibitor has had very questionable efficacy and safety concerns.[vi]

All of the cellular interactions we have discussed thus far have been the result of varying forms of oxidation. Both types of diabetes patients show a higher level of oxidative damage to their DNA than euglycemic patients.[vii] One of the possible pathways of this damage is through non-enzymatic advanced glycosylation end products (AGE).[viii]

AGE is the result of years of accumulated glycated damage to molecules that are not replaced regularly, but have a low turnover rate. The primary examples are the matrix protein complexes and chromosomal DNA, which are subject to irreversible corruption that can cause genetic mutation.[ix] [x]

Also, reactive oxygen species (ROS) are thought to be implicated in the pathogenesis of diabetes as well as other diseases.[xi] Reactive oxygen species are usually comprised of radicals that have the ability to oxidize and damage DNA, proteins and carbohydrates. Hyperglycemia appears to induce oxidative stress on cells and this can cause an increase in the production of free radicals.[xii]

Conversely, some studies show first an increase in free radical production after eating that actually heightens post prandial blood sugar.[xiii] Human antioxidant enzymes are mobilized during hyperglycemia, but they cannot meet the continued demand due to increased oxidative stress.[xiv] This problem is compounded by a possible breakdown in the ability to produce these enzymes from a decreased intake of the needed precursors or an inability to synthesis them.[xv]

Antioxidant supplementation may provide the only means in which to reverse this process.[xvi] Studies on the beneficial effects of antioxidants and how they pertain especially to diabetics have been postulated for several decades. More recent clinical trials confirm the uses of typical antioxidants alone or in congruence with other natural supplements may retard or even prevent the normal progression of diabetic complications.

The far reaching implication of this significant fact has been a highly underrated by the medical community. We at times have overlooked a tremendous opportunity to alter the normal course of a disease by the use of something as benign as a vitamin.

Most of these studies have focused their attention on vitamins C and E. Vitamin C has the same transport mechanism as that of glucose in the body. When the plasma concentration of vitamin C is plentiful it tries to compete with glucose in binding with hemoglobin and protein amino groups. This action reduces or inhibits excessive glycosylation of red blood cells and proteins, which in turn will decrease the creation of free radicals.

Also, vitamin C may function as a natural aldose reductase inhibitor preventing the conversion of sugars to their corresponding alcohols by not allowing cellular destabilization in susceptible sites. Last, the prevalent long term depletion of vitamin C, common in diabetes, may contribute to depressed immune function, compromised wound healing ability and reduced blood vessel integrity. These and other related aliments can possibly be arrested and reversed by vitamin C supplementation.

One of the latest entries in the antioxidant arsenal for diabetics is alpha lipoic acid. It appears to recycle available vitamin C and E. If the great success in the early studies are any indication, this natural supplement alone could profoundly effect the rate of diabetic complications.

Dr. Brian P. Jakes, Jr., N.D., C.N.C. is a Board Certified Doctor of Naturopathy as well as a Certified Nutritional Consultant. In his practice, in Mandeville, LA, Dr. Jakes works with physicians to treat a large number of diabetes patients. This is an excerpt from his upcoming book; “Diabetes: The Essence Of A Cure”

[i] H. Franklin Bunn, K. H. Gabbay, P. M. Gallop. The Glycosylation of Hemoglobin: Relevance to Diabetes Mellitus. Science, Vol 200 7 April 1978 p21-27.

[ii] Lee PD, Sherman LD, O’Day MR, Rognerud CL, Ou CN. Comparisons of home blood glucose testing and glycated protein measurements. Diabetes Res Clin Pract 1992 Apr;16(1):53-62.

[iii] Bernstein RE. Nonenzymatically glycosylated proteins. Adv Clin Chem 1987;26:1-78.

[iv] Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med 1991;10(5):339-52.

[v] Morrison AD, Clements RS, Travis SB. Glucose utilization by the polyol pathway in human erythrocytes.

Biochem Biophys Res Commun 1970;40:199-205.

[vi] Pfeifer M, Schumer M, Gelber A. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes 46(Suppl 2):S82-89,1997.

[vii] P. Dandona, K Thusu, S Cook, B Snyder, J Makowski, D Armstrong, T Nicotera. Oxidative damage to DNA in diabetes mellitus. Lancet Vol 347 February 17, 1996 p 444-445.

[viii] H. Vlassara. Recent Progress in Advanced Glycation End Products and Diabetic Complications. Diabetes, Vol. 46 Suppl. 2 September 1997 pS19-S25.

[ix] Bucala R, Vlassara H. Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis 1995 Dec;26(6):875-88.

[x] Kawakami M, Kuroki M. Role of advanced glycation end products (AGE) in the development of diabetic microangiopathies and the beneficial effects of AGE inhibitors. Nippon Rinsho 1999 Mar;57(3):567-72.

[xi] Toyokuni S. Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 1999 Feb;49(2):91-102.

[xii] A Ceriello, P Dello Russo, P Amstad, and P Cerutti. High Glucose Induces Antioxidant Enzymes in Human Endothelial Cells in Culture. Diabetes Vol 45 April 1996 p 471-476.

[xiii] Ceriello A, Bortolotti N, Motz E, et al. Meal-generated oxidative stress in type 2 diabetic patients. Diabetes Care 1998 Sep;21(9):1529-33.

[xiv] Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosci 1999 Mar 15;4:D339-45.

[xv] Kelly FJ. Use of antioxidants in the prevention and treatment of disease. J Int Fed Clin Chem 1998 Mar;10(1):21-3.

[xvi] B. Halliwell, J. Gutteridge. Lipid Peroxidation, Oxygen Radicals, Cell Damage, and Antioxidant Therapy. Lancet, June 23, 1984 p1396-1397.