GLYCATION AND DISEASE.

Glucose is useful as a source of ATP, energy for the cell, via the classic glycolysis which itself includes three different pathways. They all require the use of enzymes. However, glucose has to penetrate the cell, a reaction heavily dependent on insulin to occur. On the other hand, glucose outside of the cell has a choice of a series of spontaneous reactions, not requiring any enzymatic help.  This process of spontaneous glucose reaction with other products, protein, lipids, nucleic acid, is called glycation1,2. The products formed as a result of this chemical reaction are glycation products which can be intermediate or end products, in which case the terminology of Advanced Glycating End Products, henceforth referred to as AGEs. Ordinarily, this occurs at a low intensity and the products are cleared by the kidney. Examples of intermediate glycated products include fructosamine and hemoglobin A1C; the former occurs between glucose and an amino acid and the latter between glucose and hemoglobin. Either is used as a surrogate marker for the control of diabetes1,2,3..

However, when glucose begins to accumulate outside of the cell because it can’t get in, for any number of reasons, the most common being insulin dysfunction or insufficiency, then glycation becomes more prevalent.

Besides endogenous AGEs, they can also be found from an exogenous source, i.e., diet, sometime  referred to dAGEs. 

Fig.1. Glucose and AGE formation pathways incorporating the polyol pathway and AGE formation by the a-oxoaldehy- des glyoxal, methyl glyoxal and 3-DG. 3-DG, 3-deoxygluco- sone; MGO, methylglyoxal; CML, N-e-carboxymethyl) lysine; CEL, N-e carboxyethyl)lysine; DOLD, deoxyglucasone-ly-sine dimer; MOLD, methyl glyoxal-lysine dimer; GOLD, gly-oxal-lysine dimer . From Singh et al, Glycation end-products: a review. Diabetologia 2001. 44: 129±146.

Disease formation.

The accumulation of AGEs results in some dire consequences via a plethora of nefarious pathologies.

  • Pathological cross-linking of proteins. In the presence of AGEs in diabetes, an aging process is accelerated. Collagen is the archetype of a cross-linked protein. This irreversible process occurs extensively, ending in a dysfunction of the protein matrix and stiffness. Vessel walls are affected, atherosclerosis is enhanced, renal glomeruli become sclerosed and the basement membrane of capillaries become thickened1,2,3.
  • Inflammation as a chain reaction. The first step is an increase in the oxidative stress by activation of reactive oxygen species (ROS) and as a result causes a proinflammatory milieu, generation of free radicals, thrombosis, vasoconstriction and most certainly endothelium dysfunction. This becomes amplified in perfusion-sensitive highly specialized organs such as eyes, kidneys, nerves, brain, heart. The nexus between glucose toxicity causing high concentration of AGEs and inflammation establishes synergistic damage, perpetuating a vicious cycle by positive feedback.

In practical terms, diabetes carries a very high-risk factor for coronary artery disease. The mechanism involved includes:

  • increased oxidative stress.
  • activation of protein kinase C (PKC).
  • chronic inflammation.
  • mitochondrial dysfunction.
  • and activation of the renin-angiotensin system (RAS)3.

 

The importance of oxidative stress can’t be overemphasized in cardiovascular disease pathogenesis. AGEs cause the increased in the concentration of ROS and this perturbs the normal homeostasis between oxidation and reduction in favor of oxidation. By the way, reduction is commonly referred to as antioxidation.

Disease progression can occur via a variety of mechanisms1, 2, 3,6:

  • Lipid peroxidation. ROS activation results in reduction of protective nitric oxide, increased in endothelin-1. This type of endothelium dysfunction also is associated with vasoconstriction. (In a previous Newsletter (#240, October 2018), an in-depth review of nitric oxide can be found.)
  • Protein structural changes.  Disruption in lens crystalline yields cataract; increase in cell membrane and matrix changes in diabetic kidney resulting in glomerulosclerosis.
  • Platelet dysfunction. Decrease in survival, increase in stickiness and aggregation as well as decreased sensitivity to fibrin/fibrinogen following glycation. Thrombosis/fibrinolysis are enhanced.
  • Alzheimer’s disease. Glycation of β-amyloid accelerates progression of condition. In fact some advocates go so far as calling Alzheimer, diabetes type 3, hinging on the fact that the brain uses glucose primarily as a source of energy and as the third largest organ so energy-dependent, glycation becomes very important. It’s estimated that glycation occurs in the brain at higher rate than in other organs5.
  • PCOS. Elevated levels of AGEs (endogenous as well as exogenous) accelerate PCOS in females via several mechanisms among which an increase in testosterone levels, excess deposit of collagens associated with irregular cycles and formation of cyst in ovaries respectively6. Low level of vitamin D is known to be part of the pathology.

 

Physical signs.

The accumulation of AGEs results in their infiltration of soft tissue and organs. The skin is a common organ affected and its exam can reveal quite a good trove about a patient’s level of diabetes control.  As AGEs accumulate in it, it loses its smooth consistency and instead takes on a doughy texture almost like wood and lacks mobility. This is variably referred to as diabetic thick skin or scleroderma-like skin changes. It affects primarily but not solely, the hands and feet as well as the legs and forearms4. Another related finding is the so-called Limited joint mobility. Most commonly it affects the hands and one can look for the “prayer sign,” the inability to have both palms touch each other.

“Prayer sign”

  

Limited joint ability, from Rosen, J. Skin Manifestations of Diabetes Mellitus. [Updated 2018 Jan 4]. In: Feingold KR, Anawalt B, Boyce A, et al., editors.

  

Measurement of AGEs.

No standard commercial test exists to evaluate specific AGEs. However, there are newer techniques being suggested, for example, skin fluorescence5.

Modulation of level of AGEs.

  • Exogenous. Processed foods made via dry heat produce glycated products. When taken orally, absorption varies from 10-30%. Examples include commonly consumed staples such as cookies, biscuits, chips. A reduction of their consumption is the most obvious solution6.
  • Endogenous. Such modulation would involve both enhanced glycolysis and inhibition of glycation. The pharmacopoeia for enhanced glycolysis harkens back to the available antihyperglycemic agents7 and other nonpharmacologic interventions such as diet and exercise. Vitamin D plays a therapeutic role in PCOS, usually associated with a low level of the vitamin8. However, for the other conditions, there are other agents that have been proven to help9,10,10,11,12,13. ACEIs, ARBs, benfotiamine (a synthetic and highly absorbable form of thiamine available OTC), pyridoxamine, statins. The mechanism involved varies. ACEs, ARBs, statins would seem to act primarily as antioxidants, whereas benfotiamine as a cofactor of transketolase accelerates the pentose phosphate pathway (an offshoot pathway of glycolysis). It happens to be inexpensive. Mechanism of pyridoxine is not clear, but its level is usually low in diabetics10.

Control of diabetes is a multi-pronged intervention. Proper dietary habits, exercise, pharmacologic means, all contribute to risk reduction. Our group is so susceptible to its complications that we need to be proactive and very aggressive in our approach.

 

Reynald Altéma, MD.

 

 

References:

1.     Singh et al, Glycation end-products: a review. Diabetologia 200; 44: 129±146.

  1. Kuzan A. Toxicity of advanced glycation end products (Review). Biomed Rep. 2021;14(5):46. doi:10.3892/br.2021.1422
  2. Yang P, Feng J, Peng Q, Liu X, Fan Z. Advanced Glycation End Products: Potential Mechanism and Therapeutic Target in Cardiovascular Complications under Diabetes. Oxid Med Cell Longev. 2019; 2019:9570616. Published 2019 Dec 6. doi:10.1155/2019/9570616
  3. Rosen J, Yosipovitch G. Skin Manifestations of Diabetes Mellitus. [Updated 2018 Jan 4]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481900/
  4. Fokkens BT, Smit AJ. Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes. Glycoconj J. 2016 Aug;33(4):527-35.
  5. Gill V, Kumar V, Singh K, Kumar A, Kim JJ. Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health. Biomolecules. 2019 Dec 17;9(12):888.
  6. Medical Letter, Vol 61 (1584), November 4, 2019.

8.     Merhi, Z. Cross talk between advanced glycation end products and vitamin D: A compelling paradigm for the treatment of ovarian dysfunction in PCOS. Mol. Cell. Endocrinol. 2019, 479, 20–26.

  1. Volvert ML, Seyen S, Piette M, Evrard B, Gangolf M, Plumier JC, Bettendorff L. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 2008 Jun 12;8:10.
  2. Valdés-Ramos R, Guadarrama-López AL, Martínez-Carrillo BE, Benítez-Arciniega AD. Vitamins and type 2 diabetes mellitus. Endocr Metab Immune Disord Drug Targets. 2015;15(1):54-63.
  3. A. Nenna, F. Nappi, S. S. Avtaar Singh et al., “Pharmacologic approaches against advanced glycation end products (AGEs) in diabetic cardiovascular disease,” Research in Cardiovascular Medicine, vol. 4, no. 2, article e26949, 2015.
  4. D. J. Borg and J. M. Forbes, “Targeting advanced glycation with pharmaceutical agents: where are we now?,” Glycoconjugate Journal, vol. 33, no. 4, pp. 653–670, 2016.
  5. P. Balakumar, A. Rohilla, P. Krishan, P. Solairaj, and A. Thangathirupathi, “The multifaceted therapeutic potential of benfotiamine,” Pharmacological Research, vol. 61, no. 6, pp. 482–488, 2010.

 

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