Overview of advanced glycation end - products (AGE s )

1. Part 4 Overview of advanced glycation end-products (AGEs)

2. Supplements: Improve AGEs Effects • Alpha-Lipoic Acid • Effective inhibitor of AGE formation in diabetes • Limited to animal studies • More favorable supplement to consider • N-Acetylcysteine (NAC) • Antioxidant precursor to a natural antioxidant , glutathione, known to be depleted in diabetic patients • Findings by De Mattia et al. demonstrated reductions in pro-atherosclerotic vascular adhesion molecules from NAC supplementation in Type 2 diabetics

3. Supplements: Improve AGEs Effects • Benfotiamine • Lipophillic derivative of the B-vitamin thiamine • May prevent inflammation caused by AGE intake by shunting glycolytic intermediates to the reductive pentose pathway • Findings by Stirban et al. demonstrated that the administration of 1050 mg of benfotiamine per day to Type 2 diabetic patients: • Reduced inflammatory markers • Improved circulations • Reduced pro-atherosclerotic adhesion molecules

4. Supplements: Improve AGEs Effects • L-Carnosine • Scientific reviews suggest: • Carnosine is a potent inhibitor of the formation of AGE products • Has therapeutic potential in diabetes and diabetic complications • Clinical studies are non-existent in U.S. literature • Impossible to recommend a dose • Lack of studies in humans make it difficult to determine the safety of carnosine

5. Supplements: Improve AGEs Effects • Vitamin C and Vitamin E • Preliminary animal research suggests a combination of vitamin C and vitamin E may prevent AGE product formation • Findings by Konen et al. supplemented 22 diabetic patients with vitamin C and vitamin E for one year and did not observe a reduction in AGE content of skin samples

6. Pharmacological Agents Under Investigation Specifically Aiming at AGEs • AGE Breakers (4,5- dimethyl-3 phenacylthiazolium, also known ALT-711) • Break AGE protein-protein crosslinks in vitro • Improve arterial compliance in a phase 2 clinical trial in the elderly • Inhibitor of AGEs (Aminoguandine) • Hydrazine compound that prevents AGE formation by reacting mostly with derivatives of early glycation products that are not bound to proteins • Also NOS inhibitor

7. Pharmacological Agents Under Investigation Specifically Aiming at AGEs • Findings by Bolton et al. in a placebo controlled, randomized trial in Type 1 diabetic patients demonstrated: • Slower reduction in glomerular filtration rate • Reduced 24-hour urinary proteinuria and progression of retinopathy • Did not attenuate the time to doubling of serum creatinine

8. “More Common” Pharmacological Agents that May Reduce AGE Accumulation • Antihypertensives (Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers) • Reduce AGE accumulation in concert with the severity of diabetic nephropathy • Antihyperglycemic (Metformin) • Diamino biguanide compound that may decrease AGE accumulation by reducing methylglyoxal levels • A scavenger of reactive oxygen species, reducing oxidative stress • Treatment improves endothelial function in Type 2 diabetic patients

9. Metabolic Activation Therapy (MAT) Role in Diabetic Patients • Metabolic Activation Therapy (MAT) • Patented procedure developed by Dr. Thomas T. Aoki • Chronic therapy to stop the advancement of diabetic complications or to control A1c values when all other therapeutic options have failed • Does not reverse tissue damage that has already occurred due to progression of the disease • Activate the cells in the liver and elsewhere to synthesize glucokinase and other insulin-dependent enzymes with the delivery of insulin at a target level equal to that of a non-diabetic person, 200-1,000 microU/mL

10. Metabolic Activation Therapy (MAT) Role in Diabetic Patients • Higher level at the portal vein in conjunction with the pulsatile fashion, 10 pulses per hour • Mimics the body's first phase of insulin secretion • Enhances the liver’s processing of glucose or activating it to maintain metabolic homeostasis, resulting in other tissues and organs being affected • Glucose is recognized as an alternate source of energy and its uses less oxygen for its utilization • Allowing tissues with decreased circulation to function with less demand for oxygen, resulting in normal functioning, damage repair, and healing

11. Conclusion • The formation of advanced glycation end-products (AGEs) is a contributing factor in complications found in diabetic patients. • AGE formation in diabetic patients occurs as a consequence to chronically elevated blood glucose levels. • Primary sources of AGEs should be avoided or limited if possible. • Dietary intake of AGEs affect blood vessel inflammation and oxidation of “bad” cholesterol, leading to increased atherosclerosis. • Dietary modifications are strongly recommended to reducing AGEs effects in all patients.

12. Conclusion • Supplements may be beneficial to improving or preventing the effects of AGE products in diabetic patients; however, studies are limited by small sample size of humans, only animal studies, or lack of studies altogether. • The investigation of pharmacological agents specifically aiming at AGEs: AGE breakers and inhibitors. • Common pharmacological agents that may reduce AGE accumulation: antihypertensives (ACEIs and ARBs) and metformin. • Metabolic Activation Therapy (MAT) may have its advantage in reducing the effects of AGEs by allowing tissues with decreased circulation to function with less demand for oxygen, resulting in normal functioning, damage repair, and healing through the activation of the diabetic patient’s metabolism by directly burning glucose.

13. References • Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovascular Research. 2004; 63: 582-592. • Henning C, Smuda M, Girndt M et al. Molecular basis of maillard amide-AGE formation in vivo. J Biol Chem. 2011 Nov 8. • Kanwar YS, Sun L, Xie P et al. 2011. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011 Feb 28;6:395-423. • Melpomeni P, Uribarri J, Vlassara H. Glucose, Advanced Glycation End Products, and Diabetes Complications: What Is New and What Works. Clinical Diabetes. 2003; 21(4): 186-187. • Peppa M & Vlassera H. Advanced glycation end products and diabetic complications: A General overview. Hormones. 2005, 4(1): 28-37 • Ramasamy R, Schmidt AM, Yan FS. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab. 2008 May;4(5):285-93. • Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):953-61. • Uribarri J, Woodruff S, Goodman S et al. grilling, broiling, roasting, searing, and frying propagate and accelerate new AGE formation. J Am Diet Assoc. 2010 Jun;110(6):911-16.e12. • Yamagishi S. Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Exp Gerontol. 2011 Apr;46(4):217-24.

14. References • Bradley R. AGE in Food: Are You What You Eat?. Diabetes Action research and Education Foundation. December 2006. Accessed at http://www.diabetesaction.org. • De Mattia G, et al. Reduction of oxidative stress by oral N-acetyl-l-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes. Diabetologia.1998;41:1392-1396. • Stirban A, Negrean M, Stratmann B, et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individual with type 2 diabetes. Diabetes Care. 2006;29:2064-2071. • Guiotto A, Calderan A, Ruzza P, et al. Carnosine and carnosine-related antioxidants: a review. Curr Med Chem. 2005;12:2293-315.. • Yatoh, S., et al., Antioxidants and an inhibitor of advanced glycation ameliorate death of retinal microvascular cells in diabetic retinopathy. Diabetes Metab Res Rev, 2006. 22(1): 38-45. • Konen et al. J Nutr Health Aging. 2000;4:81-4. • Goldin A, Beckman JA, Achmidt AM, and Creager MA. Basic science for clinicians: advanced glycation end products sparking the development of diabetic vascular injury. Circulation American Heart Association Journal. 2006;114:597-605. • Meerwaldt R, Links T, Zeebregts C, et al. The clinical relevance of assessing advanced glycaion endproducts accumulation in diabetes. Cardiovascular Diabetology. 2008;7:29. • Justino VM. Hope for Advanced Diabetic Patients-Metabolic Activation Therapy. June 24, 2008. Accessed at http://www.diabetesincontrol.com/articles/54-feature/5868.

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