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

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 NAC –relatively safe, with stomach irritation and agitation being reported the most from supplementation.

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 Note: Recommended doses and safety are indefinable due to lack of long-term, large clinical studies

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

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

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

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

“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

Metabolic Activation Therapy (MAT) Role in Diabetic Patients 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 MAT procedure is either a weekly protocol of 6 or 4 hour sessions. For one hour, the patient receives regular insulin IV in a pulsatile manner, after which they are given 20 minutes and enough carbohydrates to keep their blood glucose at a target between 150-250mg/dL. Most of the carbohydrates given, 75%, are given in liquids to ensure that the majority of the load gets burned during the session. These two phases are repeated twice. The activation is confirmed by using the patient’s respiratory quotient. A target range of 0.9 – 1.0 ensures that the therapy has activated the patient’s metabolism and is actively burning glucose.

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

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.

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.

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