Anti-Glycation Supplements Part III (Glycation: Part II of II)

Pyridoxal-5’-phosphate (Vitamin B6): What is known as ‘Vitamin B6’ has three vitamers (chemically individual related compounds): pyridoxine, pyridoxamine, and pyridoxal. Some sources incorrectly state pyridoxamine to be the strongest anti-glycation agent, but the most effective form of vitamin B6 is the metabolically active form that the vitamers convert to – pyridoxal-5’-phosphate (P5P). Against pyridoxamine, P5P more efficiently reduced the accumulation of major advanced protein glycation products CML and imidazolone in vivo. (222) Moreover, the same study revealed P5P to be an anti-DNA glycation agent based on its inhibition of N2-(1-carboxyethyl)-2′-deoxyguanosine (CEdG), unlike pyridoxamine which offered no protection at all against this particular AGE adduct. (223) P5P has additionally proven to be a potent retarder of lipid glycation and compared very favorably in this ability against both formidable pharmaceutical and natural protein glycation inhibitors including aminoguadinine, carnosine, ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), quercetin and rutin (flavonoids), and amino acids lysine and cysteine. (224) It was briefly discussed in Glycation: Part I (See here) how DNA glycation is an underrated threat in diabetes and its complications, though lipid glycation also has a substantial impact in the development of diabetes and related complications. (225-228)

Other than preventing the accumulation of lipid-AGEs, an ability that most other potent anti-AGE compounds do not share, P5P is a renowned anti-AGE nutrient for its unusual but effective mechanism of trapping intermediate carbonyl products (pre-AGEs) to directly block AGE formation. Although the main theme of this article series was to focus on existing AGEs formed in food that are exogenously absorbed, some food products such as honey (229) are high in intermediate AGE products and form AGEs inside the body rapidly with the glycation process already set in motion. In this instance, P5P can loosely prevent dietary sourced AGEs if they are currently in the intermediate phase of glycation such as in processed or cooked carbohydrate foods where necessary amino acids will not be present for the formation of irreversible late-term AGE products.

By inhibiting all forms of glycation and outcompeting other powerful natural AGE inhibitors and pharmaceuticals, P5P demonstrates protection against a host of diabetic complications in vivo. (222)(230)

Riboflavin: There is presently a limited amount of data on riboflavin as an anti-glycation agent, but early research suggests it does have AGE-inhibiting potential based on in vitro results against methylglyoxal-induced glycation of bovine serum albumin. (89) It is also observed that a deficiency in the B2 vitamin, which is seen in much greater frequency in diabetics, causes even more lipid peroxidation … sharply increasing the potential for glycation. (90-91) Therefore, repletion in this vitamin should also be a goal in limiting AGE formation.

Selenium Yeast: Selenium in the organic form, such as yeast-bound selenium has been shown to strongly inhibit glycation and AGEs at physiological concentrations more impressively than other formidable anti-glycation agents including ascorbic acid (vitamin C), tocopherol (vitamin E), niacinamide, carnosine, and pyridoxal (active vitamin B6) at similar concentrations. (102) Sodium selenite as inorganic selenium was also included but did not significantly prevent glycation, especially compared to yeast-bound selenium. (I03) Selenium itself has decreased glucose, glyclated hemoglobin, lipid peroxidation products, and downregulated RAGE (receptors for AGEs) and AGE-induced activation of NFkB in vivo (104), but the added yeast component is theorized to further contribute to glycation-limiting abilities by addition of lysine – also a glycation limiter, at least in vitro. (105) Additionally, organic selenium has greater bioavailability and appears to possess better radical-scavenging abilities, which translates to better AGE inhibition. (106-108)

As far back as the early 1980s, it was discovered that high doses of selenium (500mcg w/ co-supplementation of vitamin E, C, and A) worked to reverse the beginnings of diabetic retinopathy and halt the process in advanced cases. (109) Diabetic retinopathy is majorly associated with glycation damage, notably by inducing VEGF expression (110) Therefore, selenium’s pivotal role in diabetic eye damage would be explainable.

One caveat with recommending a similar dose for potent anti-glycation effects is selenium’s status as a trace element. As such, the therapeutic window is narrow, meaning negative side effects and toxicity can result from high dosages. There is also some concern about selenium’s relationship to diabetes. In diabetes there is an increased concentration of plasma selenium (111), which does not exactly mean that diabetics have more selenium storage or consume more selenium-containing foods but rather that there is a higher demand of selenium usage and in a broader sense, a greater strain on antioxidant response to combat the increased lipid peroxidation and AGE generation in the disease. Defense of selenium as a reactant and not as a causal agent in this disease in discussed in greater detail in “Selenium”. In short, the verdict suggests a helpful role rather than a harmful one, but nevertheless those already with diabetes should take precautions before adding supplementary selenium to their regime.

Silymarin/Milk Thistle: Found in milk thistle, this flavonoid is rich in health-enhancing properties, two of which pertinent to glycation are anti-inflammation activity and carbonyl trapping ability. Using diabetic rats, silymarin prompted a decrease in inflammatory markers (255), and when compared with other polyphenols, silymarin was one out of the three of five tested to exhibit an inhibitory effect on the inflammatory marker TNF-alpha and the inflammatory mediator nitric oxide induced by glycation. (256)With an interdependent existence between inflammation and AGEs, silymarin could both prevent endogenously formed AGEs and lessen the inflammation produced from existing AGEs.

As for a more direct anti-AGE action, silymarin displays blockage of late stage glycation by trapping reactive carbonyls and subsequent cross-linking as well as mitigating glycated albumin concentrations … equaling less AGE accumulation and resulting in protection from diabetic complications in diabetic rodents. (255) This leaves potential to obviate AGE intake from food with reversible, mid-term glycation products.
Silymarin in a dosage of 200mg daily used as an adjunct to gliberclamide in a double-blinded placebo-controlled study demonstrated mass improvement in glycated hemoglobin values on top of lowering fasting glucose levels and BMI in type II diabetes who responded poorly to glibenclamide therapy alone. (257)

Taurine: In diabetes, greater excretion rates of the sulfur-containing amino acid occur. (241) The increased AGE accumulation seen in diabetes occurs partially due to the loss of taurine as taurine was confirmed as an anti-(protein)glycation nutrient in human RBC (red blood cells)(242), which explains the accompaniment of increased Hlabc with the diminished plasma taurine concentrations. (243) In vivo, taurine markedly decreased the accumulation of CML, a protein-based AGE, in red blood cells. (244) Compared to the supplementation of vitamin E and selenium, diabetes-associated mortality (the most popular being vascular-related ) in diabetic rats was lower in those supplemented with taurine.( 245) Taurine’s opposing effect on diabetic vascular complications can be understood by its capability to significantly block glycation of red blood cells. The alteration of RBC adhesion as affected by glycation correlates with the severity of vascular complications in diabetes. (246) Additionally, there is a well-recognized association between glycated hemoglobin and microvascular disease and a stronger predictive capacity of glycated hemoglobin for cardiovascular disease than fasting glucose.(247-248) In a very short-term human study involving young type I diabetics, 500mg of daily taurine reversed measures of endothelial dysfunction including arterial stiffness and flow-mediated dilatation to normal levels seen in non-diabetic before any effect could be observed on glycation activity represented by glycated hemoglobin and fructosamine levels. (249) As AGEs are notable contributors of endothelial dysfunction (250-251), this could mean taurine can immediately reduce AGE activity (eg. communication with AGE receptors, AGE-mediated oxidative stress and inflammation) without lowering AGE concentrations.

Second to its protective power over erythrocytes, it has an indirect anti-AGE mechanism as a chief inhibitor of lipid peroxidation. (252) Due to its strength in suppressing lipid peroxidation, taurine by itself was superior to vitamin E combined with selenium for better control of diabetic retinopathy. (253) By extension, uncooked or treated dietary fats lacking the sufficient protein to generate AGE formation will be protected by taurine from glycating endogenously and forming AGEs through lipid peroxidation.

Despite promising findings, taurine’s anti-glycation benefits may be tissue-selective, or at least much stronger for the health of the retina and the nerves. It may even slightly negatively affect the kidney when supplemented alone judging by an increase in the glomeruler volume and an increase in glomerular cell loss of diabetic rats. Moreover, a non-effect on AGE reduction was observed in the kidney. However, when taurine was supplemented alongside NAC (N-acetylcysteine), adverse glomeruler changes were completely reversed and the synergic relationship of the nutrients became a strong target for allaying kidney- residing AGE accumulatio, moreso than when either was used alone. (254)

Repletion of taurine status is the norm in the generally healthy as acquired by diet, so further supplementation is rarely indicated. Taurine supplementation will be of most use primarily to diabetics where taurine clearance is amplified and in vegetarians where taurine is deficient in the diet. For optimal effect of glycation reduction and glycaton-related symptoms, taurine replenishment should accompany NAC supplementation.

Thiamine: Thiamine, otherwise known as vitamin B1, is vital to energy metabolism and glucose metabolism. (56) A mild deficiency in the vitamin is enough to adversely affect glucose metabolism and enhance glycation activity. (57) A significant thiamine deficiency exists in type I and type II diabetes from the disease-mediated dysregulation of thiamine transport and resultant thiamine excretion that not even twice the consumption of the recommended daily value can account for. (58-59)

As yet another mechanism by which AGE levels increase in diabetes, a thiamine deficiency indirectly creates a bigger AGE burden since enzymes that require thiamine as a cofactor to inhibit glycation formation pathways cannot perform their function.(60-61) On top of inhibiting biochemical pathways that facilitate the accumulation of AGEs, thiamine is helpful with anti-glycation as a protector of oxidative stress and as a possible metal chelator. (63-65) It is an even stronger AGE-inhibitor than aminoguanidine in vitro, which only weakly inhibited late stages of glycation (62), and furthermore, thiamine in vitro outperformed carnosine by completely inhibiting the formation of AGE cross-linking.

Given that the disease process fuels the loss of available thiamine and renders cells more susceptible to glycation (66), thiamine should have a designated role over conventional AGE-inhibitors like aminoguaidine for diabetes control. Replenishment of thiamine by means of high-dose therapy in diabetic rats normalizes CML as well as CEL (N-carboxyethyl-lysine) – another AGE product – in plasma, and it does so by preventing the formation of AGE precursors, namely glyoxal and methylglyoxal, that form in excess in lipid peroxidation and in a hyperglycemic environment. (67-69) Other than the demonstrating blockage of DNA damage by glycated protein (70), thiamine inhibits DNA glycation (71), possibly implicating it in post-diabetic carcinogenesis prevention. In a human trial where diabetic patients with nephropathy were divided into two groups receiving either vitamin B6 treatment with thiamine and vitamin B6 treatment alone, only the group given thiamine reduced DNA-AGEs in leukocytes (white blood cells). (72) Other human data presents compelling evidence for a prominent role of thiamine in preventing (and perhaps reversing) the development of diabetic nephropathy. Thiamine administered in three 100mg capsules daily to type II diabetics with microalbuminuria (urinary albumin leakage) prompted a regression in UAE (urinary albumin excretion) from baseline scores, resulting in significantly lowered UAE compared that of the placebo group. (75) In another study with patients already experiencing early diabetic nephropathy, 250mg of thiamine combined with 250mg of pyridoxine (vitamin B6) therapy led to a halt in serum AGEs whereas the untreated placebo group revealed an increase in serum AGEs after the 5-month course of the study. (73) . In another double-blind placebo-controlled trial., high doses of thiamine (300mg) for three months prevented the progression of glycation, kidney dysfunction, and microangioplasty in type II diabetics based on the thiamine-induced reduction of glycated hemoglobin, microalbuminuria, and PKC (protein kinase C) respectively. (74) Although thiamine was not used as therapy in humans for diabetes-related vascular disease, a strong association with found between thiamine loss and sVCAM-1 (soluble vascular adhesion molecule 1), a marker and risk factor for vascular (micro and macro) dysfunction and disease. (76) Another study with type II diabetics has found a significant correlation between dietary thiamine and EPC/endothelial progenitor cells, which underlie healthy endothelial function (77). Two human trials have detected improvement in pain symptoms with thiamine, including from its synthetic derivative – benfotiamine, in a specific microvascular diabetic complication, neuropathy. (81-82) Taken altogether, the multiple and growing findings strengthen the indication that supplemental thiamine in human trials will protect against other macro and microvascular complications in diabetics, extending to diabetic retinopathy and cardiomyopathy, and this would corroborate with its success in rodent diabetic models. (78-80) The closest confirmation of this is a human study that, as an exception, used benfotiamine against dietary AGE exposure in the form of a heat-processed meal. It was shown that exogenous AGE consumption dramatically reduced blood flow responsiveness to stimuli and impaired FMD ( flow-mediated vasodilatation) – both features of atherosclerosis and future heart complications and stroke (84-87) – whereas supplementation with 1500mg of benfotiamine completely thwarted these effects in type II diabetics. (83)

Thiamine is water-soluble while its synthetic derivative benfotiamine is lipid-soluble. It is suggested that benfotiamine might be a better alternative since the fat-soluble variant leads to higher blood and tissue levels compared to equal amounts of thiamine. (88) Both are safely ingested in large amounts, so ~30-50mg of thiamine in B-complex formulas is patently safe and more than adequate for preventative purposes. However, diabetics often require 100-1000mg to overcome deficiency and achieve high enough concentrations to offset hyperglycemia and glycation-induced damage. Alcohol consumption will decrease thiamine absorption and is not recommended especially in thiamine stores are in need of replenishment.

Vitamin C&E (plus bioflavonoids): Ascorbic acid acts as an antagonist to glycation by competing with the bonding of protein to glucose, including vital proteins hemoglobin and albumin. (39-40) The same research that validated GSE’s (grape seed extract) ability to lower AGE-induced 8-isoprostane formation identified vitamin C’s efficacy in this domain as well due to a secondary indirect anti-glycation mechanism as an antioxidant. Vitamin C administered in tablet form totaling 1.2 g (or 1200mg) reduced 8-isoprostane levels to a greater extent than GSE did in an amount of 530mg. (41) In vivo evidence for protection from the glycation of hemoglobin is captured human studies. One gram of vitamin C (divided in two doses) significantly decreased HbA1c – a measure of glycated hemoglobin in diabetic patients after twelve months, which corresponded to when serum vitamin C levels became markedly elevated. Granted, these patients were concurrently treated with metformin at equal dosages (500mg x 2), although this trial was placebo-controlled and double-blinded. Patients on metformin alone did not experience equally impressive declines. Rather, declines in HbA1c did not reach statistical significance. (42) Supplementation with as much as 20 grams of oral vitamin C has been studied with more pronounced effects. Each increase of 30 30 micromol/L of ascorbic in plasma correlated with an approximate 0.1 decrease in HbA1c/glycated hemoglobin. (43) Supplementation <1g does not produce auspicious changes in this measure or in fasting glucose in diabetic subjects. (44) It is recommended that at least one gram of ascorbic acid is taken to produce auspicious changes in terms of glycation in diabetes. Complimentary intake of vitamin C with diet is likely to help as well, including for preventative purposes. Vitamin C intake is negatively associated with HbA1c in nondiabetic subjects. (45) In this group, a high dietary intake and/or ~200-500mg of extra supplementation is all that would be required.

Vitamin C with bioflavonoids might offer even more betterment in an AGE-rich milieu. One gram of vitamin C plus bioflavonoids decreased serum protein glycation by an average of 46.8% by four weeks in normal college-aged and middle-aged study participants. (46) Rutin, a flavonoid found in citrus food and naturally consumed alongside ascorbic acid, is also a natural aldose reductase inhibitor, which will prevent the conversion of glucose to fructose, and in turn, inhibit further glycation due to the enhanced reactivity of fructose to autooxidation. (47-48) In diabetic rats it was shown to have comparable effects to aminoguanidine on preventing collagen-linked AGE fluorescence. (49) Rutin and its metabolites were found to inhibit both fluorescent (e.g., pentosidine) and nonfluorescent (e.g., CML) AGEs in a later in vitro study (50), which corroborates with the results in vivo from aldose reductase inhibitors. While rutin was not tested specifically, an aldose reductase inhibitor reduced AGEs and their intermediates such as CML and 3-DG (3-deoxyglucosone) in diabetic patients. (51)

Other citrus flavonoids such as hesperidin and naringin possess strong activity against AGE formation. (52-53) The rutin and hesperidin in lemon juice probably had a potentiating effect on the dramatic reduction of AGEs during the cooking of beef mentioned in Glycation I. (54) It is fair to assume that the synergic intake numerous bioflavonoids and vitamin C naturally found together in food accounts for the negative correlation between dietary vitamin C and HbA1c.

Moreover, co-supplementation of vitamin C and E is a popular method of antioxidant supplementation for good reason. As expected, the established antioxidant synergy between vitamin C and vitamin E extends to anti-glycation. A combination of vitamin C and vitamin E inhibits glycation better than either used alone, probably owing to their synergistic effect on inhibiting lipid peroxidation, one of the known causes of AGE formation. (46) (55)

Whole Spices and Herbs: Popular culinary spices such as cloves, Jamaican allspice, and cinnamon are among the most potent household spices in terms of in vitro anti-glycation activity. (197) Among herbs, rosemary, sage, tarragon, and marjoram were shown to also contain strong AGE inhibitory potential in vitro. (198) Limited in vivo studies of the several herbs and spices appear to suggest promising anti-preglycation and anti-glycation activity as well. (199-200) Inhibitory strength correlated with phenolic content (197), so it may be more convenient to include a plentiful selection of these herbs and spices into daily meals as opposed to supplementing with single phenolic compounds.

Zinc: Zinc levels decline in the face of AGE exposure. (123) Nearly 25% of diabetic patients have lowered serum zinc concentrations, and all diabetics suffer from hyperzincuria, or high zinc loss through urine. (124) If zinc stores are not so deprived as to reflect a deficiency in serum, it is almost certain that tissue is lacking in zinc considering the increased rate of zinc loss. Faulty zinc metabolism is not restricted to type II diabetes; depressed zinc levels is also a feature in type I diabetes. (125) With diabetes (type I and type II) being ‘AGE-ing’ diseases, the untrammeled rate of glycation most likely is to blame.

Correcting a zinc deficiency will not be limited to restoring zinc concentrations and avoiding consequences of deficiency (e.g., impaired immune function, defective wound healing, poor bone growth, anemia, hypogonadism, diarrhea, skin lesions, etc. (126)) but zinc also restrains the effect of glycation on endothelial cells and tubular epithelial cells that manifest as vascular and renal complications by upregulation intracellular NO (nitric oxide) production, which is otherwise disrupted by AGEs. (123)(127-128) Additionally, zinc interferes with AGEs activation of the NF-kappaB signaling pathway and RAGE expression (receptor for advanced glycation end products) to limit late-term AGE-induced inflammation and deleterious AGE-related signaling mechanisms. (123) Zinc confers benefits to a multifarious range of diabetic conditions that are known to stem from and/or worsen with glycation including fasting blood glucose, postprandial blood glucose, insulin secretion, glycated hemoglobin/ HbA1c, lipid peroxidation, systolic and diastolic blood pressures, neuropathy symptoms, cardiovascular risk markers (e.g., homocysteine, microalbuminuria), and glomerular dysfunction. (129) Very general mechanisms have been proposed such as an ‘antioxidant effect’, though it is known that beyond oxidative stress, inflammation and AGE-RAGE interaction causes the aforementioned disturbances.

For diabetes purposes, doses normally ranging from 20 to 30mg are used to correct deficiency and improve disease symptoms. Zinc supplementation containing as much as 660mg of zinc sulphate (i.e. 150mg of elemental zinc) was used to significantly lower HbA1c, triglycerides, cholesterol, and systolic blood pressure by 12 weeks in type II diabetic subjects (130), but such high doses are not advised in self-treatment without follow-ups.

Serious but reversible potential side effects from zinc overload due to long-term excess zinc consumption include zinc-induced copper deficiency symptoms (e.g., anemia, neutropenia, leucopenia, myelodysplastic syndrome, nephrotic syndrome, immune suppression, and thrombogenesis. (131-132) A large decline in HDL cholesterol is also reported in healthy individuals given exceedingly high amounts of zinc, and this trend has repeated itself in later studies in amounts over 50mg daily. (133)

Milder and more common side effects from zinc supplementation (e.g., abdominal pain, nausea, loss of appetite and vomiting) are less common in the amounts recommended especially when taken with a meal. (134-135) For prevention in the healthy, ~15mg is ideal.

Concluding Remarks

As is seen, the amount of safe, natural substances that perform against the glycation reaction is vast. Furthermore, differing mechanisms disallow the possibility for much of these substances to substitute for each other. Instead, they should act as complimentary allies. An intensive and costly supplementary regimedoes not necessarily follow despite the implication; rather, at least some of these sources should be sourced from the diet while others can be supplemented together as certain extracts that contain a number of anti-glycation compounds. In the catechin section, some extracts and food sources were mentioned. Another perfect example would be tomato paste. As a whole, it is a potent inhibitor of glycation (surpassing aminoguanidine in efficacy (323)) since it is made up of lycopene, rutin, naringin, quercetin, luteolin and chlorogenic acid (324-325) to name a few, leaving multiple avenues for glycation suppression. If the taste is displeasing, tomato-based supplements and powders are available. Other examples include red grape seed extract, which contains a number of flavonoids and cinnamic acids (e.g., catechin, epicatechin, chlorogenic acid, ferulic acid, etc. (326-327); Chrysanthemum morifolium, comprised of apigenin, chlorogenic acid, hesperidin, luteolin, and other healthful polyphenols that are responsible for imparting the ability the flower (extract or powder) to block both nonfluorescent and fluorescent AGE formation (328); ginkgo biloba, which not only is neuroprotective but with the flavonoids quercetin, kaempferol, and isorhamnetin (not previously mentioned), is efficiently AGE-preventing (including intermediate products and post-AGE biological dysfunction) (330-333); and milk thistle that is made up of silymarin and also apigenin, naringin, chrysoeriol (not previously mentioned), eriodictyol (not previously mentioned), etc. that is more effective than silymarin alone in preventing the development of diabetic complications (e.g. nephropathy) fueled by glycation. (334) Mulberry leaf extract, which already serves as a nontoxic herbal type II diabetes treatment in Asia, is composed of many single anti-glycation aids including but not limited to chlorogenic acid, rutin, quercetin, kaempferol derivative, gallic acid (not previous mentioned), luteolin, morin (not previously mentioned), umbelliferone (not previously mentioned), etc. (335-337) With multiple anti-diabetic and anti-glycative components, in vivo results reveal hypoglycemic effects (decreased endogenous glycation), lowered lipid hydroperoxide concentrations (pre-AGE markers), decreased MDA (intermediate AGE), reduced HbA1c levels and equally promising results (e.g., ) in human trials. (335)(338-340)

Overall a diverse and minimally cooked diet replete with healthful foods will automatically provide hearty servings of the amino acids, vitamins, minerals, herbs and spices, and polyphenols presented here, and at the same time, replace highly-processed harmful choices that would have otherwise been consumed.

*Choosing to supplement any compound here in high amounts would require medical guidance, especially if taking other forms of medication.

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