Grape seed Extract: A derivative of whole grape seeds and a naturally high source of phenolic compounds (flavonoids and anthocyanins), red grape seed extract significantly prevents the formation of AGEs at varying concentrations. In the presence of RGSE (red grape seed extract), fructosamine is dramatically reduced, which, as a glycation product, correlates with the decrease of AGE formation and CML. Some of this anti-glycation activity may also be attributed to its metal-chelating power as transition metals induce self-oxidation of glucose and encourage AGE formation. (33) Being composed of vitamin E, flavonoids, linoleic acid, and proanthocyanidins , grape seed can further defend against AGEs through down-regulating AGE-induced RAGE expression by its proanthocyanidins in a concentration dependent manner. (37) This mode of action is useful against AGEs that have already formed.
In vivo, grape seed proanthocyanidin extracts mediated diabetic peripheral neuropathic pain in diabetic rats by reducing damage as an anti-glycation therapeutic agent, and similarity, decreased proteinuria and worked against the progression of diabetic nephropathy in another group of diabetic rats that directly correlated with the reduction of serum AGEs . (34-35 ) Owing to its ability on existing AGEs, proanthocyanidins in grape seed extract significantly reduced AGEs as well as AGE-RAGE interaction to preserve the myocardial integrity in streptozocin-induced diabetes in rodents, mitigating the development of diabetic cardiomyopathy.(38) Grape seed extract was also included in a human trial and caused a large diminution of 8-isoprostane levels – a marker of lipid peroxidation that induces AGEs and is generated by AGEs. (36)
Inositol (Vitamin B8): Inositol is found in plant and animal sources of the diet. Supplementation with inositol is usually not indicated in the healthy. When glucose is elevated, a perturbation in metabolic activity occurs that leads to inositol depletion and this in turn inhibits enzyme activity which causes a decrease in the uptake of inositol. (201) Hence, reduced inositol concentrations due to enhanced excretion rates is featured in diabetes (202) and most likely represented – albeit not as dramatically – in the pre-diabetic.
Inositol has shown repeatedly to possess strong anti-glycation properties. (203-205) Out of several isomers of inositol, D-chiro-inositol appears to be predominantly exhausted in the diabetic condition with mean urinary excretion 6 times to 37 times the rate of that of nondiabetics in noninsulin dependant and insulin dependent diabetes respectively. (206) A strong correlation was found with D-chiro-inositol excretion and fasting glucose and glycated hemoglobin. (207) The metabolism of another isomer, myo-inositol is disturbed as well in diabetes (202)(208) Like D-chiro-inositol, myo-inositol is a mediator of insulin function. (209) The specific enzymatic activity (Na+-K+-ATPase) downregulated by hyperglycemia-induced inositol depletion is further inhibited by AGEs that result from the loss of inositol. (210) Tersely stated: hyperglycemia depletes inositol, AGEs increase, insulin resistance worsens, Na+-K+-ATPase activity declines, and inositol is further reduced … with more AGE production and loss of insulin activity. The vicious cycle and increase in diabetic conditions (e.g., neuropathy, retinopathy, etc.) that arise from this are prevented, ameliorated, and even reversed by replenishment of inositol. (211-217) This is of course accomplished by inositol acting against AGEs. Measures directly related to glycation such as glycated hemoglobin (HbA1c) and fructosamine in type II diabetic patients were fittingly reduced by 1200mg of D-chiro-inositol supplementation. (218)
As D-chiro-inositol is the deficient isomer in diabetes and conversion from myo-inositol to D-chiro-inositol seems to be defective (219), supplementation with that isomer specifically will make the most sense over the alternative – myo-inositol. The efficacy of combined D-chiro-inositol and myo-inostitol should not be ruled out, though, based on myo-insitol’s success in improving insulin resistance in gestational diabetes in human subjects. (220) According to human studies, 1 gram or over daily seems to be the requirement for clinically significant results. (218)(221) Measurable benefit is doubtful in the healthy, though nondiabetics with declining glucose control might consider additional inositol.
Lycopene: The ‘tomato carotenoid’ proved to be an impressive multi-pathway inhibitor of glycation and the deleterious effects that occur with it. In both rodent models and in humans, lycopene greatly repressed MDA (malondialdehyde) formation which helped lead to improved renal function in rats (287) and in a dose of only 12mg, boosted the antioxidant profile in human subjects with heightened oxidative stress levels at baseline. (288) Suppressing the generation of MDA is paramount in avoiding glycation as the AGE intermediate is extremely glycating and will eventually lead to the generation of dangerous AGEs technically termed ‘ALEs’ (advanced lipoxidation end products), which are arguably equally as threatening as typical AGEs. (289-290) Research indicates ALEs specifically may be heavily involved in diabetic retinopathy. In agreement with these findings, higher concentrations of lycopene in humans are linked to a reduced risk of the disease whereas diabetics with retinal complications display dramatically reduced levels. (291-292) Additionally, lycopene dose-dependently prevents the irreversible glycation of LDLs … leaving clear implications for alleviating atherosclerotic risk in diabetics. (293) Lycopene is also a hypoglycemic flavonoid (based on both rodent and human studies) (294-295), meaning improved glucose control as a result of lycopene will decrease glycation in another way mediated by hyperglycemia. Biological stress from existing AGEs in circulation can also be mollified by inhibiting the inflammatory response from AGE receptors (RAGE).(296-297)
Manganese: Often an under-recognized trace mineral, manganese displays inhibitory effects on AGE formation, dose-dependently decreases in oxidative stress, downregulates NF-κB expression, and restores MnSod enzymatic activity. (123) Manganese is a cofactor for manganese superoxide dismutase (MnSod) – an enzyme that serves a critical duty in protecting against mitochondrial oxidative stress. (136) When MnSod is under-expressed, oxidative stress accumulates and damages mitochondrial DNA while sparking the formation of specific types of advanced glycation end-products (AGEs) in DNA. (137) In a recent cross-sectional study, it was reported that the diabetic group had significantly lower serum manganese levels compared to the control group. (138) Another study had found decreased concentrations of manganese in the serum of type I diabetic children with microvascular complications who were studied alongside with normal children. (139) Curiously, there also seems to be enhanced urinary manganese excretion in diabetics. (140-142) It has not yet been elucidated whether long-term manganese deficiency causes or if the expression of the disease depletes manganese. Like the glycation process, it probably both involved in disease initiation and is depleted by the disease itself.
Microvascular complications in diabetes likely stem from and are aggravated by a deficient MnSod response from inadequate manganese since MnSod is expressed during the microvascular assault that is largely mediated by glycation. (143) Expectedly, diabetics with microvascular complications also show an impaired MnSod response. (144) On the other hand, overexpression of MnSod protects diabetic hearts. (145)
MnSod also safeguards insulin-producing pancreatic beta cells from AGE-stimulated oxidative stress to preserve genetic expression of pre-insulin, insulin synthesis, and insulin release to manage properly glucose. (146-148)
Moreover, diabetics with higher manganese concentrations were found to be better protected from oxidized LDL cholesterol than those with lower circulating levels. (149) This protection extends to the normal population as per the findings of lower MnSod activity with higher amounts of oxLDL. (150) Since AGEs can oxidize LDL, their decreased formation, in this case due to high MnSod response, is responsible for the reduction of oxLDL. (151) Ostensibly, reducing oxLDL may not relate to advanced glycation product control, but advanced glycation products/AGEs (e.g., CML) are formed directly from oxidized LDL. (69) (152-153) The potential for damage from already formed AGEs is thwarted as well. Existing tissue AGEs have an interdependent relationship with oxLDL and bind to the same receptors oxLDLs (oxidized LDLs) binds to as glycoxidized LDL to profoundly potentiate the atherogenic effects of oxLDL. (154) Interestingly, hyperglycemia was not sufficient on its own to enhance lesions in atherosclerotic mice while the oxidation of LDL in concert with the hyperglycemia triggered adverse changes in lesions. (155)
The suppressive effect of manganese on oxLDL also indirectly inhibits the lectin-like oxidized LDL receptor (LOX-1), which is a vehicle by which oxLDL can unleash its havoc on endothelial cells. (156) It is induced more potently by glycoxidized LDL whereas it is not significantly increased by glycated LDL. (157) LOX-1 is relevant to cardiovascular complications, peripheral artery disease, nephropathy, and neuropathy in diabetes. (158-161) Furthermore, oxLDL increases class B scavenger receptor CD36 expression which in turn bind to AGEs to promote worsening insulin resistance, vascular oxidative injury, increased leukocyte adhesion, and atherogenesis. (162-165)
Daily allowances for manganese have not been set, but the adequate intake for adults to prevent deficiency is roughly 2-3mg with an upper tolerable intake level of ~11mg based on dietary estimations. (166) Certain dietary factors like phytic acid, ascorbic acid, tannins, iron, and protein can influence bioavailability positively or negatively and thereby moderately alter individual required intake. (167-169) The upper tolerable intake may indeed be overly cautionary as higher amounts of 15mg and 20mg have been used in clinical trials that increased MnSod activity in normal healthy volunteers at 15mg and failed to show toxic neurological symptoms at 20mg for relatively extended periods of 124 days and 8 weeks respectively. (170-171)
Nondiabetics should supplement with 5-10mg unless advised otherwise and are carefully monitored. Diabetics, on the other hand, will typically require higher amounts being that antioxidant response is diminished by the onslaught of oxidative stress of diabetes, as shown by lower levels of antioxidants and minerals as well as decreased MnSod activity. In this group, a safe daily dose of 10-15mg is eagerly encouraged, and though these higher amounts that diabetics require have been safe and well-tolerated in medium duration studies, supplementation should be done under a physician’s care through serum tests, MRIs, and tests for neurological function in the rare event of an acquired long-term overdose. (172) Magnesium repletion is important when supplementing with manganese to prevent magnesium displacement in favor of manganese which can result in manganese cardiovascular toxicity. (173)
NAC (N-acetylcysteine): NAC is a thiol antioxidant like garlic and confers distinct health benefits from ordinary antioxidants. For example, in addition to protecting against DNA and protein glycation, NAC is capable of bolstering intracellular levels of glutathione and suppressing AGE-induced neuronal death whereas alpha-tocopherol (vitamin E) did not possess the latter two abilities. (231) In vivo studies with NAC report prevention of diabetic neuropathy and even a reverse in structural deficits of the sciatic nerve incurred by diabetes. (232)Adding NAC to methylgloxal-infused drinking water completely bypassed the insulin resistance that developed in the groups of Sprague-Dawley rats subjected to the AGE precursor without co-administration of the antioxidant. (233) The addition of NAC in another study offset over-accumulation of fluorescent AGE products in the subcutaneous tissue of diabetic rats. Most interesting from this study was the finding that NAC inhibited AGEs best in tissue and protected against AGE-mediated kidney damage most effectively when combined with taurine versus either with NAC or taurine alone, indicating synergy. (234) NAC was also tested against dietary-sourced methylgloxal and mature AGEs and was reported to spare the glutathione depletion that is otherwise incurred as negative reactivity to both endogenous and exogenous carbonyl species. (235)
NAC will guard against endogenous glycation, reactivity from ingested glycation products, and will hinder the development (or worsening) of all common diabetic complications (e.g., beta cell destruction, cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy) through its antioxidative and in particular, glutathione boosting property. Glutathione is fundamental to AGE restriction as one of its functions is to negate the formation of potent oxidant peroxynitrite and its various methods of attack … one of which includes generating more AGEs.(236-239) Since pre-formed AGEs produced endogenously or ingested through diet form peroxynitrite as one of many mechanisms mediating AGE-related damage (240), it can be said that NAC can also lower the damage caused by exogenous AGEs in addition to limiting endogenous AGE destruction.
Other Flavonoids: While some flavonoids are individually discussed here, many others deserve attention for their effects on all stages of glycation. Certain flavonoids including luteolin, rutin, and quercetin were shown to be better inhibitors of early stage glycation (e.g., HbA1C formation) than aminoguanidine. (298) Intermediate glycation initiated by methylglyoxal-mediated protein modification was blocked by luteolin and rutin whereas luteolin alone, out of the flavonoids examined, competently inhibited late-stage glycation as defined by AGE formation and final cross-linking. (299) Other more obscure flavonoids were explored as possible anti-AGE nutrients with findings demonstrating galangin (found in oregano), apigenin, kaempferol, luteolin, myricetin, and quercetin inhibiting AGE formation in that order of strength respectively with the strength of kaempferol and luteolin being essentially equal, although luteolin faired better in preventing the glycation of albumin.(300) Genistein has earned recognition as a robust methylglyoxal-trapper also capable of rescuing human serum albumin from glycation.(301) Apple flavonoids phloretin and phloridzin were also alluded to by the researchers in reference to another study where both flavonoids were found to antagonize methyglyoxal-induced glycation due to being structurally similar to the successful newly-discovered glycation inhibitor genistein and previously discussed EGCG (302) More research on genistein has found it to, in addition to preventing AGEs, down-regulate AGE-induced stimulation of fibronectin and connective tissue growth factor (CTGF), which implies a positive role against diabetic nephropathy and retinopathy by AGEs already acquired within tissue. (303-305) The flavonoid hesperidin and its derivatives impressively inhibit AGE formation in vitro (306) More exciting was its performance in a human trial along with another flavonoid where it, together with diosmin (10% hesperidin,90% diosmin as Daflon 500), decreased HbA1C (glycated hemoglobin) in type I diabetics, which surprisingly, was unrelated to any improvement in glucose control. In addition, an illusionary ‘increase’ was observed in antioxidants as a result of the sparing effect from reduced glycation-mediated oxidative stress. (307) Finally, fisetin – a rarer flavonoid found scarcely throughout the diet – can abate protein glycation by methylglyoxal in vivo and likewise curb diabetic complications such as kidney hypertrophy and albuminuria despite a lack of change in blood sugar. (308) Additionally, this flavonoid was shown to lower the severity of glycation in human HbA (hemoglobin). (309) Fisetin and anti-diabetic effects in humans are not evaluated as of yet, but based on treatment in a diabetic mouse model, the reduction of glycation activity by fisetin leads to the lowering of several glycation-related markers including RAGE expression, serum amyloid A, serum C-reactive protein (CRP), and markers of protein oxidation, and glycation inflammation. (308)
(References in Part III of III)