AGE, RAGE, and Diabetes
The Role of Advanced Glycation End Products and Therapeutic Strategies
Introduction
Advanced glycation end-products (AGEs) are groups of compounds that result from the non-enzymatic reaction of reducing sugars with free amino groups of biological molecules (Mendez 2010). ey are formed slowly by the Maillard reaction, which is dependent on glucose levels. ey also form rapidly by a pathway that involves reactive carbonyl compounds during oxidative stress (Smit 2010). AGEs can also accumulate in humans by exogenous intake from food and smoking tobacco (Uribarri 2005). Many AGEs are believed to be clinically signi cant in humans including 3-deoxy-glucosone, glyoxal, methylglyoxal, pentosidine, and N-carboxylmethyllysine (Goh 2008). Some of these compounds have intrinsic uorescence and as such skin auto uorescence (SAF) has been utilized to quickly and easily detect AGE accumulation in a point of care setting (Smit 2010).
Receptors of AGEs (RAGEs) are signal transduction receptors that belong to the immunoglobulin superfamily. ey are expressed in a variety of cell types, such as endothelial cells, smooth muscle cells, lymphocytes, monocytes, and neurons (Schmidt 2000). Ligands binding to RAGE can generate oxidative stress, synthesize and secrete proin ammatory cytokines, and cause chemotaxis (Jackus 2004). ese all contribute to the progression of vascular damage. erefore, AGEs are important because they do not simply re ect hyperglycemia, but represent a cumulative metabolic burden, oxidative stress, and systemic in ammation (Meerwaldt 2008).
Diabetic complications have long been believed to be the result of prolonged hyperglycemia. However, blood glucose levels alone do not reveal the whole picture. Even in patients with type II diabetes who have achieved HbA1c and glucose targets, trials have shown that those who have higher levels of AGEs su er from more microvascular and cardiovascular complications (Holman 2008). AGEs play a pivotal role in the cause of diabetic complications, including retinopathy, neuropathy, nephropathy, and other complications throughout the human body. AGEs also provide new possible targets for the treatment of both type I and type II diabetes. is paper examines the importance of AGEs in the development of diabetic complications and reviews the evidence for promising therapeutic interventions.
Diabetic Retinopathy Retinopathy is the most common microvascular complication of diabetes and involves vision impairment due to microaneurysms, blood barrier dysfunction, and capillary dropout (Stitt 2010). AGEs are elevated in the ocular tissues and vitreous collagen of diabetic subjects when compared to nondiabetic subjects (Stitt 2001). AGEs contribute to the pathogenesis of diabetic retinopathy through various mechanisms. ey accumulate heavily in Muller macroglia, which have a unique role in the architecture and physiology of the retina (de Gooyer 2006). In these locations, AGEs contribute to excitotoxicity in retinal neurons by promoting the synthesis of glutamate (Lieth 1998).
AGEs induce basement membrane thickening and contribute to the breakdown of the inner blood-retinal barrier (Stitt 1997). AGEs upregulate vascular endothelial growth factor (VEGF), which promotes retinal neovascularization and increases permeability to proteins across the retinal barrier (Lu 1998). With regards to oxidative stress, it has been shown that the concentration of superoxide is elevated in the retina of diabetic rats (Du 2003). By increasing oxidative stress, toxic e ects occur to retinal pericytes and cause subsequent apoptosis (Chen 2006). e inhibition of superoxide with antioxidants can protect against capillary degeneration during diabetic retinopathy (Kowluru 2001). Even at low concentrations, AGEs cause proangiogenic responses in retinal microvascular endothelial cells (Mamputu 2004).
Diabetic Neuropathy
Neuropathy is a common complication of diabetes in which nerves are damaged, partially as a result of decreased blood ow and hyperglycemia (Bansal 2006). Also associated with neuropathy is diabetic foot, a complication in which the foot becomes ulcerated, infected, or gangrenous. AGE levels are related to both peripheral and autonomic neuropathy, even before clinical manifestations of neuropathy (Meerwaldt 2005). Skin AGE accumulation is also linked to the severity of neuropathic foot ulceration. is is believed to be largely due to endothelial dysfunction that is caused and worsened by AGEs.
AGEs damage vascularity through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging RAGE, causing upregulation of the transcription factor NF-kB and its target genes. AGE-bound RAGE also increases endothelial permeability to macromolecules, blocks nitric oxide activity in the endothelium and causes the production of reactive oxygen species (Goldin 2006). Decreased nitric oxide production leads to impaired cutaneous vasodilation and decreased neurogenic vascular responses (Williams 2006). In addition, AGEs worsen diabetic neuropathy by reducing sensorimotor conduction velocity and decreasing blood ow to peripheral nerves (Chen 2004). e blockage of RAGE accelerates wound closure in diabetic mice and suppresses levels of cytokines such as tumor necrosis factor (Goova 2001).
Diabetic Nephropathy
Diabetic nephropathy is a syndrome characterized by persistent albuminuria, a progressive decline in glomerular ltration rate, and elevated arterial blood pressure. e kidney plays an important role in the clearance and metabolism of AGEs. Almost all renal structures are susceptible to the accumulation of AGEs and their consequences including basement membranes, mesangial cells, endothelial cells, podocytes, and tubules (Schleicher 1997). In intrarenal arteries, medial smooth muscle cells are injured by the interaction between glycoxidation and complement activation, which contributes to the progression of diabetic nephropathy (Uesugi 2004). Kidney podocytes and endothelial cells express speci c RAGEs. eir activation leads to multiple pathophysiological e ects including hypertrophy with cell cycle arrest and apoptosis, altered migration, and generation of proin ammatory cytokines (Busch 2010). RAGE drives the development of glomerulosclerosis and promotes podocyte activation in the course of diabetic nephropathy (Wendt 2003).
In the progression of renal disease, there is delayed protein turnover and accelerated oxidative stress. is leads to enhanced formation of AGEs, resulting in a vicious cycle (Kanwar 2008). In monitoring nephropathy, urinary protein-bound AGE concentrations closely parallel changes in albuminuria, re ecting the severity of diabetic nephropathy (Coughlan 2011). Skin auto uorescence (SAF) also independently predicts renal risk in diabetes and in chronic kidney disease (Smit 2010). Renal pathological changes are reduced by AGE formation inhibitors, as well as with agents that are postulated to reduce AGE accumulation (Soulis-Liparota 1995). Treatments targeting RAGE have also been shown to attenuate nephropathy (Flyvbjerg 2004).
Other Complications
AGE accumulation and subsequent RAGE activation has been associated with numerous other complications. AGEs have been shown to adversely a ect virtually all cells, tissues, and organ systems. Circulating AGEs are associated with an increased risk of developing many chronic diseases. e accumulation of AGEs accelerates the multisystem functional decline that occurs with aging (Semba 2009). For these reasons, it is important to screen all diabetic patients for these pathologies and to work with them clinically, focusing on prevention.
Both type I and type II diabetes have been associated with reduced cognitive performance (Kodl 2008). Type II diabetes is strongly associated with the risk of incident Alzheimer’s disease (Ott 1999). Studies of post-mortem samples have shown that brains of patients with the combination of Alzheimer disease and diabetes had higher AGE levels and an increased number of B-amyloid dense plaques (Valente 2010). Even in older adults without diabetes, high peripheral AGE levels are associated with greater cognitive decline (Ya e 2011). Patients with diabetes and renal disease show high concentrations of vitamin B12, but metabolic evidence of a de ciency that is reversible after treatment. Megalin mediates the uptake of vitamin B12 by cells. AGEs might overload megalin and lower vitamin B12 uptake by cells by preventing its delivery (Obeid 2011).
Among patients with diabetes, AGEs have been correlated to the risk of cardiomyopathy and peripheral arterial disease (Goh 2008). AGEs are linked to atherosclerosis by enhancing endothelial dysfunction, elevating vascular low-density lipoprotein, promoting plaque destabilization via effects on matrix metalloproteinases, inducing neointimal proliferation, and inhibiting vascular repair in response to injury. A correlation has been demonstrated between AGE concentration and the severity of atherosclerotic lesions (Stitt 1997). In addition, AGEs likely contribute to erectile dysfunction in patients with diabetes. Studies have shown the preservation of erectile function in animals treated with drugs that inhibit AGE formation (Usta 2003). In one study, diabetic men had significantly higher mean levels of RAGE protein and DNA fragmentation in spermatozoa. These were directly correlated, suggesting a central role for RAGE in disturbances in sexual function of men with diabetes (Karimi 2011). AGEs also play a role in the loss of lens transparency and in cataract formation (Hashim 2011).
AGEs are implicated in other disease processes throughout the body that are not typically associated with diabetes. Increased levels of AGEs have been found in rheumatoid arthritis (de Groot 2010). Experimental and clinical studies have highlighted the idea that RAGE is involved in the development of liver fibrosis and inflammation and leads to apoptosis (Basta 2011). RAGE has been implicated in acute lung injury both as a marker of alveolar injury and as an important contributor to alveolar inflammation (Uchida 2006). RAGE is highly expressed in colorectal cancer tissues and is associated with increased microvessel density. Knockdown of RAGE inhibited expression of VEGF and SP1 protein in colorectal cancer cells, suggesting that the silence of RAGE expression could effectively inhibit colorectal cancer angiogenesis (Liang 2011).
Therapeutic Interventions
There are many potential therapies that can be used to treat the morbidity caused by AGEs. Multiple pharmaceuticals have been developed and studied for this purpose, including antiglycation agents, AGE inhibitors (Bicu 2010), sulfonylureas (Li 2008), statins (Ishibashi 2011 and Lu 2011), and angiotensin receptor blockers (Grossin 2010). In diabetes, the rate of formation of AGEs exceeds that of normal aging. Over time, even modest hyperglycemia results in a significant accumulation of AGEs (Monnier 2005). Therefore, it is highly likely that any pharmacological therapy that has shown benefit in treating diabetes or hyperglycemia will be beneficial for treating AGEs to some extent.
To treat AGE accumulation, the most obvious starting points for any health care practitioner are diet and lifestyle modification. A significant source of AGEs is smoking tobacco and thus patients should be encouraged to quit smoking. Since AGEs are also found in foods, a diet should be recommended that focuses on low-AGE containing foods in conjunction with low-AGE producing cooking methods. One study examined the AGE content of various foods. Meat groups contain the highest levels of AGEs, except for lamb. Fats contain more AGEs relative to carbohydrates. This may be due to the higher water content or higher level of antioxidants and vitamins in carbohydrate-containing foods, which may diminish new AGE formation. A reduced intake of dietary AGEs can also be achieved by increasing the consumption of fish, legumes, low-fat milk products, vegetables, fruit, and whole grains and by reducing intake of solid fats, fatty meats, full-fat dairy products, and highly processed foods (Uribarri 2010).
Incorporating dietary arginine has also been shown to decrease AGE and RAGE interactions and consequently reduce tissue damage in rats with type II diabetes (Pai 2010). Dietary rutin, found in buckwheat and asparagus, suppresses glycation, purportedly due to its high flavonoid content (Muthenna 2011). In terms of cooking methods, patients should be advised to boil, poach, stew, or steam food and to avoid frying, baking, or grilling. This strategy may limit dietary AGE intake by up to 50% (Uribarri 2011). Another lifestyle measure that should be recommended for patients is exercise. Moderate intensity aerobic physical activity for 150 minutes, or vigorous aerobic exercise for 90 minutes per week are recommended, distributed over at least three days, with no more than two close days of inactivity (Coccheri 2007).
In addition to these strategies, particular therapeutic options have been studied and have additional evidence to support their use. Aged garlic extract and S-allyl cysteine have been shown to prevent the formation of AGEs, in particular the formation of glucose-derived and methylglyoxal-derived AGEs, as well as the formation of carboxymethyllysine (Ahmad 2007). S-allyl cysteine has been reported to inhibit NF-kB activation in a dose-dependent manner and may protect against intracellular oxidative stress once RAGEs are activated (Ide 2001). Aged garlic extract contains approximately 50 times the amount of S-allyl cysteine compared to raw garlic and also contains other antioxidants.
One trial in diabetic rats showed that omega-3 fatty acids reduce AGEs (deAssis 2011). Alpha-lipoic acid has been studied and been demonstrated to have beneficial effects on the development of diabetic retinopathy by inhibiting the accumulation of oxidatively modified DNA and nitrotyrosine in the retina (Kowluru 2004). Similarly, N-Acetylcarnosine lubricant eye drops are able to decrease the complications of AGEs and have shown benefit in improving the quality of vision and length of life for diabetes mellitus patients (Babizhayev 2009).
Many botanical options have also been studied. Silymarin has antioxidant and reactive carbonyl trapping activities, which may contribute to its antiglycation effect (Wu 2011). Ilex paraguariensis water extracts are capable of inhibiting AGE formation in a dose-dependent fashion (Lunceford 2005). Hibiscus sabdariffa polyphenolic extract has been demonstrated to inhibit high glucosestimulated cellular changes in rats as well as AGE and RAGE formation (Peng 2011). Other herbal options that have been studied and shown to have a favourable effect on AGEs are curcumin (Mrdula 2007), cumin (Kumar 2009), and ginger (Saraswat 2010).
Finally, a novel therapy for treating AGE accumulation is chelation therapy. The chelation of transition metals means they are not available to participate in autooxidative glycation and glyco-oxidation reactions, which are capable of generating free radicals that accompany AGE formation during hyperglycemia. EDTA has shown benefit for this purpose in diabetic patients (Wolff 1991). Another chelating agent that has been studied is triethylenetetramine (TETA), which acts as a highly selective divalent copper chelator. TETA has been shown to suppress oxidative stress and prevent or reverse diabetic organ damage (Cooper 2011). More research is warranted to determine the most effective approaches in combating AGEs and RAGEs.
References
Ahmad M, Pischetsrieder M, Ahmed N. Aged garlic extract and S-allyl cysteine prevent formation of advanced glycation endproducts. Eur Journ of Pharmacol. 2007; 561(1-3):32-38.
Babizhayev M, Micans P, Guiotto A, Kasus-Jacobi A. N-Acetylcarnosine Lubricant Eyedrops Possess All-In-One Universal Antioxidant Protective Effects of L-Carnosine in Aqueous and Lipid Membrane Environments, Aldehyde Scavenging, and Transglycation Activities Inherent to Cataracts: A Clinical Study of the New Vision- Saving Drug N-Acetylcarnosine Eyedrop Therapy in a Database Population of Over 50,500 Patients. American Journal of Therapeutics. 2009; 16(6):517-533.
Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82(964):95- 100.
Basta G, Navarra T, De Simone P, Del Turco S, Gastaldelli A, Filipponi F. What Is the Role of the Receptor for Advanced Glycation End Products-Ligand Axis in Liver Injury? Liver Transpl. 2011; 17(6):633-640.
Bicu M, Mota M, Panduru NM, Graunteanu C, Mota E. Oxidative stress in diabetic kidney disease. Rom J Intern Med. 2010; 48(4):307-12.
Busch M, Franke S, Ruster C, Wolf G. Advanced glycation end-products and the kidney. Eur J Clin Invest. 2010; 40(8):742-755.
Chen AS, Taguchi T, Sugiura M, Wakasugi Y, Kamei A, Wang MW, Miwa I. Pyridoxal-aminoguanidine adduct is more effective than aminoguanidine in preventing neuropathy and cataract in diabetic rats. Horm Metab Res. 2004; 36(3):183-187.
Chen BH, Jiang DY, Tang LS. Advanced glycation end-products induce apoptosis involving the singaling pathways of oxidative stress in bovine retinal pericytes. Life Sci. 2006; 79(11):1040-1048.
Coccheri S. Approaches to Prevention of Cardiovascular Complications and Events in Diabetes Mellitus. Drugs. 2007; 67(7):997-1026.
Cooper GJ. Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer’s disease. Drugs. 2011; 71(10):1281-320.
Coughlan M, Patel S, Jerums G, Penfold S, Nguyen T, Sourris K, Panagiotopoulos S, Srivastava P, Cooper M, Burrell L, MacIsaac R, Forbes J. Advanced Glycation Urinary Protein-Bound Biomarkers and Severity of Diabetic Nephropathy in Man. Am J Nephrol. 2011; 34(4):347-355.
de Assis, A, Rech A, Longoni A, Rotta L, Denardin C, Pasquali M, Souza D, Perry M, Moreira J. Omega 3-Polyunsaturated fatty acids prevent lipoperoxidation, modulate antioxidant enzymes, and reduce lipid content but do not alter glycogen metabolism in the livers of diabetic rats fed on a high fat thermolyzed diet. Mol Cell Biochem. 2011. [Epub ahead of print]
de Gooyer TE, Stevenson KA, Humphries P, Simpson DA, Gardiner TA, Stitt AW. Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci. 2006; 47(12):5561-5568.
de Groot L, Posthumus MD, Kallenberg CG, Bijl M. Risk factors and early detection of atherosclerosis in rheumatoid arthritis. Eur J Clin Invest. 2010; 40(9):835-42.
Du Y, Miller CM, Kem TS. Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med. 2003; 35(11):1491-1499.References Flyvbjerg A, Denner L, Schrijvers BF, Tilton RG, Mogensen TH, Paludan SR, Rasch R. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes. 2004; 53(1):166-172.
Goh S and Cooper M. The Role of Advanced Glycation End Products in Progression and Complications of Diabetes. J Clin Endocrinol Metab. 2008; 93(4):1143-1152.
Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114(6):597- 605.
Goova MT, Li J, Kislinger T, Qu W, Lu Y, Bucciarelli LG, Nowygrod S, Wolf BM, Caliste X, Yan SF, Stern DM, Schmidt AM. Blockage of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol. 2001; 159(2):513-25.
Grossin N, Boulanger E, Wautier M, Wautier J. The different isoforms of the receptor for advanced glycation end products are modulated by pharmacological agents. Clinical Hemorheology and Microcirculation. 2010; 45(2-4):143-153.
Hashim Z and Zarina S. Advanced glycation end products in diabetic and nondiabetic human subjects suffering from cataract. Age (Dordr). 2011; 33(3):377-84.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359(15):1565- 1576.
Ide N and Lau B. Garlic compounds minimize intracellular oxidative stress and inhibit nuclear factor-kappa B activation. J Nutr. 2001; 131(3s):1020S-1026S.
Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Rosuvastatin blocks advanced glycation end products-elicited reduction of macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. Horm Metab Res. 2011; 43(9):619-24.
Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53(2):131-142.
Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, Chugh S, Danesh FR. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood). 2008; 233(1):4-11.
Karimi J, Goodarzi M, Tavilani H, Khodadadi I, Amiri I. Increased receptor for advanced glycation end products in spermatozoa of diabetic men and its association with sperm nuclear DNA fragmentation. Andrologia. 2011 [Epub ahead of print]
Kodl CT and Seaquist ER. Cognitive dysfunction and diabetes mellitus. Endocr Rev. 2008; 29(4):494-511.
Kowluru RA, Engerman RL, Case GL, Kern TS. Retinal glutamate in diabetes and effect of antioxidants. Neurochem Int. 2001; 38(5):385-390.
Kowluru RA and Odenbach S. Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats. Diabetes. 2004; 53(12):3233-3238.
Kumar PA, Reddy PY, Srinivas PN, Reddy GB. Delay of diabetic cataract in rats by the antiglycating potential of cumin through modulation of alpha-crystallin chaperone activity. J Nutr Biochem. 2009; 20(7):553-62.
Li W, Ota K, Nakamura J, Naruse K, Nakashima E, Oiso Y, Hamada Y. Antiglycation effect of gliclazide on in vitro AGE formation from glucose and methylglyoxal. Exp Biol Med (Maywood). 2008; 233(2):176-9.
Liang H, Zhong Y, Zhou S, Peng L. Knockdown of RAGE expression inhibits colorectal cancer cell invasion and suppresses angiogenesis in vitro and in vivo. Cancer Letters. 2011; 313(1):91-98.
Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, Strother JM. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Diabetes. 1998; 47(5):815-20.
Lu L, Peng W, Wang W, Wang L, Chen Q, Shen W. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats. Biomed & Biotechnol. 2011; 12(8):652-659.
Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998; 101(6):1219-1224.
Lunceford N and Gugliucci A. Ilex paraguariensis extracts inhibit AGE formation more efficiently than green tea. Fitoterapia. 2005; 76(5):419-427.
Mamputu JC and Renier G. Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide. Diabetes Obes Metab. 2004; 6(2):95-103.
Meerwaldt R, Links TP, Graaff R, Hoogenberg K, Lefrandt JD, Baynes JW, Gans RO, Smit AJ. Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy. Diabetologia. 2005; 48(8):1637-44.
Meerwaldt R, Links T, Zeebregts C, Tio R, Hillebrands L, Smit A. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes. Cardiovascular Diabetology. 2008; 7(29):1-8.
Mendez J, Xie J, Aguilar-Hernandez M, Mendez-Valenzuela V. Trends in advanced glycation end products research in diabetes mellitus and its complications. Mol Cell Biochem. 2010; 341(1-2):33-41.
Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci. 2005; 1043:567-581.
Mrdula T, Suryanarayana P, Srinivas PN, Reddy GB. Effect of curcumin on hyperglycemia-induced vascular endothelial growth factor expression in streptozotocin-induced diabetic rat retina. Biochem Biophys Res Commun. 2007; 361(2):528-32.
Muthenna P, Akileshwari C, Saraswat M, Reddy G. Inhibition of advanced glycation end-product formation on eye lens protein by rutin. British Journal of Nutrition. 2011. [Epub ahead of print]
Obeid R, Shannan B, Herrmann W. Advanced glycation end products overload might explain intracellular cobalamin deficiency in renal dysfunction, diabetes and aging. Med Hypotheses. 2011; 77(5):884-8.
Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the rotterdam study. Neurology. 1999; 53(9):1937- 1942.
Pai M, Huang K, Wu C, Yeh S. Effects of dietary arginine on inflammatory mediator and receptor of advanced glycation endproducts (RAGE) expression in rats with streptozotocin-induced type 2 diabetes. British Journal of Nutrition. 2010; 104(5):686-692.
Peng C, Chyau C, Chan K, Chan T, Wang C, Huang C. Hibiscus sabdariffa Polyphenolic Extract Inhibits Hyperglycemia, Hyperlipidemia, and Glycation- Oxidative Stress while Improving Insulin Resistance. J Agric and Food Chem. 2011; 59(18):9901-9909.
Saraswat M, Suryanarayana P, Reddy PY, Patil MA, Balakrishna N, Reddy GB. Antiglycating potential of Zingiber officinalis and delay of diabetic cataract in rats. Mol Vis. 2010; 16:1525-37.
Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest. 1997; 99(3):457-68.
Schmidt AM, Yan SD, Yan SF, Stern DM. The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta. 2000; 1498(2-3):99-111.
Semba R, Nicklett E, Ferrucci L. Does Accumulation of Advanced Glycation End Products Contribute to the Aging Phenotype? J Gerontol A Biol Sci Med Sci. 2010; 65A(9):963-975.
Smit A and Gerrits E. Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease. Current Opinion in Nephrology and Hypertension. 2010; 19(6):527-533.
Soulis-Liparota T, Cooper ME, Dunlop M, Jerums G. The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. Diabetologia. 2005; 38(4):387-394.
Stitt AW. Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br J Ophthalmol. 2001; 85(6):746-753.
Stitt AW. AGEs and Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2010; 51(10):4867-4874.
Stitt AW, He C, Friedman S, Scher L, Rossi P, Ong L, Founds H, Li YM, Bucala R, Vlassara H. Elevated AGE-modified ApoB in sera of euglycemic normolipidemic patients with atherosclerosis: relationship to tissue AGEs. Mol Med. 1997; 3(9):617- 627.
Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, Vlassara H. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol. 1997; 150(2):523-531.
Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med. 2006; 173(9):1008- 1015.
Uesugi N, Sakata N, Nagaku M, Abe M, Horiuchi S, Hisano S, Iwasaki H. Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: glycoxidation-mediated local complement activation. Am J Kidney Dis. 2004; 44(2):224-38.
Uribarri J, Cai W, Ramdas M, Goodman S, Pyzik R, Chen X, Zhu L, Striker GE, Vlassara H. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care. 2011; 34(7):1610-6.
Uribarri J, Cai W, Sandu O, Peppa M, Goldbert T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the body’s AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005; 1043:461-466.
Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker G, Vlassar H. Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet. J Am Diet Assoc. 2010; 110(6):911-916.
Usta MF, Bivalacqua TJ, Yang DY, Ramanitharan A, Sell DR, Viswanathan A, Monnier VM, Hellstrom WJ. The protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats. J Urol. 2003; 170(4 Pt 1):1437-42.
Valente T, Gella A, Fernandez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis. 2010; 37(1):67-76.
Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D’Agati VD, Schmidt AM. RAGE drives the development of glumerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic neuropathy. Am J Pathol. 2003; 162(4):1123-37.
Williams SB, Cusco JA, Roddy MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin dependent diabetes mellitus. J Am Coll Cardiol. 1996; 27(3):567-574.
Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med. 1991; 10(5):339-52.
Wu CH, Huang SM, Yen GC. Silymarin: a novel antioxidant with antiglycation and antiinflammatory properties in vitro and in vivo. Antioxid Redox Signal. 2011; 14(3):353-66.
Yaffe K, Lindquist K, Schwartz A, Vitartas C, Vittinghoff E, Satterfield S, Simonsick E, Launer L, Rosano C, Cauley J, Harris T. Advanced glycation end product level, diabetes, and accelerated cognitive aging. Neurology. 2011; 77(14):1351-1356.
