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School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester M1 5GD, UK
3 To whom correspondence should be addressed. E-mail: n.ahmed{at}mmu.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • aged garlic extract • diabetes mellitus • hyperglycemia • S-allylcysteine • glycation
Diabetes mellitus is an endocrine disorder characterized by chronic hyperglycemia, which results from an absolute or relative deficiency of or resistance to insulin. Diabetes affects 1–2% of the population, and there are around 100 million diabetic patients worldwide. This figure is expected to double over the next 10–15 y. Individuals affected by diabetes are prone to long-term complications such as retinopathy, cataract, neuropathy, atherosclerosis, nephropathy, embryopathy, and delayed healing of wounds (1).
Hyperglycemia has a key role in the pathogenesis of diabetic complications. This has been demonstrated by the Diabetes Control and Complications Trial (2) and the more recent UK Prospective Diabetes Study (3). Both of these studies have shown that diabetic patients with poor blood glucose control are more likely to develop chronic complications.
Advanced glycation endproducts. The precise mechanism underlying pathogenesis of diabetic complications is unclear. It has been suggested that during hyperglycemia, a direct reaction, referred to as the Maillard, or browning, reaction occurs between body proteins and sugars. Food scientists have been interested in the Maillard reaction for many years because it is associated with food spoilage, altered taste, and loss in nutritional value.
Protein glycation (also referred to as nonenzymatic glycosylation) is the first part of the Maillard reaction and occurs when a sugar carbonyl group reacts with a protein amino group to form a labile Schiff base that subsequently rearranges to a stable Amadori product (Fig. 1). Formation of the Schiff base occurs over a period of hours, whereas Amadori products form over a number of days. Glycation occurs spontaneously whenever proteins are exposed to reducing sugars and is dependent on the degree and duration of hyperglycemia in vivo.
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Glycation and free radicals. Glucose and Amadori products can undergo autoxidation in the presence of transition metals to generate free radicals. Autoxidation of glucose (autoxidative glycation) generates a ketoimine capable of reacting with proteins to form AGEPs and also generates free radicals such as the superoxide radical in the process. Similarly, Amadori products undergo metal-catalyzed oxidation (glycoxidation), generating reactive dicarbonyl compounds capable of forming AGEPs and free radicals (7). Free radicals can damage proteins, lipids, and nucleic acids and might contribute toward tissue damage in diabetes (8).
AGEPs and diabetic pathology.
Increased glycation and accumulation of tissue AGEPs can alter protein conformation and impair function by altering enzyme activity, modifying protein half-life, altering immunogenicity, and cross-linking of structural proteins (9,10). Many cells possess receptors for advanced glycation endproducts (RAGEs), and the interaction of AGEPs with their receptors can generate intracellular oxidative stress and activation of nuclear factor 
B (NF-B). The latter can stimulate generation of proinflammatory and adhesion molecules that in turn increase vascular permeability, which underlies the pathology of diabetic vascular complications (11). It is generally accepted that accumulation of tissue AGEPs together with increased oxidative stress has an important role in the pathogenesis of diabetic complications (10). This is outlined in Figure 2.
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The nucleophilic hydrazine compound aminoguanidine has received the most interest and is effective in reducing AGEP formation in vitro as well as in animal and human studies (15). The mechanism of action of aminoguanidine is still unclear, but it may act by blocking carbonyl groups on free sugars, Amadori products, or dicarbonyl intermediates such as 3-DG (16). However, phase III clinical trials in which aminoguanidine therapy was used to treat diabetic nephropathy proved unsuccessful because of the high toxicity encountered in many patients (15).
Other compounds such as aspirin also have a protective effect and act by acetylation of free amino groups, protecting them against glycation (17). However, there are serious concerns about the toxicity of many of these pharmacological compounds. Furthermore, some of these compounds do not possess antioxidant activity, and recent studies suggest that glycation and AGEP-induced toxicity are associated with increased free radical activity. Recent studies in the author's laboratory have demonstrated the benefits of using compounds with combined antiglycation and antioxidant properties (18). Such compounds not only prevent AGEP formation but also reduce free radical–mediated toxicity.
Natural products with anti-glycation activity. Recent studies have highlighted the benefits of using medicinal plants with combined antiglycation and antioxidant properties in diabetic patients. Green tea from the leaves of Camellia sinensis is a popular drink worldwide. It contains large amounts of tannins (flavonoids), which are known for their antioxidant properties. Recently a study has shown that green tea has antiglycation activity in addition to antioxidant activity (19). Both of these properties are believed to reside in the tannin component in green tea. In this study green tea extract and tannin inhibited AGEP formation in a dose-dependent manner, with tannin being the more potent inhibitor. Other substances such as caffeine and theanine had no effect on AGEPs. Both green-tea extract and tannin had antioxidant activity, but tannin had the greater effect. Again, related substances such as caffeine and theanine had little antioxidant activity (19).
Garcinol, isolated from Garcinia indica fruit rind, has been shown to possess antioxidant, metal-chelating, and antiglycation properties in an in vitro system (20). In the same study, garcinol proved to be a more effective inhibitor than aminoguanidine. Recently, a water-soluble fraction obtained from tomato paste inhibited formation of AGEPs and proved to be more effective than aminoguanidine (21). This tomato fraction contained rutin, a potent antioxidant also responsible for the antiglycation activity.
Antiglycation properties of garlic. Garlic (Allium sativum) has been used historically for treatment of diseases associated with aging (22). Garlic is available commercially in different preparations, one of which is aged garlic extract (AGE). This is garlic that has been extracted and aged up to 20 mo, reducing its harsh irritating taste and odor. AGE has potent antioxidant activity and a high concentration of organosulfur compounds such as S-allylcysteine. The latter is an established antioxidant and free-radical scavenger (23). AGE protects against atherosclerosis by preventing hypertension, reducing serum cholesterol and triglycerides, and by inhibiting platelet aggregation and LDL oxidation (24,25). AGE also increases activity of antioxidant enzymes such as catalase, superoxidase dismutase, and glutathione peroxidase (26). Certain Maillard products found in AGE have been reported to possess antioxidant activity and contribute to AGE's beneficial activity (23). However, this contrasts with other studies suggesting that certain dietary AGEPs, such as carboxymethyllysine and methylglyoxal derivatives, act in the circulation in the same ways as endogenously derived AGEPs capable of inducing intracellular oxidative stress and inflammatory reactions that might contribute to the pathology of diabetic complications (27). The same study showed that the harmful effects of these AGEPs could be prevented by using antioxidants or antiglycation compounds; thus, some of the Maillard products within AGE may have a protective effect. Further studies are required to investigate the possible dual role of some dietary Maillard products. However, AGE is described as being relatively safe, as clinical studies suggest no evidence of serious toxicity even at high doses (28).
Recent studies in the author's laboratory have shown that AGE is an effective inhibitor of AGEPs in vitro (Fig. 3). The key ingredient responsible for the antiglycation properties of AGE was S-allylcysteine, which proved an effective inhibitor of AGEPs (Fig. 4). Similarly, another study has shown that 4 organosulfur compounds derived from garlic, diallyl sulfide, S-ethylcysteine, S-allylcysteine, and N-acetylcysteine, protect LDL against oxidation and glycation and may therefore explain why garlic protects against cardiovascular disease (29).
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FOOTNOTES |
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2 Author disclosure: No relationships to disclose.
4 Abbreviations used: AGE, aged garlic extract; AGEP, advanced glycation endproduct; NF-B, nuclear factor B; RAGE, receptor for advanced glycation endproducts.
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LITERATURE CITED |
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