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Current Drug Targets
ISSN (Print): 1389-4501
ISSN (Online): 1873-5592
VOLUME: 13
ISSUE: 4
DOI: 10.2174/138945012799499758      Price:  $58









Advanced Glycation End Products as Environmental Risk Factors for the Development of Type 1 Diabetes

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Author(s): Felicia Y.T. Yap, Phillip Kantharidis, Melinda T. Coughlan, Robyn Slattery and Josephine M. Forbes
Pages 526-540 (15)
Abstract:
The globally rising incidence of Type 1 diabetes (T1D) is no longer restricted to individuals with higher risk genotypes, but is now significantly increasing in a population with lower risk genotypes, likely as the result of environmental factors. In this review, we discuss the potential of advanced glycation end products (AGEs) as environmental contributors to the development of T1D. AGEs are nonenzymatically formed protein modifications found in the body, as well as, consumed in our daily diets. To date, many studies have provided evidence of AGE involvement in β cell dysfunction, whether by AGE modification itself or via interaction with AGE receptors. The receptor for AGE (RAGE) and AGE-receptor-1 (AGE-R1) are of particular interest, given that studies have demonstrated the deleterious effects of RAGE modulation and the protection afforded by AGE-R1 in the context of diabetes. More interestingly, we have recently found that two RAGE polymorphism are predictive of T1D in humans while the third is protective. Moreover, soluble RAGE (sRAGE) levels (a circulating competitive inhibitor of RAGE) were greatly reduced at seroconversion to autoantibodies in both children on high risk of T1D background and in an animal model of autoiummune diabetes. Taken together with the fact that AGEs have also shown to be involved in immunomodulation, it is tempting to postulate that dietary AGEs, RAGE and even AGE-R1 could be working synergistically or independently to breach the tightly regulated immune system, providing a missing link in the development of T1D.
Keywords:
AGEs, AGE-R1, OST48, RAGE, RAGE polymorphism, oxidative stress, type 1 diabetes, genetic, autoimmunity
Affiliation:
BakerIDI Diabetes and Heart Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.