Novel Pathways of AGE Formation in Diabetes

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DESCRIPTION (provided by applicant): The Maillard reaction, the reaction of carbonyl compounds with amino group on proteins occurs at an accelerated rate in diabetes. This reaction produces products known as, advanced glycation end products or AGEs that are detrimental to proteins and cell functions. AGEs have been implicated in all major complications of diabetes. Several inhibitors against AGE synthesis have been tested and a few of them have shown promising results in inhibiting diabetic complications. However, these inhibitors do not appear to be highly specific and may not inhibit intracellular AGEs. In order to develop more specific and potent inhibitors, a thorough knowledge of AGE chemistry is essential. Recently, a new pathway for AGE synthesis has been uncovered. In this pathway, the Amadori products, the initial condensation products of the Maillard reaction undergo spontaneous long-range carbonyl shift to produce protein-bound dideoxyosones. The dideoxyosones can potentially produce significant amounts of AGEs in proteins. Such AGEs may include lysine-arginine and lysine-lysine cross linking structures. In this proposal, we plan to first establish occurrence of dideoxyosone-mediated AGE synthesis in vivo using a novel immunological method and then deduce chemical structure of major AGE specifically arising from dideoxyosone, develop methods for their detection in tissues, assess importance of this pathway for AGE synthesis in diabetes. Our study is expected to provide novel insights into AGE formation in diabetes and may lead to new pharmacological agents to prevent AGE formation and complications in diabetes.