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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK068045-01
Application #
6808782
Study Section
Metabolism Study Section (MET)
Program Officer
Jones, Teresa L Z
Project Start
2004-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$151,000
Indirect Cost
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Puttaiah, Shivaprakash; Biswas, Ashis; Staniszewska, Magdalena et al. (2007) Methylglyoxal inhibits glycation-mediated loss in chaperone function and synthesis of pentosidine in alpha-crystallin. Exp Eye Res 84:914-21
Miller, Antonia G; Smith, Dawn G; Bhat, Manjunatha et al. (2006) Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions. J Biol Chem 281:11864-71
Puttaiah, Shivaprakash; Zhang, Yuming; Pilch, Heather A et al. (2006) Detection of dideoxyosone intermediates of glycation using a monoclonal antibody: characterization of major epitope structures. Arch Biochem Biophys 446:186-96
Padival, Simi; Nagaraj, Ram H (2006) Pyridoxamine inhibits maillard reactions in diabetic rat lenses. Ophthalmic Res 38:294-302