A number of years ago we proposed that nonenzymatic addition of glucose to a variety of susceptible body proteins might produce functional alterations which contribute to the development of the pathological complications of diabetes mellitus. Experimental evaluation of this hypothesis led first to the development of hemoglobin A1c as a convenient measure of the integrated blood glucose over time, and more recently to the recognition that further rearrangements of glucose-protein addition products, Advanced Glycosylation Endproducts (AGE), occur in vivo on proteins which are noted to be altered in diabetes and aging. In contrast to the simple Amadori glucose-protein adducts which reach an equilibrium concentration after 3-4 weeks, AGE accumulate with age on long-lived proteins such as lens crystallins and dura collagen. The AGE adducts have been shown to crosslink proteins, trap soluble proteins to long-lived proteins, act as specific signals when attached to proteins for uptake by macrophages and when attached to DNA cause dysfunction and mutations. During the next grant period we plan to develop an RIA to measure 2-(2-furoyl)-4(5)-(2-furanyl-1H-imidazole (FFI), a specific AGE, in proteins and tissues of normal, diabetic and aged individuals. Measurement of FFI on proteins with different half-lifes should give a profile of glucose metabolism over long periods of time. Further chemical studies are also proposed to identify other AGE-adducts of proteins and nucleic acids. Special emphasis will be placed on finding AGE-DNA and protein-AGE-DNA adducts in vivo. These studies should advance our knowledge of Advanced Glycosylation Endproducts in vivo and provide the framework for studies of aging and rationale for the design of pharmacological investigation aimed at preventing diabetic complications.
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