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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK019655-13
Application #
3226487
Study Section
Biochemistry Study Section (BIO)
Project Start
1977-04-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Al-Abed, Y; Bucala, R (2000) Structure of a synthetic glucose derived advanced glycation end product that is immunologically cross-reactive with its naturally occurring counterparts. Bioconjug Chem 11:39-45
Al-Abed, Y; Mitsuhashi, T; Li, H et al. (1999) Inhibition of advanced glycation endproduct formation by acetaldehyde: role in the cardioprotective effect of ethanol. Proc Natl Acad Sci U S A 96:2385-90
Fishbane, S; Bucala, R; Pereira, B J et al. (1997) Reduction of plasma apolipoprotein-B by effective removal of circulating glycation derivatives in uremia. Kidney Int 52:1645-50
Al-Abed, Y; Bucala, R (1997) Efficient scavenging of fatty acid oxidation products by aminoguanidine. Chem Res Toxicol 10:875-9
Pushkarsky, T; Rourke, L; Spiegel, L A et al. (1997) Molecular characterization of a mouse genomic element mobilized by advanced glycation endproduct modified-DNA (AGE-DNA). Mol Med 3:740-9
Wolffenbuttel, B H; Giordano, D; Founds, H W et al. (1996) Long-term assessment of glucose control by haemoglobin-AGE measurement. Lancet 347:513-5
Al-Abed, Y; Liebich, H; Voelter, W et al. (1996) Hydroxyalkenal formation induced by advanced glycosylation of low density lipoprotein. J Biol Chem 271:2892-6
Bucala, R; Vlassara, H (1995) Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis 26:875-88
Zimmerman, G A; Meistrell 3rd, M; Bloom, O et al. (1995) Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci U S A 92:3744-8
Bucala, R; Mitchell, R; Arnold, K et al. (1995) Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor. J Biol Chem 270:10828-32

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