GLYCATION OF PROTEIN IN DIABETES

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One of the chemical consequences of chronic hyperglycemia in diabetes is an increased body burden of glycated (nonenzymatically glycosylated) proteins. Glycation is recognized as the first step in a complex series of Maillard or browning reactions between glucose and protein which lead, in vitro, to the denaturation, crosslinking and insolubilization of protein. It is hypothesized that these same reactions may also occur in vivo, and that the alterations in protein structure may precipitate the development of pathology in tissues in diabetes and during normal aging. Indeed, the development of chronic complications in the eye, kidney and vasculature in diabetes is associated with increased crosslinking ahd insolubilization of lens, basement membrane and connective tissue proteins. Concomitant increases in glycation, browning and fluorescence of these long-lived extracellular proteins suggest that the Maillard reaction may be involved in these processes. The major objective of this research proposal is to continue studies on the glycation of protein and the role of the browning reaction of glycated proteins in the pathophysiology of diabetes and aging. Specific aims include: (1) structural characterization of Maillard products formed in model amino acid-glucose browning systems; (2) studies of factors which direct the specificity of glycation of protein in vitro and in vivo; (3)\studies on the structure and mechanism of formation of fluorescent and crosslinking compounds generated during Maillard reactions of model proteins in vitro; and (4) development and application of methods for measurement of Maillard reaction products and their catabolites in vivo. We expect that a better understanding of the extent to which Maillard reactions occur in vivo under normal and pathological conditions will increase our understanding of their role in the complications of diabetes. This knowledge should provide a better basis for the design and evaluation of therapeutic approaches to the management of diabetes.