Complications of atherosclerosis are the leading cause of morbidity and mortality in subjects with diabetes mellitus. Epidemiologic research has indicated that the traditional risk factors for cardiovascular disease are not sufficient in and of themselves to account for this increased risk. Therefore, efforts to define factors that may play a role in the increase of morbidity associated with diabetics is warranted. It has recently been shown that nonenzymatic glucosylation of lipoproteins occurs in normals and to a much greater extent in diabetics. The purpose of this project is to more carefully define both the qualitative and quantitative aspects of nonenzymatic glucosylation of lipoproteins, and to relate such alterations in lipoprotein structure to changes in lipoprotein function. The role that glucosylated plasma apoproteins may play in the lipoprotein abnormalities frequently observed in diabetic patients will be investigated by accomplishing three specific aims. The first is to identify which apoproteins can become glucosylated in the plasma of a limited number of hyperglycemic diabetics and to characterize this apoprotein glucosylation. The second is to identify both the prevalence and the degree of apoprotein glucosylation in euglycemic and hyperglycemic individuals representing the entire spectrum of blood glucose control. This identification and characterization will be accomplished immunochemically using recently generated mouse monoclonal antibodies that specifically bind and identify glucosylated amino acid residues on proteins. The third specific aim will be to begin to identify the functional consequences of apoprotein glucosylation. This will be accomplished by preparing in vitro glucosylated plasma lipoproteins and measuring selected in vitro functional parameters including lipoprotein regulation of: a) lymphocyte function, b) the expression of monocyte procoagulant activity, c) platelet reactivity, and d) ovarian cell steroidogenesis. If functional abnormalities are found, the physiologic significance of apoprotein glucosylation will be identified by placing special emphasis on relating the degree and/or site of apoprotein glucosylation to the extent of the functional defect. Using the immunochemical techniques proposed, these studies should provide for the first time a comprehensive quantitation of the extent and the prevalence of apoprotein glucosylation so that the physiologic consequences of apoprotein glucosylation can be identified.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032108-02
Application #
3343352
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1984-04-01
Project End
1987-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037