Insulin-dependent diabetes is a major health problem in the U.S. as well as in many other countries. The disease is characterized by a specific disappearance of the pancreatic B cells leading to a life-long dependence on daily insulin injections. The etiology and pathogenesis are unclear but both viruses or other environmental factors may be able to induce the disease against a background of the major histocompatibility antigens HLA-DR 3 and/or 4. It is of considerable interest therefore that newly diagnosed diabetic patients have autoantibodies reacting with pancreatic B cells. The antibodies, which may be present before the clinical onset of the disease, can be detected in a variety of islet cell preparations. However, current assay systems are cumbersome and qualitative. Furthermore, the antigens detected in these assays are not known nor is it known how different assay systems relate to each other or their predictive value for diabetes. Using radioactively labelled proteins from human or rat pancreatic islet cells it was demonstrated that sera from human diabetic patients or spontaneously diabetic BB rats detect a major antigen being a Mr 64000 protein. This protein will be isolated and characterized to determine its structure and reactivity with autoantibodies in diabetic sera. Techniques of gelelectrophoresis, electroelution of protein components and analysis of amino acid sequences will be used to determine the primary structure. Long term objectives include determination of the complete structure by molecular cloning and use of the isolated protein or synthetic peptides thereof to develop quantitative and reproducible assay for autoantibodies associated with onset of insulin-dependent diabetes. Knowledge of an islet cell antigen may prove useful to explain the mechanisms by which the immune response in certain individuals is directed against self-pancreatic B cell antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033873-03
Application #
3232272
Study Section
(SSS)
Project Start
1984-05-01
Project End
1987-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Steno Diabetes Center
Department
Type
DUNS #
City
Gentofte
State
Country
Denmark
Zip Code
Lernmark, A; Kloppel, G; Stenger, D et al. (1995) Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch 425:631-40
Li, L; Hagopian, W A; Brashear, H R et al. (1994) Identification of autoantibody epitopes of glutamic acid decarboxylase in stiff-man syndrome patients. J Immunol 152:930-4
Grubin, C E; Daniels, T; Toivola, B et al. (1994) A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37:344-50
Lernmark, A (1994) Molecular biology of IDDM. Diabetologia 37 Suppl 2:S73-81
Hagopian, W A; Karlsen, A E; Gottsater, A et al. (1993) Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest 91:368-74
Landin-Olsson, M; Palmer, J P; Lernmark, A et al. (1992) Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. Diabetologia 35:1068-73
Barmeier, H; Ahlmen, J; Landin-Olsson, M et al. (1992) Quantitative analysis of islet glutamic acid decarboxylase p64 autoantibodies in insulin-dependent diabetes mellitus. Autoimmunity 13:187-96
Pollema, C H; Ruzicka, J; Christian, G D et al. (1992) Sequential injection immunoassay utilizing immunomagnetic beads. Anal Chem 64:1356-61
Karlsen, A E; Hagopian, W A; Petersen, J S et al. (1992) Recombinant glutamic acid decarboxylase (representing the single isoform expressed in human islets) detects IDDM-associated 64,000-M(r) autoantibodies. Diabetes 41:1355-9
Barmeier, H; McCulloch, D K; Neifing, J L et al. (1991) Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 34:727-33

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