The current competing renewal encompasses our wet lab human studies directed at understanding the natural history and pathogenesis of Type 1 diabetes and applying that knowledge to develop improved prediction of the disease. In parallel, with other funding, we study the NOD mouse model, and the two sets of studies are intersecting with the hypothesis that insulin is a primary target of the autoimmunity that leads to beta cell destruction. As demonstrated by these studies, multiple genetic factors contribute to the appearance of islet autoantibodies in prospectively followed children including DR,DQ, and DP alleles, insulin gene, and PTPN22 R620W polymorphisms, while some loci have little influence (CTLA4). In the last funding period we discovered that in children followed from birth alleles DPB1*0402 and DRB1*0403 almost completely prevent islet autoimmunity in children less than 10 years old. In the last study period we also collaborated with Dr. Hutton who discovered the fourth major islet autoantigen (ZnT8) to define the predictive potential of ZnT8 autoantibodies. In children followed from birth we have recently discovered that mean levels of insulin autoantibodies inversely correlate with rate of progression to diabetes with no correlation for GAD65 or IA-2 autoantibodies. In addition, we have initial promising data for a non-radioactive plate capture insulin autoantibody assay that promises with its precision, sensitivity and specificity, to allow us to explore determinants of insulin autoantibodies in children developing diabetes, new onset patients, twins and even normal controls. We believe our MSD insulin autoantibody assay utilizing proinsulin can be improved but even with its current performance will likely replace fluid phase insulin autoantibody radioassays. An important specific aim is to fully characterize the MSD insulin autoantibody assay and to test modifying N-Hydroxy-succinamide labeling and biotinylation of proinsulin to further enhance the assay. Given new assay technology with high precision we are now in a position to explore determinants of multiple levels of insulin autoantibodies, (e.g. higher levels correlating with rate of progression to diabetes and low insulin inhibitable levels found in normal controls which may be potentially genetically determined. We will test the hypothesis that levels of insulin autoantibodies are correlated with abnormalities of T lymphocytes targeting insulin similar to our studies in the NOD mouse and specifically levels of insulin autoantibodies mark the rate of beta cell autoimmunity. These studies should improve our ability to design trials for the prevention of Type 1 diabetes as we better define the natural history of the disease.

Public Health Relevance

We have developed a plate capture non-radioactive assay for insulin autoantibodies that we believe will both revolutionize measurement of insulin autoantibodies and help inform our understanding of the natural history of Type 1 diabetes. In particular we will explore hypothesis that insulin autoantibodies are present at a low level in most individuals, and their levels in multiple autoantibody positive individuals inversely specifically correlate with rate of progression to diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Spain, Lisa M
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University of Colorado Denver
Schools of Medicine
United States
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Michels, Aaron W; Gottlieb, Peter A (2018) Learning From Past Failures of Oral Insulin Trials. Diabetes 67:1211-1215
Steck, Andrea K; Dong, Fran; Frohnert, Brigitte I et al. (2018) Predicting progression to diabetes in islet autoantibody positive children. J Autoimmun 90:59-63
Liu, Chih-Wei; Bramer, Lisa; Webb-Robertson, Bobbie-Jo et al. (2018) Temporal expression profiling of plasma proteins reveals oxidative stress in early stages of Type 1 Diabetes progression. J Proteomics 172:100-110
Wang, Yang; Sosinowski, Tomasz; Novikov, Andrey et al. (2018) C-terminal modification of the insulin B:11-23 peptide creates superagonists in mouse and human type 1 diabetes. Proc Natl Acad Sci U S A 115:162-167
Frohnert, Brigitte I; Laimighofer, Michael; Krumsiek, Jan et al. (2018) Prediction of type 1 diabetes using a genetic risk model in the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes 19:277-283
Akturk, Halis Kaan; Alkanani, Aimon; Zhao, Zhiyuan et al. (2018) PD-1 Inhibitor Immune-Related Adverse Events in Patients With Preexisting Endocrine Autoimmunity. J Clin Endocrinol Metab 103:3589-3592
Ostrov, David A; Alkanani, Aimon; McDaniel, Kristen A et al. (2018) Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. J Clin Invest 128:1888-1902
Burrack, Adam L; Landry, Laurie G; Siebert, Janet et al. (2018) Simultaneous Recognition of Allogeneic MHC and Cognate Autoantigen by Autoreactive T Cells in Transplant Rejection. J Immunol 200:1504-1512
Waugh, Kathleen; Snell-Bergeon, Janet; Michels, Aaron et al. (2017) Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY). PLoS One 12:e0174840
Michels, Aaron W; Landry, Laurie G; McDaniel, Kristen A et al. (2017) Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes. Diabetes 66:722-734

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