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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK032083-32
Application #
8638938
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
32
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Yang, Junbao; Chow, I-Ting; Sosinowski, Tomasz et al. (2014) Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc Natl Acad Sci U S A 111:14840-5
Simmons, Kimber; Michels, Aaron W (2014) Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. Rheum Dis Clin North Am 40:797-811
Steck, Andrea K; Dong, Fran; Taki, Iman et al. (2014) Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. Diabetes Care 37:2031-3
Zhang, Li; Crawford, Frances; Yu, Liping et al. (2014) Monoclonal antibody blocking the recognition of an insulin peptide-MHC complex modulates type 1 diabetes. Proc Natl Acad Sci U S A 111:2656-61
Steck, Andrea K; Dong, Fran; Wong, Randall et al. (2014) Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers. Pediatr Diabetes 15:355-62
Jin, Yulan; Sharma, Ashok; Bai, Shan et al. (2014) Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function. Diabetes 63:2506-15
Bettini, Maria; Blanchfield, Lori; Castellaw, Ashley et al. (2014) TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential. J Immunol 193:571-9
Michels, Aaron W (2013) Targeting the trimolecular complex. Clin Immunol 149:339-44
Yu, Liping; Dong, Fran; Miao, Dongmei et al. (2013) Proinsulin/Insulin autoantibodies measured with electrochemiluminescent assay are the earliest indicator of prediabetic islet autoimmunity. Diabetes Care 36:2266-70
Sosinowski, Tomasz; Eisenbarth, George S (2013) Type 1 diabetes: primary antigen/peptide/register/trimolecular complex. Immunol Res 55:270-6

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