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Carbonyl Post-Translational Modification Associated with Early Onset Type 1 Diabetes Autoimmunity

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posted on 22.06.2022, 12:02 authored by Mei-Ling Yang, Sean E. Connolly, Renelle Gee, TuKiet T. Lam, Jean Kanyo, Jian Peng, Perrin Guyer, Farooq Syed, Hubert M. Tse, Steven G. Clarke, Catherine F. Clarke, Eddie A. James, Cate Speake, Carmella Evans-Molina, Peter Arvan, Kevan C. Herold, Li Wen, Mark J. Mamula

Inflammation and oxidative stress in pancreatic islets amplify the appearance of various post-translational modifications (PTMs) to self-proteins.  Herein, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in non-obese diabetic mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase beta subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes.  We found the carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin to insulin ratios.  Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes. 

Funding

This research was supported by the Training Program in Investigative Rheumatology (5T32-AR007107) to S.E.C., Innovative Grant from the Juvenile Diabetes Research Foundation (1-lNO-2022-1116-A-N) to M.J.M., and National Institutes of Health Grant (DK104205-01) to K.H. and M.J.M. L.W. was supported by National Institutes of Health Grant (DK092882) and Diabetes Research Center (DK-11-015).

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