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- Title
Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity.
- Authors
Yang, Mei-Ling; Connolly, Sean E.; Gee, Renelle J.; Lam, TuKiet T.; Kanyo, Jean; Peng, Jian; Guyer, Perrin; Syed, Farooq; Tse, Hubert M.; Clarke, Steven G.; Clarke, Catherine F.; James, Eddie A.; Speake, Cate; Evans-Molina, Carmella; Arvan, Peter; Herold, Kevan C.; Wen, Li; Mamula, Mark J.
- Abstract
Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that 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.
- Subjects
PROTEIN metabolism; PROTEINS; ANIMAL experimentation; TYPE 1 diabetes; ISLANDS of Langerhans; INSULIN; PROINSULIN; IMMUNITY; RESEARCH funding; MICE; ANTIGENS
- Publication
Diabetes, 2022, Vol 71, Issue 9, p1979
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db21-0989