Carbonyl Post-Translational Modification Associated with Early Onset Type 1 Diabetes Autoimmunity
Yang, M.-L.; Connolly, S.; Gee, R.; Lam, T.; Kanyo, J.; Clarke, S. G.; Clarke, C. F.; James, E. A.; Speake, C.; Evans-Molina, C.; Wen, L.; Herold, K. C.; Mamula, M.
Show abstract
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 (NOD) mice. Of particular 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. Moreover, circulating autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and those creating autoantigenic forms of insulin in type 1 diabetes.
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