Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity

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 beta 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.

Automated summary

In this study, the researchers found a group of carbonylated proteins in pancreatic islets before the onset of hyperglycemia in NOD mice. They discovered that carbonylated prolyl-4-hydroxylase beta subunit (P4Hb) is an autoantigen in both human and murine type 1 diabetes. They also found that carbonylated P4Hb is increased in stressed islets, leading to decreased insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and early human type 1 diabetes patients. Additionally, the researchers identified autoreactive CD4(+) T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. These findings provide mechanistic insight into the pathways of proinsulin metabolism and the formation of autoantigens in type 1 diabetes.