The canonical notion that type 1 diabetes (T1D) results following a complete destruction of β cells has recently been questioned as small amounts of C-peptide are detectable in patients with long-standing disease. Previously, we analyzed protein and gene expression levels for proinsulin, insulin, C-peptide, and islet amyloid polypeptide within pancreatic tissues from T1D, autoantibody positive (Ab+), and control organs. Insulin and C-peptide levels were low to undetectable in extracts from the T1D cohort; however, proinsulin and INS mRNA were detected in the majority of T1D pancreata. Interestingly, heterogeneous nuclear RNA (hnRNA) for insulin and INS-IGF2, both originating from the INS promoter, were essentially undetectable in T1D pancreata, arguing for a silent INS promoter. Expression of PCSK1, a convertase responsible for proinsulin processing, was reduced in T1D pancreata, supportive of persistent proinsulin. These data implicate the existence of β cells enriched for inefficient insulin/C-peptide production in T1D patients, potentially less susceptible to autoimmune destruction. Moving forward, we propose to expand these studies to address the molecular mechanisms, including those of genetics (at a single cell to whole pancreas level) that contribute to novel aspects of T1D development, including the stress responses, protein misfolding, and mitochondrial dysfunction. Follow up experiments will determine the relationship of autoantigens to autoantibody titer. It is well known that autoantibodies wane after the onset of type 1 diabetes. Herein we are investigating the rate of loss of autoantibodies post onset with loss of these target proteins in the beta cells.
