Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata

Cell Metab. 2017 Sep 5;26(3):568-575.e3. doi: 10.1016/j.cmet.2017.08.013.


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. 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.

Keywords: PCSK1; PCSK2; insulin mRNA; insulin promoter; insulin-positive single cells; pancreas; proconvertases; proinsulin; type 1 diabetes.

MeSH terms

  • Adult
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Gene Expression Regulation
  • Glucagon / metabolism
  • Humans
  • Insulin / genetics*
  • Insulin / metabolism
  • Male
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Pancreas, Exocrine / metabolism
  • Pancreas, Exocrine / pathology
  • Proinsulin / metabolism*
  • Proprotein Convertase 1 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Young Adult


  • Insulin
  • RNA, Messenger
  • Glucagon
  • Proinsulin
  • PCSK1 protein, human
  • Proprotein Convertase 1