Novel Human Insulin Isoforms and Cα-Peptide Product in Islets of Langerhans and Choroid Plexus

Diabetes. 2021 Dec;70(12):2947-2956. doi: 10.2337/db21-0198. Epub 2021 Oct 14.


Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amyloid / analysis
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Animals
  • Autopsy
  • C-Peptide / analysis
  • C-Peptide / chemistry
  • C-Peptide / metabolism*
  • Choroid Plexus / chemistry
  • Choroid Plexus / metabolism*
  • Choroid Plexus / pathology
  • Humans
  • Insulin / analysis
  • Insulin / chemistry
  • Insulin / metabolism*
  • Islet Amyloid Polypeptide / analysis
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / metabolism
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Mice
  • Proinsulin / analysis
  • Proinsulin / chemistry
  • Proinsulin / metabolism
  • Protein Isoforms / analysis
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism


  • Amyloid
  • C-Peptide
  • Insulin
  • Islet Amyloid Polypeptide
  • Protein Isoforms
  • Proinsulin

Associated data

  • figshare/10.2337/figshare.16640458