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

Abstract

<a>Human insulin (<i>INS</i>) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (<i>Ins2</i>) 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 <i>INS</i> isoform expression in postmortem <u>ChP</u> and islets of Langerhans. We uncovered novel <i>INS</i> upstream open reading frame (uORF) 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 C</a>a-peptide. The middle portion of the conventional C-peptide contains b-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Ca-peptide. Islet amyloid polypeptide (<i>IAPP</i>) is not expressed in ChP and its amyloid formation was inhibited <i>in vitro</i> by Ca-peptide more efficiently than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase processed Ca-peptide was significantly increased in islets from type 2 diabetes mellitus (T2DM) autopsy donors. Intriguingly, 100 years after the discovery of insulin we found that <i>INS</i> isoforms are present in ChP <a>from insulin-deficient autopsy donors.</a> <p> </p>