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Novel Human Insulin Isoforms and Cα-peptide Product in Islets of Langerhans and Choroid Plexus
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posted on 2021-10-18, 13:47 authored by Qing-Rong Liu, Min Zhu, Pingbo Zhang, Caio H. Mazucanti, Nicholas S. Huang, Doyle L. Lang, Qinghua Chen, Pavan Auluck, Stefano Marenco, Jennifer F. O’Connell, Luigi Ferrucci, Chee W. Chia, Josephine M. EganHuman 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
(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 Ca-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 (IAPP) is not
expressed in ChP and its amyloid formation was inhibited in vitro 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 INS isoforms are present in
ChP from insulin-deficient autopsy donors.