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

<a>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 (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 (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 <a>from insulin-deficient autopsy donors.</a>

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

10.2337/figshare.16640458.v1 ◽

2021 ◽

Author(s):

Qing-Rong Liu ◽

Min Zhu ◽

Pingbo Zhang ◽

Caio H. Mazucanti ◽

Nicholas S. Huang ◽

...

Keyword(s):

Choroid Plexus ◽

Islets Of Langerhans ◽

Human Insulin ◽

Mammalian Species ◽

Peptide Sequence ◽

Upstream Open Reading Frame ◽

Amyloid Formation ◽

Islet Amyloid ◽

C Peptide

<a>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 (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 (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 <a>from insulin-deficient autopsy donors.</a>

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Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Journal of Biological Chemistry ◽

10.1074/jbc.274.48.34059 ◽

1999 ◽

Vol 274 (48) ◽

pp. 34059-34066 ◽

Cited By ~ 40

Author(s):

Wendy M. MacFarlane ◽

Joanna C. Chapman ◽

Ruth M. Shepherd ◽

Molly N. Hashmi ◽

Noritaka Kamimura ◽

...

Keyword(s):

Cell Line ◽

Islets Of Langerhans ◽

Human Insulin ◽

Hyperinsulinemic Hypoglycemia ◽

Secreting Cell

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Organization of tight junctions in the choroid plexus epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100082546 ◽

1978 ◽

Vol 36 (2) ◽

pp. 336-337

Author(s):

B. Van Deurs ◽

J. K. Koehler

Keyword(s):

Choroid Plexus ◽

Present Report ◽

Freeze Fracture ◽

Barrier Properties ◽

Cell Junctions ◽

Structural Basis ◽

Apical Surface ◽

Choroid Plexus Epithelium ◽

Solid Nitrogen ◽

Special Composition

The choroid plexus epithelium constitutes a blood-cerebrospinal fluid (CSF) barrier, and is involved in regulation of the special composition of the CSF. The epithelium is provided with an ouabain-sensitive Na/K-pump located at the apical surface, actively pumping ions into the CSF. The choroid plexus epithelium has been described as “leaky” with a low transepithelial resistance, and a passive transepithelial flux following a paracellular route (intercellular spaces and cell junctions) also takes place. The present report describes the structural basis for these “barrier” properties of the choroid plexus epithelium as revealed by freeze fracture.Choroid plexus from the lateral, third and fourth ventricles of rats were used. The tissue was fixed in glutaraldehyde and stored in 30% glycerol. Freezing was performed either in liquid nitrogen-cooled Freon 22, or directly in a mixture of liquid and solid nitrogen prepared in a special vacuum chamber. The latter method was always used, and considered necessary, when preparations of complementary (double) replicas were made.

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