α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine.
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
24 Mar 2021
24 Mar 2021
Historique:
entrez:
25
6
2021
pubmed:
26
6
2021
medline:
26
6
2021
Statut:
epublish
Résumé
Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure-function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.
Identifiants
pubmed: 34168810
doi: 10.1039/d1sc01167g
pii: d1sc01167g
pmc: PMC8179678
doi:
Types de publication
Journal Article
Langues
eng
Pagination
5853-5864Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK123183
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008283
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM149438
Pays : United States
Informations de copyright
This journal is © The Royal Society of Chemistry.
Déclaration de conflit d'intérêts
There are no conflicts to declare.
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