Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.
Animals
Insulin-Secreting Cells
/ metabolism
Receptors, Interleukin
/ metabolism
Female
Humans
Male
Insulin
/ metabolism
Mice
Homeostasis
Glucose
/ metabolism
Mice, Knockout
Insulin Secretion
Mice, Inbred C57BL
Interleukin-22
Glucose Intolerance
/ metabolism
Interleukins
/ metabolism
Aging
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 May 2024
29 May 2024
Historique:
received:
27
11
2023
accepted:
26
04
2024
medline:
30
5
2024
pubmed:
30
5
2024
entrez:
29
5
2024
Statut:
epublish
Résumé
The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
Identifiants
pubmed: 38811550
doi: 10.1038/s41467-024-48320-2
pii: 10.1038/s41467-024-48320-2
doi:
Substances chimiques
interleukin-22 receptor
0
Receptors, Interleukin
0
Insulin
0
Glucose
IY9XDZ35W2
Interleukin-22
0
Interleukins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4527Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : Ideas Grant
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : Developmental Grant
Organisme : Gastroenterological Society of Australia (GESA)
ID : Clinical Collaborative Grant
Informations de copyright
© 2024. The Author(s).
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