Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction.
Amyloid
/ metabolism
Animals
Apoptosis
Blood Glucose
/ metabolism
Diabetes Mellitus, Type 2
/ metabolism
Disease Models, Animal
Glucose
/ metabolism
Glucose Intolerance
/ metabolism
Glucose Tolerance Test
Humans
Insulin
/ metabolism
Insulin Secretion
Insulin-Secreting Cells
/ metabolism
Islet Amyloid Polypeptide
/ genetics
Islets of Langerhans
/ metabolism
Macrophages
/ metabolism
Male
Mice
Mice, Transgenic
alpha 1-Antitrypsin
/ genetics
Alpha1-antitrypsin
Amyloid
IAPP
Islet inflammation
Macrophage
β-Cell
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
12
03
2020
accepted:
21
03
2020
pubmed:
2
4
2020
medline:
7
7
2021
entrez:
2
4
2020
Statut:
ppublish
Résumé
Pancreatic β-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic β-cells. Mice overexpressing hIAPP (hIAPP-Tg) in pancreatic β-cells were used as a model of amyloid-induced β-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity. Nontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential β-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced β-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced β-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1β by macrophages. Remarkably, AAT protected β-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic β-cells. These results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic β-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic β-cell function for the treatment of T2D.
Identifiants
pubmed: 32229246
pii: S2212-8778(20)30058-2
doi: 10.1016/j.molmet.2020.100984
pmc: PMC7186564
pii:
doi:
Substances chimiques
Amyloid
0
Blood Glucose
0
Insulin
0
Islet Amyloid Polypeptide
0
alpha 1-Antitrypsin
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100984Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.
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