ArticleMolecular metabolism2020
Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction.
Article in Molecular metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- QBP1 Peptide as a Potential Anti-Amyloidogenic Therapy for Type 2 Diabetes: An In Vitro Study.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The Welander TIA1 mutation dedifferentiates insulin-producing cells: Reversal by a GLP-1 receptor agonist.The Journal of biological chemistry · 2026Article
- Flavones in pomelo peel resist fibril formation of human islet amyloid polypeptide.Chinese herbal medicines · 2025Article
- Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.Scientific reports · 2024Article
- Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.medRxiv : the preprint server for health sciences · 2023Article
- Pharmacological inhibitors of β-cell dysfunction and death as therapeutics for diabetes.Frontiers in endocrinology · 2023Review
- Islet-on-a-chip for the study of pancreatic β-cell function.In vitro models · 2022Review
- A new strategy to reconcile amyloid cross-seeding and amyloid prevention in a binary system of α-synuclein fragmental peptide and hIAPP.Protein science : a publication of the Protein Society · 2022Article
- 4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity.Scientific reports · 2021Article
- In Situ LSPR Sensing of Secreted Insulin in Organ-on-Chip.Biosensors · 2021Article
- Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.Developmental cell · 2021Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivePancreatic 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.
methodsMice 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.
resultsNontreated 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.
conclusionsThese 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.
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