ArticleThe Journal of experimental medicine2015
Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity.
Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 60 citations in OpenAlex.
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- Non-Genetic-Induced Zebrafish Model for Type 2 Diabetes with Emphasis on Tools in Model Validation.International journal of molecular sciences · 2023Review
- RELA governs a network of islet-specific metabolic genes necessary for beta cell function.Diabetologia · 2023Article
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- Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals.International journal of molecular sciences · 2023Article
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- Assessment of the Hypoglycemic and Hypolipidemic Activity of Flavonoid-Rich Extract fromMolecules (Basel, Switzerland) · 2022Article
- High glucose-induced ROS-accumulation in embryo-larval stages of zebrafish leads to mitochondria-mediated apoptosis.Apoptosis : an international journal on programmed cell death · 2022Article
- NF-κB-inducing kinase (NIK) is activated in pancreatic β-cells but does not contribute to the development of diabetes.Cell death & disease · 2022Article
- Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat.Scientific reports · 2022Article
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.