Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity.

J Exp Med 2015 Jul 29;212(8):1239-54. Epub 2015 Jun 29.

Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia

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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http://dx.doi.org/10.1084/jem.20150218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516791PMC
July 2015
21 Reads
4 Citations
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