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

Elisabeth K. Malle, Nathan W. Zammit, Stacey N. Walters, Yen Chin Koay, Jianmin Wu, Bernice M. Tan, Jeanette E. Villanueva, Robert Brink, Tom Loudovaris, James Cantley, Shelli R. McAlpine, Daniel Hesselson, Shane T. Grey

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1239-1254
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number8
DOIs
Publication statusPublished - 29 Jun 2015

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