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

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.

Type Journal
Authors Malle, E.K.; Zammit, N.W.; Walters, S.N.; Koay, Y.C.; Wu, J.; Tan, B.M.; Villanueva, J.; Brink, R.; Loudovaris, T.; Cantley, J.; McAlpine, S.R.; Hesselson, D.; Grey, S.T.
Responsible Garvan Author A/Prof Shane Grey
Publisher Name JOURNAL OF EXPERIMENTAL MEDICINE
Published Date 2015-06-29
Published Volume 212
Published Issue 8
Published Pages 1239-1254
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26122662
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/12914