| First Author | Malle EK | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 8 | Pages | 1239-54 |
| PubMed ID | 26122662 | Mgi Jnum | J:226450 |
| Mgi Id | MGI:5697273 | Doi | 10.1084/jem.20150218 |
| Citation | Malle EK, et al. (2015) Nuclear factor kappaB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. J Exp Med 212(8):1239-54 |
| abstractText | The nuclear factor kappaB (NF-kappaB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. Whereas canonical NF-kappaB signaling is well studied, there is little information on the divergent noncanonical NF-kappaB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-kappaB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of beta 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-kappaB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-kappaB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-kappaB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. |
