| First Author | Li X | Year | 2018 |
| Journal | Theranostics | Volume | 8 |
| Issue | 21 | Pages | 5960-5971 |
| PubMed ID | 30613274 | Mgi Jnum | J:295646 |
| Mgi Id | MGI:6454168 | Doi | 10.7150/thno.28960 |
| Citation | Li X, et al. (2018) Islet alpha-cell Inflammation Induced By NF-kappaB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics 8(21):5960-5971 |
| abstractText | Islet alpha-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet alpha-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-kappaB inducing kinase (NIK) regulates pancreatic alpha-cell function, both in vitro and in vivo, and to assess how islet alpha-cell inflammation induced by NIK affects the development of pancreatitis. Methods: We utilized adenovirus-mediated NIK overexpression, ELISA, qPCR, RNA-seq, and Western blot analyses to study the role of NIK in islet alpha cells in vitro. Islet alpha-cell-specific NIK overexpressing (alpha-NIK-OE) mice were generated, and pancreatic alpha/beta-cell function and the occurrence of pancreatitis in these mice were assessed via ELISA, qPCR, and immunohistochemical analyses. Results: The LTbetaR/noncanonical NF-kappaB signaling pathway is present in islet alpha cells. Overexpression of NIK in alphaTC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, alpha-cell specific overexpression of NIK (alpha-NIK-OE) results in alpha-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, alpha-NIK-OE mice also display a reduced beta-cell mass, growth retardation, pancreatitis, and postnatal death. Conclusions: Islet alpha-cell specific overexpression of NIK results in islet alpha-cell dysfunction and causes islet beta-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet alpha cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice. |
