Islet ?-cell Inflammation Induced By NF-?B inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

ABSTRACT: Islet ?-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet ?-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-?B inducing kinase (NIK) regulates pancreatic ?-cell function, both in vitro and in vivo, and to assess how islet ?-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 ? cells in vitro. Islet ?-cell-specific NIK overexpressing (?-NIK-OE) mice were generated, and pancreatic ?/?-cell function and the occurrence of pancreatitis in these mice were assessed via ELISA, qPCR, and immunohistochemical analyses. Results: The LT?R/noncanonical NF-?B signaling pathway is present in islet ? cells. Overexpression of NIK in ?TC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, ?-cell specific overexpression of NIK (?-NIK-OE) results in ?-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, ?-NIK-OE mice also display a reduced ?-cell mass, growth retardation, pancreatitis, and postnatal death. Conclusions: Islet ?-cell specific overexpression of NIK results in islet ?-cell dysfunction and causes islet ?-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet ? cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice.

SUBMITTER: Li X 

PROVIDER: S-EPMC6299425 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature