Conclusions/interpretation
APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes.
Methods
Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-α, IL-1β and IFN-γ) was assessed ex vivo.
Results
Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell-specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFκB inhibitor, α (IκBα) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFκB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFκB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. Conclusions/interpretation: APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes.