Intra-islet inflammation in Type-2 Diabetes: Evidence that the E3 ligase TRAF2 is a key protective factor for pancreatic beta cells (#146)
Activation of the JNK and NF-κB signaling pathways are associated with beta cell failure and apoptosis. TNFα-receptor associated factor 2 (TRAF2), an E3-ubiquitin ligase, mediates activation of both these pathways. We predicted that genetic deletion of TRAF2 in beta cells would improve their function and prevent diabetes; an idea previously untested in islets.We generated beta cell specific TRAF2 knockout mice (bTRAF2), examined TNFα-signaling and subjected mice to a diet-induced obesity model. bTRAF2 islets appeared normal, showed robust insulin labeling, and bTRAF2 mice displayed normal glucose tolerance at 8 weeks of age. Analyzing TNFα-induced signaling ex-vivo, bTRAF2 islets displayed delayed degradation of IκBα compared to wildtype. Phosphorylation of JNK was delayed, and profoundly prolonged. Deleting TRAF2 in Min6 beta cells using siRNA emulated delayed, prolonged JNK-activation. Further, we found increased processing of p100 to p52 in unstimulated bTRAF2 islets indicating cell-intrinsic activation of the non-canonical NF-κB pathway. bTRAF2 islets were hyper-responsive to TNFα-stimulation compared to wildtype showing 3-7fold increased gene expression for CXCL10, ICAM1 and TNFα, genes regulated by the non-canonical pathway. Also the basal levels for these genes were increased ~2.5fold compared to wildtype. When fed a high-fat-diet for 8 weeks, glucose intolerance in bTRAF2 versus wildtype mice was greatly exacerbated. This was due to a defect in first-phase insulin secretion in bTRAF2 mice determined by i.v.GTT. Intriguingly, TRAF2 mRNA levels were reduced in wildtype islets isolated from high-fat-diet fed mice versus islets from chow-fed mice. Thus, mice lacking TRAF2 in islets exhibit a hyper-inflammatory profile and severe defects in glucose control and insulin secretion under a high-fat-feeding regimen. At the molecular level TRAF2 controls the cellular tempo of JNK and NF-κB activation and reigns in the non-canonical NF-κB pathway. Loss of this control circuit exacerbates diabetes suggesting that TRAF2 functions as a key protective factor in beta cells.