The non-canonical NF-kappaB pathway as a novel player in beta cell dysfunction in diabetes

Loss of pancreatic β cell mass and function is a feature of both type-1 and type-2 diabetes. The non-canonical NF-κB pathway has recently garnered attention at being involved in the development of peripheral insulin resistance (liver, muscle) in diabetes. Whether pancreatic β cell non-canonical NF-κB signalling contributes to glucose homeostasis and diabetes is unknown. We found that the non-canonical NF-κB pathway was activated in islets from diet-induced obese (DIO) mice compared to chow controls, as evidenced by accumulation of NF-κB-inducing kinase (NIK), IKKα phosphorylation, p100 to p52 processing and RelB accumulation. To examine the effect of NIK accumulation in β cells, we generated a genetic β cell-specific mouse model of constitutive NIK activation. The TRAF2/TRAF3/BIRC2/3 E3 ubiquitin ligase complex tightly controls activation of NIK. Deletion of either component (βTRAF or βBIRC) promotes β cell-intrinsic NIK activation. βTRAF2 mice showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a DIO model. β cell mass was increased in βTRAF2 mice, indicating severely impaired insulin secretory capacity. βTRAF2 islets exhibited dysregulated TNFα-stimulated canonical NF-κB and MAPK signalling. To dissect out whether NIK activation was promoting β cell dysfunction, we next utilized a β cell-specific deletion of TRAF3. βTRAF3 mice phenocopied βTRAF2 mice showing defective first-phase insulin secretion and increased β cell mass. βTRAF3 islets exhibited hyper-activation of NIK but normal TNFα-stimulated canonical NF-κB and MAPK signalling. Next, we set out to determine whether increased β cell expansion in NIK ON mice per se might trigger β cell dysfunction or whether acute NIK activation would also alter β cell function. Using a drug-based approach, we examined function in islets treated with a BIRC-inhibitor (MV1; Smac-mimetic). Ex vivo, MV1-treated mouse islets showed impaired GSIS. In vivo, MV1 disrupted glucose homeostasis as MV1-treated islets failed to provide normal metabolic control in syngeneic transplant recipients, and MV1-injected zebrafish larvae exhibited hyper-glycosuria. In summary, we have discovered that the diabetic milieu triggers β cell-intrinsic NIK activation. Constitutive as well as acute activation of NIK precipitates β cell secretory defects in mice and fish. Thus, NIK is a critical signalling node regulating glucose homeostasis in diabetes