TRAF2 forms a complex with the E3-ubiquitin-ligase proteins BIRC2/3, which degrades the NFκB-inducing kinase (NIK) preventing activation of the non-canonical NFκB pathway. We previously demonstrated that mice deficient for TRAF2 in beta-cells (βTRAF2) showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a diet-induced obesity model (DIO). βTRAF2 islets also displayed hyperactivation of the non-canonical NFκB pathway. To further dissect out the function of this E3-ubiquitin ligase complex in beta-cells, we generated a beta-cell-specific BIRC2/3 double-knockout (βBIRC) mouse. We also treated islets with BIRC-inhibitors (MV1: also called a Smac-mimetic). We hypothesized that genetic (βBIRC mice) or drug-based (MV1) deletion of BIRC would impair beta-cell function. βBIRC mice showed increased glucose intolerance in a DIO model (45%kCal fat), thus phenocopying βTRAF2 mice. We determined the common molecular denominator to be increased cell-intrinsic NIK with increased p100 to p52 processing in both βTRAF2 and βBIRC islets. Thus, loss of BIRC proteins derails control of non-canonical NFκB signaling with beta-cell dysfunction. Next, we synthesized, and then treated C57BL/6 islets with the drug MV1. MV1 triggered p100 to p52 processing indicating non-canonical NFκB activation. In a GSIS assay, MV1-treated islets showed decreased insulin secretion in response to 20mM, but not 2mM glucose or KCl. We then transplanted defined numbers of vehicle-control and MV1-treated islets into syngeneic diabetic mice and tested beta-cell function by i.p.GTT on postoperative day (POD) 3 and 10. MV1 did not reduce islet mass or induce beta cell apoptosis. However, at POD3 MV1-treated-islet recipients showed a severe decrease in glucose tolerance compared to controls, but recovered normal function by POD10. In summary, without TRAF2 or BIRC2/3, beta-cells exhibit severe defects in insulin secretion under a glucose load. These data define NIK and non-canonical NFκB as novel players in islet dysfunction and identify them as potential drug targets in diabetes.