RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes

Treatment for type 1 diabetes (T1D) requires stimulation of functional beta cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa beta (NF-kappa B) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human beta cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human beta cell death through RANK-TRAF6 interaction and induction of NF-kappa B activation. Osteoprotegerin and denosumab protected beta cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, beta cell proliferation, and mass in these mice. Serum from T1D subjects induced human beta cell death and dysfunction, but not alpha cell death. Osteoprotegerin and denosumab reduced T1D serum-induced beta cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.