Accumulating evidence demonstrates the link between glucose and bone metabolism. The receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is an essential signaling axis maintaining the balance between bone resorption and bone formation. In recent years, it has been found that RANKL and RANK are distributed not only in bone but also in the liver, muscle, adipose tissue, pancreas, and other tissues that may influence glucose metabolism. Some scholars have suggested that the blockage of the RANKL signaling may protect islet β-cell function and prevent diabetes; simultaneously, there also exist different views that RANKL can improve insulin resistance through inducing the beige adipocyte differentiation and increase energy expenditure. Currently, the results of the regulatory effect on glucose metabolism of RANKL remain conflicting. Denosumab (Dmab), a fully human monoclonal antibody that can bind to RANKL and prevent osteoclast formation, is a commonly used antiosteoporosis drug. Recent basic studies have found that Dmab seems to regulate glucose homeostasis and β-cell function in humanized mice or in vitro human β-cell models. Besides, some clinical data have also reported the glucometabolic effects of Dmab, however, with limited and inconsistent results. This review mainly describes the impact of the RANKL signaling pathway on glucose metabolism and summarizes clinical evidence that links Dmab and DM to seek a new therapeutic strategy for diabetes.

中文翻译：

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RANKL抑制：治疗糖尿病的新靶点？

越来越多的证据证明了葡萄糖和骨代谢之间的联系。核因子kB配体受体激活剂（RANKL）/NF-κB受体激活剂（RANK）/骨保护素（OPG）轴是维持骨吸收和骨形成之间平衡的重要信号轴。近年来发现RANKL和RANK不仅分布在骨骼中，还分布在肝脏、肌肉、脂肪组织、胰腺和其他可能影响糖代谢的组织中。有学者提出，阻断RANKL信号传导可能保护胰岛β细胞功能，预防糖尿病；同时，也存在不同观点认为RANKL可以通过诱导米色脂肪细胞分化来改善胰岛素抵抗，增加能量消耗。目前，RANKL对糖代谢的调节作用结果仍存在争议。地诺单抗（Dmab）是一种全人源单克隆抗体，可以与 RANKL 结合并阻止破骨细胞形成，是常用的抗骨质疏松药物。最近的基础研究发现，Dmab 似乎可以调节人源化小鼠或体外人 β 细胞模型中的葡萄糖稳态和 β 细胞功能。此外，一些临床数据也报道了 Dmab 的糖代谢作用，但结果有限且不一致。本文主要阐述RANKL信号通路对糖代谢的影响，并总结Dmab与DM联系的临床证据，以寻求新的糖尿病治疗策略。