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RANKL inhibition: a new target of treating diabetes mellitus?

Baodi Xing1, Jie Yu1, Huabing Zhang2

  • 1Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Therapeutic Advances in Endocrinology and Metabolism
|May 24, 2023
PubMed

Insights

The receptor activator of nuclear factor-kappa B ligand (RANKL) pathway impacts glucose metabolism, but findings are conflicting. Denosumab (Dmab) shows potential in regulating glucose homeostasis and beta-cell function, suggesting new diabetes therapeutic strategies.

Area of Science:

  • Endocrinology
  • Metabolism
  • Bone Biology

Background:

  • The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is crucial for bone metabolism.
  • RANKL and RANK are expressed in tissues beyond bone, including those involved in glucose regulation, such as the liver, muscle, adipose tissue, and pancreas.

Purpose of the Study:

  • To review the impact of the RANKL signaling pathway on glucose metabolism.
  • To summarize clinical evidence linking Denosumab (Dmab) and diabetes mellitus (DM).
  • To explore new therapeutic strategies for diabetes.

Main Methods:

  • Review of existing literature on RANKL signaling and glucose metabolism.
  • Analysis of basic research on Denosumab (Dmab) in humanized mice and in vitro models.
  • Examination of clinical data on the glucometabolic effects of Denosumab (Dmab).

Main Results:

  • Evidence suggests a link between glucose and bone metabolism via the RANKL/RANK/OPG axis.
  • Conflicting results exist regarding RANKL's role in glucose metabolism, with some studies suggesting a protective effect on islet beta-cells and others indicating improved insulin resistance.
  • Denosumab (Dmab) shows potential in regulating glucose homeostasis and beta-cell function in preclinical and in vitro studies, though clinical data are limited and inconsistent.

Conclusions:

  • The RANKL pathway's role in glucose metabolism is complex and requires further investigation.
  • Denosumab (Dmab) may offer a novel therapeutic avenue for diabetes, but more robust clinical evidence is needed.
  • Understanding the interplay between bone metabolism and glucose regulation could lead to innovative diabetes treatments.
Keywords:
RANKLdenosumabdiabetes mellitusglucose metabolisminsulin resistance

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