Editors' ChoiceDiabetes

High RANKs for Diabetes and Osteoporosis

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Science Translational Medicine  20 Mar 2013:
Vol. 5, Issue 177, pp. 177ec49
DOI: 10.1126/scitranslmed.3006110

Chronic, low-grade inflammation is a part of the pathogenesis of obesity and type 2 diabetes, with inflammatory signals contributing to both insulin resistance (in the liver, adipose tissue, and skeletal muscle) and pancreatic β-cell failure. Our growing arsenal of antidiabetic medications do not yet contain an anti-inflammatory drug designed to improve insulin sensitivity and decrease glucose levels. Nevertheless, new work suggests that we may already have such a drug in hand. Kiechl and colleagues suggest that receptor activator of nuclear factor–κB (RANK) and its ligand (RANKL) are central to the development of hepatic insulin resistance and diabetes. An existing osteoporosis drug could interfere with this pathway.

The authors performed a prospective, population-based study and found that high concentrations of soluble RANKL in blood independently predicted the incidence of type 2 diabetes. They investigated the direct effect of RANKL on hepatic insulin resistance in both genetic and nutritional mouse models of obesity and diabetes. Blockade of RANKL signaling normalized fasting glucose in mice and significantly decreased insulin levels; it also improved glucose and insulin tolerance. A glucose clamp experiment revealed an improvement in hepatic glucose production after inhibition of RANKL signaling. These results corroborate the previously suggested role of nuclear factor–κB (NFκB) as a mediator of hepatic insulin resistance and provide evidence that RANKL acts directly to regulate metabolism in the liver.

Of interest, denosumab—a monoclonal antibody against RANKL—was approved by the U.S. Food and Drug Administration in June 2010 for the treatment of osteoporosis, a disease in which RANKL promotes osteoclast maturation and bone resorption. The new results may provide the missing mechanistic link for the epidemiological correlations between type 2 diabetes and bone resorption markers, osteoporosis and fragility fractures. Denosumab, or other inhibitors of RANK/RANKL signaling, could potentially prevent bone fractures and improve glycemic control simultaneously in osteoporotic patients with diabetes.

S. Kiechl et al., Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat. Med. 19, 358–363 (2013). [Abstract]

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