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RANKL signaling to the liver associated with type 2 diabetes risk


Kiechl et al. examined serum concentrations of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in a study population of 844 people set up to survey atherosclerosis epidemiology and pathogenesis.

During a period of 15 years from 1990, 9.2% developed type 2 diabetes mellitus (T2DM). The concentrations of soluble RANKL detected in the serum of subjects who did and who did not develop T2DM were significantly different, with the highest concentrations of RANKL associated with a significantly increased risk of developing T2DM (Odds Ratio 4.06 [95% Confidence Interval 2.01–8.20])

To test the hypothesis that RANKL signaling to the liver is central to the link between RANKL and T2DM, the authors then developed mice with a liver-specific Rank knockout. These mice did not develop insulin resistance when fed on a high-fat diet for 4 weeks, unlike their wild-type counterparts. Other mouse experimental approaches confirmed the suspicion that RANKL signaling is important in T2DM pathogenesis, suggesting that blocking RANKL could have therapeutic benefits.

Editor’s comment: It now seems that RANKL, as well as the bone molecule osteocalcin, plays an important role in glucose homeostasis. If RANKL also regulates liver glucose metabolism in humans, then denosumab could have beneficial effects on glycemic control in diabetics, in addition to its bone-sparing effects.

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