Recent research suggests that bone plays an active role in regulating glucose homeostasis through both osteocalcin-dependent and osteocalcin-independent mechanisms. Our studies investigating the mechanism behind NPY’s action on osteoblastic Y1 receptors, has excitingly led to the identification of a novel pathway originating in bone which directly acts to alter whole-body glucose homeostasis by affecting insulin secretion and insulin action1. We have now identified osteoglycin, a secreted proteoglycan, as a mediator in this pathway.
We targeted the first exon of osteoglycin using CRISPR technology to generate osteoglycin knockout mice (Ogn-/-). These mice display an anabolic bone phenotype with significant increases in femur length, femoral BMD and BMC, and cancellous bone volume. Interestingly, despite no difference in body weight or adiposity, Ogn-/- mice have higher serum glucose levels and impaired glucose clearance during a glucose tolerance test (GTT) associated with increased insulin levels. This effect is even more pronounced when the mice have been fed a high fat diet.
Consistent with these findings, exogenous osteoglycin improved glucose tolerance. Pre-treating wildtype mice with osteoglycin prior to a GTT led to glucose levels being significantly lower both at the start and throughout the GTT whilst insulin levels were higher at the start of the GTT but then returned to baseline earlier than controls. In addition, insulin-induced Akt phosphorylation in muscle was significantly enhanced by pre-treatment with osteoglycin suggesting that osteoglycin can improve insulin action on target tissue as well as insulin secretion.
Furthermore, in a cohort of type 2 diabetic patients, serum osteoglycin levels were significantly lower compared to both lean and obese/overweight but insulin-sensitive patients.
Together these data identify osteoglycin as a novel factor capable of regulating glucose homeostasis and suggest that targeting osteoglycin has huge potential for the development of treatments for diseases such as obesity and type 2 diabetes.