Type 2 diabetes mellitus (T2DM) is associated with skeletal complications, including an
increased risk of fractures. Reduced blood supply and bone strength may contribute to
this skeletal fragility. We hypothesized that long-term administration of Exenatide, a glucagon-like
peptide-1 receptor agonist, would improve bone architecture and strength of
T2DM mice by increasing blood flow to bone, thereby stimulating bone formation. In this
study, we used a model of obesity and severe T2DM, the leptin receptor-deficient db/db
mouse to assess alterations in bone quality and hindlimb blood flow and to examine
the beneficial effects of 4 weeks administration of Exenatide. As expected, diabetic mice
showed marked alterations in bone structure, remodeling and strength, and basal vascular
tone compared with lean mice. Exenatide treatment improved trabecular bone mass
and architecture by increasing bone formation rate, but only in diabetic mice. Although
there was no effect on hindlimb perfusion at the end of this treatment, Exenatide administration
acutely increased tibial blood flow. While Exenatide treatment did not restore the
impaired bone strength, intrinsic properties of the matrix, such as collagen maturity, were
improved. The effects of Exenatide on in vitro bone formation were further investigated
in primary osteoblasts cultured under high-glucose conditions, showing that Exenatide
reversed the impairment in bone formation induced by glucose. In conclusion, Exenatide
improves trabecular bone mass by increasing bone formation and could protect against
the development of skeletal complications associated with T2DM.