Abstract
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.
Highlights
Bone fragility is an important complication in patients with type 2 diabetes mellitus (T2DM), despite a normal or high-bone mineral density (BMD) [1], implying alterations of bone quality [2]
In order to assess whether the above effects were due to direct action of exenatide on bone cells, we investigated the effect of Exenatide on bone formation by primary osteoblasts under high-glucose conditions
Similar to our previous findings [14], we found no effect of Exenatide on bone formation in vitro when osteoblasts were cultured in normal glucose concentrations
Summary
Bone fragility is an important complication in patients with type 2 diabetes mellitus (T2DM), despite a normal or high-bone mineral density (BMD) [1], implying alterations of bone quality [2]. The choice of anti-diabetic medications is crucial as some anti-diabetic therapies can themselves result in increase in fracture risk by augmenting the risk of hypoglycemia and falls or by altering bone turnover and bone quality. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are peptides secreted in the gastrointestinal tract that stimulate insulin secretion in response to the ingestion of nutrients in a glucosedependent manner and as such avoidance of hypoglycemia events [6]. Based on evidences that Glp1r KO mice and GLP-1RA-treated osteoporotic mice, exhibit modifications of bone quality [12,13,14], we hypothesized that GLP-1RAs could improve bone quality in T2DM
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