Abstract
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed.
Highlights
Published: 19 June 2021Diabetes is associated with a number of musculoskeletal complications, including increased incidences of bone fracture and osteoarthritis, which lead to joint pain and loss of function [1,2,3,4]
Xie et al examined the effects of glucose-dependent insulinotropic polypeptide (GIP) and its receptors on bone metabolism by dual-energy X-ray absorption and micro-computed tomography, and the results showed that GIP receptor (GIPR) knockout (KO) mice generated by targeted disruption of exons 4 and 5 of the GIPR gene encoding a portion of the extracellular domain have reduced total and femoral bone mineral density (BMD) as well as defects in trabecular structure and microarchitecture compared to wild-type controls [84]
Tu et al examined the effects of the GLP-1 receptor (GLP-1R) agonist, liraglutide, in a rat model of subarachnoid hemorrhage (SAH)-induced brain injury, and reported that it attenuated the increases in levels of inflammatory mediators, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, tumor necrosis factor-α (TNF-α), and IL-1β [129]
Summary
Diabetes is associated with a number of musculoskeletal complications, including increased incidences of bone fracture and osteoarthritis, which lead to joint pain and loss of function [1,2,3,4]. Hyperglycemia is known to enhance the adipogenic pathway of bone marrow-derived progenitor cells and suppress the induction of differentiation into osteoblast progenitor cells via inducing the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), resulting in suppression of bone formation [35,40,41]. Increasing adipose tissue by hyperglycemia induced expression of TNF-α and IL-6 [35,42,43] These cytokines were shown to induce the formation and activation of osteoclasts. AGEs increase the expression of sclerostin in osteocytes in vitro, which inhibits bone formation [16,56] Taken together, these results indicated that hyperglycemia inhibits bone formation and induces bone resorption. We further discuss the possible mechanisms by which incretin-related diabetes drugs may regulate bone formation and resorption
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