International Journal of Endocrinology · Mar 3, 2026

Effects of Glucagon-Like Peptide-1 Receptor Agonist on Bone Metabolism and the Expression of Insulin Receptor Substrate 1 in an Osteoporotic Rat Model

By Ye Y, He YL, He J et al.

STUDY AIM: This study aimed to investigate the effects of the GLP-1R agonist Exendin 4 on bone metabolism and insulin receptor Substrate 1 (IRS-1) expression in an osteoporotic (OP) rat model. METHODS: Female SD rats were ovariectomized to establish an OP model. The rats (n = 18) were randomized into three groups: Sham + NS, OVX + NS, and OVX + Exendin 4 groups (six rats in each group). The NS and Exendin 4 were injected via the subcutaneous route. After 12 weeks of intervention, the right femurs of the rats were removed for bone morphometric analysis by micro-CT scanning. Furthermore, bone biomechanical tests were conducted on the left femurs in the form of three-point bending tests. Besides, the bilateral tibias were removed for bone tissue sectioning, HE staining, and detection of IRS-1 expression via immunohistochemical staining. Moreover, the serum calcium and phosphorus levels were determined using a fully-automatic biochemical analyzer. The serum levels of bone metabolism-related parameters were analyzed using ELISA kits. RESULTS: (1) The OVX + NS group showed a significant decrease in the number and thickness of trabeculae, fractured bone scaffold structure, and multiple adipocytes in the bone marrow cavity. Moreover, the trabeculae of the OVX + Exendin 4 group were increased in number and thickness. In addition, the bone scaffold structure was restored, and the bone marrow cavity showed fewer adipocytes than the OVX + NS group. And, the OVX + Exendin 4 group showed significantly increased BMD, BV/TV, Tb.Th, Tb.N, and bone biomechanical parameter levels (p < 0.05) and significantly decreased SMI and serum levels of BALP, OCN, and CTX-1 (p < 0.05). (2) Immunohistochemical staining revealed that the OVX + Exendin 4 showed significantly increased expression of IRS-1 compared with the OVX + NS group (p < 0.05). CONCLUSION: Exendin 4 exerts its antiosteoporotic effects in OVX rats by improving BMD, restoring bone microstructures, elevating bone biomechanical parameter levels, decreasing bone turnover rate, and increasing the expression of IRS-1 in osteoblasts.

doi.org/10.1155/ije/4418640 Open access PubMed 41788539 Interventions