Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus

Abstract

Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients.

Liraglutide exerts a bone‑protective effect in ovariectomized rats with streptozotocin‑induced diabetes by inhibiting osteoclastogenesis

“…In the present study, although both STZ and OVX led to bone loss in rats, their action mechanisms are apparently different. In the diabetic rats, serum OC and osteoblast count were markedly reduced, and these observations are consistent with previous reports (13,26). In the meanwhile, serum CTX-1 and osteoclast count were only slightly increased in STZ-induced diabetes.…”

“…Since expression of functional GLP-1 receptors was identified on osteoblasts (23), the potential beneficial effects of GLP-1 RAs has been evaluated experimentally on diabetic and non-diabetic models (11,13,15,16,24,25). Previous studies have demonstrated that liraglutide treatment could increase BMD, improve bone micro-architecture and restore mechanical properties of the bone in diabetic rodents (13,14), and it also exerts beneficial effects on the bone in non-diabetic osteoporotic models (15,16). In the present study, we constructed a rat model of osteoporosis induced by both diabetes and OVX, and showed that long-term liraglutide treatment was able to ameliorate the defects in the bone of the severely osteoporotic rats.…”

“…In addition, long-term administration of liraglutide has an anabolic bone effect in weight-reduced obese women (12). Further studies on animal models demonstrated that liraglutide could prevent bone loss and counter rapid bone deterioration in diabetic rodents (13,14). Moreover, liraglutide could improve bone mass and architecture in non-diabetic osteoporotic rodent models with ovariectomy (OVX) (15,16).…”

MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus

“…Recent data suggest that incretins could also have a positive effect on bone quality in T1DM. In streptozotocin-treated mice, incretin peptides were able to prevent the alterations of cortical microarchitecture and the deterioration of bone quality (99). Clinical studies are needed to determine if the rodent data is applicable and to elucidate the effects of incretin on fracture risk.…”

The Impact of Glucagon-Like Peptide-1 on Bone Metabolism and Its Possible Mechanisms

“…It was found that GLP-1 could reduce these trends and restore normal bone structure (17). In streptozotocin-induced T1DM Swiss TO mice, liraglutide improved mechanical properties in bone tissue, but failed to reverse cortical microstructure degradation or improve whole bone mechanical properties (18). Furthermore, GLP-1 and glucose-dependent insulinotropic polypeptide double incretin receptor knockout (DIRKO) mice had increased trabecular bone mass and a higher trabecular number compared to wild-type mice, with reduced bone outer diameter, cortical thickness, and cortical area.…”