Glucagon-like peptide-1 attenuates diabetes-associated osteoporosis in ZDF rat, possibly through the RAGE pathway

Abstract

Background Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs. Methods In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway. Results Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage . Conclusions Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor.

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats

“…The hypoglycemic mechanism of Sax is to inhibit dipeptidyl dipeptidase‐4 (DPP‐4), thereby elevate the activity of glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent intestinal insulin‐releasing peptide (GIP) (Bogdanov et al., 2022; Cheng et al., 2022). However, there are more and more reports on adverse reactions of heart failure relating to Sax (Benjamin et al., 2014; Edoardo et al., 2021).…”

“…In this study the influence of GQD on pharmacokinetics was investigated by the changes of the pharmacokinetic parameters of Sax. Furthermore, the assessment of the impact of GQD on the The hypoglycemic mechanism of Sax is to inhibit dipeptidyl dipeptidase-4 (DPP-4), thereby elevate the activity of glucagon-like peptide 1 (GLP-1) and glucose-dependent intestinal insulinreleasing peptide (GIP) (Bogdanov et al, 2022;Cheng et al, 2022).…”

Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes—A Systematic Review

“…An animal study on rats showed that liraglutide improved bone remodeling parameters by increasing the bone formation marker osteocalcin and the activity of alkaline phosphatase (ALP) while decreasing CTX (a bone resorption marker) with no change in P1NP (another bone formation marker). ( 49 ) In ovariectomized mice, both liraglutide and a quinoxaline‐based compound prevented bone loss, as evidenced by increased P1NP and decreased CTX levels, indicating enhanced bone formation and reduced bone resorption. However, these effects were observed only with exenatide treatment, not with liraglutide.…”

“…Overall, animal studies suggest that GLP-1 RAs, particularly exenatide (53)(54)(55)(56)(57)61,63,64) and liraglutide, (46,(49)(50)(51)65) may have beneficial effects on bone health by promoting bone formation, improving bone microarchitecture, and potentially preventing bone loss. However, the effects on bone strength are less consistent and may depend on the specific GLP-1 RA used and the study conditions.…”

“…Another animal study demonstrated that liraglutide prevented the deterioration of trabecular microarchitecture and improved bone strength. ( 49 ) Additionally, a different animal study showed that a GLP‐1 RA improved bone loss primarily through the induction of bone formation. ( 51 ) Studies on nondiabetic mice also revealed that exenatide increased the transcription of osteogenic differentiation‐related genes, promoted osteogenic differentiation and bone repair, and improved BMC.…”