Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states

Abstract Poor control of glucose homeostasis accounts for diabetes-related bone loss. Incretins – GLP-1 and GIP – have been proposed to affect bone turnover. GLP-1, apart from its anti-diabetic and other actions, has shown to exert a bone anabolic effect in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rats. Exendin-4 (Ex-4), a peptide of non-mammalian nature, is sharing with GLP-1 part of its structural sequence, and also several glucoregulatory effects in mammals in an even more efficient manner. We have explored the effect of continuous administration (3 days by osmotic pump) of Ex-4 or saline (control) on bone turnover factors and bone structure in T2D and IR rats, compared to N, and the possible interaction of Ex-4 with the Wnt signalling pathway. Blood was taken before and after treatment for plasma measurements; tibiae and femurs were collected for gene expression of bone markers (RT-PCR) and structure (µCT) analysis; we also measured the mRNA levels of LRP5 – an activator of the Wnt pathway – and those of DKK1 and sclerostin (SOST) — both blockers of LRP5 activity. Compared to N-control, plasma glucose and insulin were respectively higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b (TRAP5b) were lower; after Ex-4, these turnover markers were further reduced in T2D and IR, while TRAP5b increased in N. Bone OC, osteoprogeterin (OPG) and receptor activator of NF-kB ligand (RANKL) mRNA were lower in T2D and IR; Ex-4 increased OC in all groups and OPG in N and IR, reduced RANKL in N and T2D but increased it in IR; the LRP5/DKK1 and LRP5/SOST mRNA ratios were similarly decreased in T2D, but in IR, the latter ratio was reduced while the former was increased; after Ex-4, both ratios augmented in N, and that of LRP5/DKK1 tended to normalize in T2D and IR. In conclusion, Ex-4 exerts osteogenis effects in T2D and IR models, and interacts with the Wnt pathway to promote bone formation.