iStable gut hormones and related analogues for treatment of fragility fractures associated with type 2 diabetes

Abstract

Incretin hormones such as glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known to augment insulin secretion from pancreatic beta-cells. There is sufficient evidence which suggests that these incretin hormones do have positive effects on bone. GIP is known to have dual action on bone as it enhances osteoblasts which are bone forming cells and reduces bone resorption by osteoclasts. There are mixed results regarding effects of GLP-1 on the bone and the mechanism of action is less clear. The main focus of this work is to assess the potential beneficial effects of bone-specific oligopeptides and its analogues on sarcoma osteogenic SAOS-2 cells as well as assess the impact of these analogues on bone directly through in-vivo studies. (D-Ala2)GIP and bone-specific (D-Ala2)GIP-Asp enhanced bone biomarker-alkaline phosphatase activity in human osteoblastic SAOS-2 cells. Bonespecific analogue (D-Ala2)GIP-Asp possessed similar insulin secretory actions as (D-Ala2)GIP in BRIN-BD11 cells. Treatment with (D-Ala2)GIP-Asp improved glucose homeostasis and insulin sensitivity in high fat fed mice. (D-Ala2)GIP-Asp increased bone mineral content (BMC) in tibia highlighting positive effects of (D-Ala2)GIP-Asp on bone. Bone matrix properties such as bone marrow diameter, total area and cortical thickness were increased in the mice treated with (DAla2)GIP-Asp. Collagen cross-linking was enhanced by (D-Ala2)GIP-Asp. The results of xenin analogue on bone were inconsistent. The bone-specific analogue namely, Xenin25[Lys13PAL]-Asp did not showed any beneficial effects on bone but overall, Xenin25[Lys13PAL] and Xenin-25[Lys13PAL]-Asp showed beneficial metabolic effects in lean as well as high fat fed mice. Once daily administration of GIP/Xenin-Asp and GIP/Xenin-Glu enhanced tibial bone mineral density. GIP/Xenin treatment increased trabecular bone volume and number of trabeculae in high fat fed mice. No effects of GIP/Xenin-Asp and GIP/Xenin-Glu were seen on bone matrix and tissue material properties. This thesis throws light upon immense potential of incretin-based therapeutic treatments for bone fragility fractures associated with type 2 diabetes.

Date of Award	Jul 2018
Original language	English
Sponsors	Vice Chanchellor's Research Scholarship
Supervisor	Peter Flatt (Supervisor) & Nigel Irwin (Supervisor)