Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus

Diabetes mellitus is correlated with modifications in bone microarchitectural and mechanical strength, leading to increased bone fragility. The incretin hormones, with a classical effect to increase insulin secretion following food ingestion, are now postulated to have important direct effects on bone. As such, glucose-dependent insulinotropic polypeptide (GIP) has dual actions on bone cells; enhancing bone�forming activity of osteoblasts and suppressing bone resorption by osteoclasts. The sister incretin of GIP, glucagon-like peptide-1 (GLP-1), is also suspected to directly influence bone health in a beneficial manner, although mechanism are less clear at present. The physiological actions of incretins are attenuated by dipeptidyl peptidase (DPP-4) activity and it is speculated that introduction of DPP-4 inhibitor may also positively affect quality of the skeleton. As such, this thesis evaluates the potential beneficial effects of a DPP-4 resistant GIP analogue, namely [D-Ala2 ]GIP, on osteoblastic-derived, SaOS-2 cells, and also preliminary in vivo studies on the impact of genetic deficiencies of GIPRs and GLP-1Rs on bone mineral density and content. Further studies characterised the beneficial effects of incretin-based therapies on metabolic control, bone microstructure and bone mechanical integrity in animal models of pharmacologically-, genetically- and environmentally-induced diabetes. GIP and related stable analogue increased bone-forming biomarkers in SaOS-2 cells and importantly, [D-Ala2 ]GIP was shown to be more potent than native GIP. Knockout mouse studies revealed that both GIPR and GLP-1R signaling are important for optimum bone mass. All diabetic mouse models displayed reduced bone mass, altered bone micromorphology and impairment of bone mechanical strength, similar to the human situation, confirming their appropriateness. The incretin-based therapeutics, [D-Ala2 ]GIP and Liraglutide, in streptozotocin-diabetic significantly increased bone matrix properties, indicating recovery of bone strength at the tissue level. The beneficial effects of administration of [D-Ala2 ]GIP�oxyntomodulin on bone health in db/db mice were more prominent as the Oxm analogue did not only improve bone strength at tissue level, but also at whole-bone level. These modifications were independent of metabolic status. Twice-daily Exendin-4 therapy improved glycaemic control and increased work required to resist bone fracture in high-fat fed mice. It was also established that Sitagliptin had neutral effects on bone microstructure and mechanical strength in high-fat mice. In summary, these data demonstrate the negative impact of diabetes mellitus on normal skeleton development and bone quality. Moreover, this thesis highlights the growing potential of incretin-based therapies for ameliorating bone defects and improving the increased fragility fracture risk associated with diabete

Effect of seeding time on the formation of gold nanoplates

Metallic nanostructures, such as gold, is very sensitive to the dielectric environment of the materials due to strong dependency of plasmon on shapes and sizes. Thus, its unique properties are very good and can be used as sensing material in plasmonic sensor. This paper reports a study on the surface density on the formation of gold nanoplates with variation of seeding time. The gold nanoplates have been grown on a quartz substrate using seed mediated growth method. In this study, the seeding time was varied from one to three hours and labelled as MP1, MP2 and MP3. The XRD analysis shows two peaks of the diffraction angle occurs at the plane (111) in position ~ 38.2º and plane (200) at ~ 44.20º. Through variation of the seeding time, the optimum surface density is 61.8 % with a total of 43.7 % of the nanoplates shape from sample MP2. The optical absorption spectrum of the sample shows two resonance peaks, ~ 550 nm and 660 nm, which are corresponding to the transverse surface plasmon resonance (t-SPR) and the longitudinal surface plasmon resonance (l-SPR) respectively. Thus, in this study, it is found that the seeding time affected the growth of the gold nanostructures with optimum seeding time of two hours. Longer seeding time caused the growth of stacking nanogold and it is not suitable to be used in sensing application because of its broad and wider optical spectrum

Effect of Reynolds number on the wake of a Next-Generation High-Speed Train using CFD analysis

Improvement to the next-generation high-speed train (NG-HST) is ongoing particularly in achieving a higher operating speed. Consequently, the aerodynamic effect of the train will be more critical as it affects the development of a wake flow characterized by complex and unsteady structures. Although the effect of Reynolds number (Re) on aerodynamic forces is negligible, its effect on the wake of NG-HSTs is unknown. In this study, the Re ranging from 7.42 × 105 to 1.62 × 106 was used to examine the characteristics of vortex structures, streamline distributions, velocity characteristics, and pressure characteristics in the wake region of an NG-HST. The Delayed Detached Eddy Simulation (DDES) is used as the turbulence model. In addition, the simulation results were compared with the previous wind tunnel experimental data. The results indicated no significant changes in the overall wake flow structure when Re was increased. According to power spectral density analysis, increasing the Reynolds number increased the turbulence intensity of the wake which gradually dissipated as the distance from the train increased. The findings of the study could be used to better understand the flow characteristics at the wake of NG-HSTs for future development