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...
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| Main Author: | |
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| Format: | Thesis |
| Language: | English |
| Published: |
2015
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| Subjects: | |
| Online Access: | http://eprints.uthm.edu.my/1751/1/24p%20SITY%20AISHAH%20MANSUR.pdf |
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| Summary: | 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 diabetes |
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