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:	Mansur, Sity Aishah
Format:	Thesis
Language:	English
Published:	2015
Subjects:	RC Internal medicine RC581-951 Specialties of internal medicine
Online Access:	http://eprints.uthm.edu.my/1751/1/24p%20SITY%20AISHAH%20MANSUR.pdf
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spelling	my-uthm-ep.17512021-10-10T04:41:14Z Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus 2015-10 Mansur, Sity Aishah RC Internal medicine RC581-951 Specialties of internal medicine 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 2015-10 Thesis http://eprints.uthm.edu.my/1751/ http://eprints.uthm.edu.my/1751/1/24p%20SITY%20AISHAH%20MANSUR.pdf text en public phd doctoral University of South Australia Faculty of Life and Health Sciences
institution	Universiti Tun Hussein Onn Malaysia
collection	UTHM Institutional Repository
language	English
topic	RC Internal medicine RC581-951 Specialties of internal medicine
spellingShingle	RC Internal medicine RC581-951 Specialties of internal medicine Mansur, Sity Aishah Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
description	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
format	Thesis
qualification_name	Doctor of Philosophy (PhD.)
qualification_level	Doctorate
author	Mansur, Sity Aishah
author_facet	Mansur, Sity Aishah
author_sort	Mansur, Sity Aishah
title	Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
title_short	Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
title_full	Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
title_fullStr	Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
title_full_unstemmed	Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
title_sort	extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus
granting_institution	University of South Australia
granting_department	Faculty of Life and Health Sciences
publishDate	2015
url	http://eprints.uthm.edu.my/1751/1/24p%20SITY%20AISHAH%20MANSUR.pdf
_version_	1747830862563508224

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

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