title: A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus.
abstract: Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala(2)]GIP-Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala(2)]GIP-Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala(2)]GIP-Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM.
authors.affiliation: Universiti Tun Hussein Onn Malaysia, Johor, Malaysia; School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Sity Aishah
authors.initials: SA
authors.lastname: Mansur
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mieczkowska
authors.affiliation: Universiti Tun Hussein Onn Malaysia, Johor, Malaysia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bouvard
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chappard
authors.affiliation: Universiti Tun Hussein Onn Malaysia, Johor, Malaysia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France. Electronic address: guillaume.mabilleau@univ-angers.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mabilleau
mesh_terms: D015502:Absorptiometry, Photon; D000595:Amino Acid Sequence; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D000071556:Cancellous Bone / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000071538:Cortical Bone / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003720:Densitometry; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D053772:Oxyntomodulin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D053772:Oxyntomodulin; D005749:Gastric Inhibitory Polypeptide
keywords: Bone quality; Bone strength; Type 2 diabetes mellitus; [d-Ala(2)]GIP–Oxm; db/db mice