Insulin therapy improves bone microstructure and material properties without restoring whole-bone strength in male insulin-deficient Akita mice

Article Article scientifique Article Insulin therapy improves bone microstructure and material properties without restoring whole-bone strength in male insulin-deficient Akita mice eng 2026-06-10 author Toillon Indira Service of Bone Diseases, Department Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland. 402862 author Badoud Isabelle Service of Bone Diseases, Department Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland. 29934 Département de médecine (DEMED) Isabelle Badoud-Georges author Ferrari Serge Livio Service of Bone Diseases, Department Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland. 24314 Département de médecine (DEMED) author Gerbaix Maude Coline Service of Bone Diseases, Department Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland. Electronic address: maude.gerbaix@unige.ch. 790754 Département de médecine (DEMED) 117971 10.1016/j.bone.2026.117971 42269903 1873-2763 https://www.sciencedirect.com/science/article/pii/S8756328226001973 Type 1 diabetes is associated with increased fracture risk, yet the respective contributions of insulin deficiency and replacement to skeletal fragility remain poorly understood. Using insulin-deficient male Akita mice, we characterized skeletal alterations and assessed the effects of early insulin therapy. Untreated male Akita mice displayed severe hyperglycemia, impaired growth, low bone formation, and marked trabecular and cortical deficits, resulting in reduced whole-bone structural mechanical properties. Insulin therapy initiated at early diabetes onset normalized glycemia, restored bone formation, and fully recovered cortical material properties. However, cortical porosity remained elevated, cortical geometry was not fully restored, and whole-bone structural mechanical properties did not improve. Gene expression profiling showed downregulation of osteoblast, osteocyte, mechanosensing, and Wnt-related genes in male Akita mice. Notably, Sp7 (Osterix) and Ostn (Osteocrin), key regulators of osteocyte dendrite formation, were downregulated in male Akita mice, suggesting disrupted osteocyte network development. Insulin upregulated osteogenic and Wnt signaling targets but incompletely restored mechanosensing pathways. Importantly, expression of the Wnt inhibitors Sost (Sclerostin) and Dkk1 (Dickkopf-1) remained elevated despite insulin treatment, potentially maintaining an inhibitory environment that limits the anabolic response to mechanical loading. These findings show that early insulin therapy improves bone health in type 1 diabetes, including turnover, trabecular structure, and cortical tissue material properties, but fails to fully rescue cortical integrity and whole-bone structural mechanical properties. This incomplete recovery likely reflects persistent defects in osteocyte function and mechanosensing in insulin-deficient bone and highlights potential therapeutic targets beyond glycemic control to reduce fracture risk in type 1 diabetes. Bone disorders Cortical thickness Insulin deficiency Knockout mice Type 1 diabetes Wnt signaling Dewey 616 Swiss National Science Foundation Mechanisms of bone fragility and response to RANK Ligand and Sclerostin inhibitors 185230 CH 56 Département de médecine 221 false 289 Métabolisme osseux 544 Bone 211 ba78e079-672a-455d-92d0-d01a68ad9545 Article (Published version) Restricted 1-s2.0-S8756328226001973-main.pdf 3072534 application/pdf e8c7f02fe491774513e6c510332247b44479384437353e48191a19c1cc2f33b4 3ea6a384-1736-4cf4-a34a-77c79eb7990a Supplemental data Restricted 1-s2.0-S8756328226001973-mmc1.pptx 191062 application/vnd.openxmlformats-officedocument.presentationml.presentation 90f87ae265ade224511b0198e5066c6d087903b5089b553a46bc148eebaf4947 b9bf8a64-c036-43d3-b60b-ccd78a7488da Supplemental data Restricted 1-s2.0-S8756328226001973-mmc2.pptx 224674 application/vnd.openxmlformats-officedocument.presentationml.presentation fe986abdab816926a72d4e008818f997cf16121f1fa13f6d82133430ba200af0 d35aff03-8fd8-4469-89b7-01b6457bbc7a Supplemental data Restricted 1-s2.0-S8756328226001973-mmc3.docx 21158 application/vnd.openxmlformats-officedocument.wordprocessingml.document 8a14ccf21d92a28058ad6070dd05be4c1489e9f7afc70a6d1007fc54fca6a73e Vignette Public 1-s2.0-S8756328226001973-ga1_lrg.jpg 282098 image/png restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Insulin therapy improves bone microstructure and material properties without restoring whole-bone strength in male insulin-deficient Akita mice	Bone			2026	4	0

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Toillon, Indira