JBMR Plus
(May 2021)
Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model
- Manisha Dixit,
- Zhongbo Liu,
- Sher Bahadur Poudel,
- Gozde Yildirim,
- Yanjiao Zhang Zhang,
- Shilpa Mehta,
- Omer Murik,
- Geona Altarescu,
- Yoshifumi Kobayashi,
- Emi Shimizu,
- Mitchell B. Schaffler,
- Shoshana Yakar
Affiliations
- Manisha Dixit
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Zhongbo Liu
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Gozde Yildirim
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Yanjiao Zhang Zhang
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Shilpa Mehta
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- Omer Murik
- Medical Genetics Institute, Shaare Zedek Medical Center Jerusalem Israel
- Geona Altarescu
- Medical Genetics Institute, Shaare Zedek Medical Center Jerusalem Israel
- Yoshifumi Kobayashi
- Oral Biology Department Rutgers School of Dental Medicine Newark NJ USA
- Emi Shimizu
- Oral Biology Department Rutgers School of Dental Medicine Newark NJ USA
- Mitchell B. Schaffler
- Department of Biomedical Engineering City College of New York New York NY USA
- Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular Pathobiology New York University College of Dentistry New York New York NY USA
- DOI
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https://doi.org/10.1002/jbm4.10483
- Journal volume & issue
-
Vol. 5,
no. 5
pp.
n/a
– n/a
Abstract
Read online
ABSTRACT Patients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated‐AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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