Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model

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.

Protective effects of low-magnitude high-frequency vibration on high glucose-induced osteoblast dysfunction and bone loss in diabetic rats

“…Thus, the effect of LMHFV on bone composition was evaluated by Raman spectral examination. Decreases in the mineral to matrix ratio and increases in the carbonate to phosphate ratio and mineral crystallinity were identified, which were consistent with those of a previous report [ 48 ]. An increase in the mineral-to-matrix ratio of the femur was reported after diabetes was treated with sitagliptin, and the ultimate stress and stiffness were ultimately improved [ 49 ].…”

Association of plasma neutrophil gelatinase-associated lipocalin and thoracic aorta calcification in maintenance hemodialysis patients with and without diabetes

“…These results suggested that "bone maybe one of the main sources of increased NGAL in MHD patients". In the present study, MHD patients with diabetes showed lower plasma NGAL level, the absent correlation between NGAL and ARC may due to impaired osteoblast function in diabetes [36][37][38]. It is confirmed that CKD patients with diabetes are more prone to present with low bone turnover states [39], the potential mechanisms probably lie in the suppression of parathyroid hormone secretion, osteoblast activity and bone turnover by hyperglycemia and insulin deficiency [40,41].…”

Remodeling of the periodontal ligament and alveolar bone during axial tooth movement in mice with type 1 diabetes

“…The results showed that BMD increased in mandible of both groups, but the increment in diabetic group was smaller than that in control group. Previous studies had suggested that the decreased BMD in patients with type 1 diabetes T1DM was due to the retardation of osteoblast activity and the inhibition of bone remodeling ( 27 ). Uncontrolled blood glucose levels and insulin deficiency are thought to be the main causes of osteopenia in T1DM.…”