Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice.

Skeletal fragility is associated with type 2 diabetes mellitus (T2D), but the underlying mechanism is not well understood. Here, in a mouse model for youth-onset T2D, we show that both trabecular and cortical bone mass is reduced due to diminished osteoblast activity. Stable isotope tracing in vivo with 13C-glucose demonstrates that both glycolysis and glucose fueling of the TCA cycle are impaired in diabetic bones. Similarly, Seahorse assays show suppression of both glycolysis and oxidative phosphorylation by diabetes in bone marrow mesenchymal cells as a whole, whereas single-cell RNA sequencing reveals distinct modes of metabolic dysregulation among the subpopulations. Metformin not only promotes glycolysis and osteoblast differentiation in vitro, but also improves bone mass in diabetic mice. Finally, osteoblast-specific overexpression of either Hif1a, a general inducer of glycolysis, or Pfkfb3 which stimulates a specific step in glycolysis, averts bone loss in T2D mice. The study identifies osteoblast-intrinsic defects in glucose metabolism as an underlying cause of diabetic osteopenia, which may be targeted therapeutically.

Relationship between oxidative stress and diabetic osteopenia in premenopausal rats / Relação entre o estresse oxidativo ea osteopenia diabética em ratos pré-menopausa

The relationship between lipid peroxidation, antioxidant defense and diabetic osteopenia remains unclear. This study evaluated the relationship among lipid peroxidation index, antioxidant defense parameters and bone metabolism in a premenopausal diabetic model using measures including thiobarbituric acid-reactive substances concentration (TBARS) and reduced glutathione (GSH) content in brain homogenates, histomorphometric analysis, biomechanical testing and bone mineral density (BMD). Female Wistar rats with regular estrous cycle were divided into two groups: Group 1: control rats (n = 15) and Group 2: diabetic rats (n = 15). Diabetes was induced by alloxan and confirmed by glycemia >250 mg/dL. The lipid peroxidation index, measured by TBARS concentration, showed a significant increase (p<0.05) in diabetic animals in comparison to control animals. However, the antioxidant parameter measured by GSH content, was significantly lower (p<0.05) in diabetic animals. Histomorphometric analysis showed a significant increase (p<0.05) in femoral trabecular separation together with a significant decrease (p<0.05) in trabecular thickness, and reduced trabecular bone volume in diabetic rats. Moreover, biomechanical testing and BMD values were significantly lower (p<0.05) in the diabetic group. Thus, our results demonstrated that increased lipid peroxidation and altered antioxidant defense could be related to the development of oxidative stress and diabetic osteopenia in premenopausal rats.

A relação entre peroxidação lipídica, defesa antioxidante e osteopenia diabética permanece obscura. Este estudo avaliou a associação entre índice de peroxidação lipídica, parâmetro de defesa antioxidante e metabolismo ósseo em um modelo diabético pré-menopausa através de medidas como a concentração de substâncias reativas ao ácido tiobarbitúrico (SRAT) e conteúdo de glutationa reduzida (GSH) no homogenato cerebral, análises histomorfométricas, teste biomecânico e densidade mineral óssea (DMO). Ratos Wistar fêmeas com ciclo estral regular foram distribuídos em dois grupos: Grupo 1 - ratas controle (n = 15) e Grupo 2 - ratas diabéticas (n = 15). O diabetes foi induzido pela aloxana e confirmado pela glicemia >250 mg/dL. O índice de peroxidação lipídica, medido pela concentração de SRAT, demonstrou um aumento significativo (p<0.05) nos animais diabéticos, em relação aos animais controle. Entretanto, o parâmetro de defesa antioxidante, mensurado pelo conteúdo de GSH, foi reduzido significativamente (p<0.05) nos animais diabéticos. As análises histomorfométricas mostraram um aumento significativo (p<0.05) da separação trabecular do fêmur, associado à diminuição significativa da espessura trabecular (p<0.05) e volume ósseo trabecular reduzido nas ratas diabéticas. Além disso, o teste biomecânico, medido pela força máxima, e valores de DMO foram reduzidos significativamente (p<0.05) no grupo diabético. Dessa maneira, nossos resultados demonstraram que a peroxidação lipídica aumentada e defesa antioxidante modificada podem estar relacionadas ao desenvolvimento do estresse oxidativo e osteopenia diabética em ratas pré-menopausadas.