Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal
Abstract
OBJECTIVE: Metformin, a leading drug used to treat diabetic patients, is reported to benefit bone homeostasis under hyperglycemia in animal models. However, both the molecular targets and the biological pathways affected by metformin in bone are not well identified or characterized. The objective of this study is to investigate the bioengergeric pathways affected by metformin in bone marrow cells of mice.
MATERIALS AND METHODS: Metabolite levels were examined in bone marrow samples extracted from metformin or PBS -treated healthy (Wild type) and hyperglycemic (diabetic) mice using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. We applied an untargeted high performance LC-MS approach which combined multimode chromatography (ion exchange, reversed phase and hydrophilic interaction (HILIC)) and Orbitrap-based ultra-high accuracy mass spectrometry to achieve a wide coverage. A multivariate clustering was applied to reveal the global trends and major metabolite players.
RESULTS: A total of 346 unique metabolites were identified, and they are grouped into distinctive clusters that reflected general and diabetes-specific responses to metformin. As evidenced by changes in the TCA and urea cycles, increased catabolism and nitrogen waste that are commonly associated with diabetes were rebalanced upon treatment with metformin. In particular, we found glutamate and succinate whose levels were drastically elevated in diabetic animals were brought back to normal…
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