title: 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.
  
  
  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 levels by metformin. These two metabolites were further validated as the major targets of metformin in bone marrow stromal cells.
  
  
  CONCLUSIONS
  Overall using limited sample size, our study revealed the metabolic pathways modulated by metformin in bones which have broad implication in our understanding of bone remodeling under hyperglycemia and in finding therapeutic interventions in mammals.
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305-5120, United States of America.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, United States of America.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biology and Chemistry, Nyack College, New York, NY 10013, United States of America.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305-5120, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D055432:Metabolomics; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D009584:Nitrogen / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D009584:Nitrogen