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Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal.

Li X, Guo Y, Yan W, Snyder MP, Li X - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University, Stanford, CA 94305-5120, United States of America.

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 levels by metformin. These two metabolites were further validated as the major targets of metformin in bone marrow stromal cells.

Conclusion: 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.

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Related in: MedlinePlus

Individual metabolite levels in bone marrow affected by metformin.Each plot shows the mean ± SEM values of respective sample groups for one particular metabolite (n = 4 for WT_PBS, WT_Met, MKR_PBS, n = 3 for MKR_Met, each sample with technical triplicates). The p-values for t-test (two-tailed, unequal variance) is also showed whenever significant (< 0.05). Plots were generated in GraphPad Prism 6.
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pone.0146152.g003: Individual metabolite levels in bone marrow affected by metformin.Each plot shows the mean ± SEM values of respective sample groups for one particular metabolite (n = 4 for WT_PBS, WT_Met, MKR_PBS, n = 3 for MKR_Met, each sample with technical triplicates). The p-values for t-test (two-tailed, unequal variance) is also showed whenever significant (< 0.05). Plots were generated in GraphPad Prism 6.

Mentions: Our study also revealed a great diversity in how individual metabolites are affected by metformin (Fig 3). Interestingly, the metformin levels in MKR cells were only 71% of those in WT, suggesting the drug uptake/delivery in MKR may not be as effective as in WT. A number of metabolites thatincreased in MKR condition were restored to the levels in WT by metformin. Metabolites in this group include succinate, aconitate, uric acid and citrate which belong to the TCA cycle and glycolysis. These results indicate that metformin is resetting metabolic pathways such as TCA cycle and glycolysis in MKR bone marrows, which could be beneficial in protection against bone damage caused by diabetic conditions.


Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal.

Li X, Guo Y, Yan W, Snyder MP, Li X - PLoS ONE (2015)

Individual metabolite levels in bone marrow affected by metformin.Each plot shows the mean ± SEM values of respective sample groups for one particular metabolite (n = 4 for WT_PBS, WT_Met, MKR_PBS, n = 3 for MKR_Met, each sample with technical triplicates). The p-values for t-test (two-tailed, unequal variance) is also showed whenever significant (< 0.05). Plots were generated in GraphPad Prism 6.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696809&req=5

pone.0146152.g003: Individual metabolite levels in bone marrow affected by metformin.Each plot shows the mean ± SEM values of respective sample groups for one particular metabolite (n = 4 for WT_PBS, WT_Met, MKR_PBS, n = 3 for MKR_Met, each sample with technical triplicates). The p-values for t-test (two-tailed, unequal variance) is also showed whenever significant (< 0.05). Plots were generated in GraphPad Prism 6.
Mentions: Our study also revealed a great diversity in how individual metabolites are affected by metformin (Fig 3). Interestingly, the metformin levels in MKR cells were only 71% of those in WT, suggesting the drug uptake/delivery in MKR may not be as effective as in WT. A number of metabolites thatincreased in MKR condition were restored to the levels in WT by metformin. Metabolites in this group include succinate, aconitate, uric acid and citrate which belong to the TCA cycle and glycolysis. These results indicate that metformin is resetting metabolic pathways such as TCA cycle and glycolysis in MKR bone marrows, which could be beneficial in protection against bone damage caused by diabetic conditions.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University, Stanford, CA 94305-5120, United States of America.

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 levels by metformin. These two metabolites were further validated as the major targets of metformin in bone marrow stromal cells.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus