CIDeRplusGeneral Information:
| Id: | 5,074 (click here to show other Interactions for entry) |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Rattus norvegicus | |
| male | |
| article | |
| Reference: | Madiraju AK et al.(2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature 510: 542-546 [PMID: 24847880] |
Interaction Information:
| Comment | Given that acute and chronic metformin treatment increased the cytoplasmic redox state and decreased the mitochondrial redox state, the study considered that metformin may block one of the two main redox shuttle systems, the malate‚Äďaspartate and glycerophosphate shuttles. Guanides/biguanides did not alter the activity of purified, recombinant cytosolic glycerophosphate dehydrogenase (cGPD). In contrast, all guanides/biguanides inhibited mitochondrial GPD (mGPD) activity by30‚Äď50% in rat mitochondrial lysates. |
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Formal Description Interaction-ID: 49892 |
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| Comment | Given that acute and chronic metformin treatment increased the cytoplasmic redox state and decreased the mitochondrial redox state, the study considered that metformin may block one of the two main redox shuttle systems, the malate‚Äďaspartate and glycerophosphate shuttles. Guanides/biguanides did not alter the activity of purified, recombinant cytosolic glycerophosphate dehydrogenase (cGPD). In contrast, all guanides/biguanides inhibited mitochondrial GPD (mGPD) activity by30‚Äď50% in rat mitochondrial lysates. |
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Formal Description Interaction-ID: 49894 |
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| Comment | Inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD) would prevent glycerol from contributing to gluconeogenic flux, as glycerol must be phosphorylated by glycerol kinase to glycerol-3-phosphate and converted to dihydroyacetone phosphate by mGPD to contribute to glucose production. Furthermore, inhibition of mGPD would halt the glycerophosphate shuttle and lead to accumulation of cytosolic NADH, which is unfavourable for conversion of lactate to pyruvate by lactate dehydrogenase (LDH). Consistent with this hypothesis, glucose production in hepatocytes from both lactate and glycerol was inhibited by metformin and mGpd knockdown. In contrast, metformin and mGpd knockdown had no effect on gluconeogenesis from dihydroxyacetone, alanine and pyruvate, substrates that enter gluconeogenesis without augmenting the cytosolic [NADH]:[NAD1] ratio. |
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Formal Description Interaction-ID: 49898 |
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| Comment | Inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD) would prevent glycerol from contributing to gluconeogenic flux, as glycerol must be phosphorylated by glycerol kinase to glycerol-3-phosphate and converted to dihydroyacetone phosphate by mGPD to contribute to glucose production. Furthermore, inhibition of mGPD would halt the glycerophosphate shuttle and lead to accumulation of cytosolic NADH, which is unfavourable for conversion of lactate to pyruvate by lactate dehydrogenase (LDH). Consistent with this hypothesis, glucose production in hepatocytes from both lactate and glycerol was inhibited by metformin and mGpd knockdown. In contrast, metformin and mGpd knockdown had no effect on gluconeogenesis from dihydroxyacetone, alanine and pyruvate, substrates that enter gluconeogenesis without augmenting the cytosolic [NADH]:[NAD1] ratio. |
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Formal Description Interaction-ID: 49899 |
gene/protein NOT affects_activity of process |
| Comment | Given that acute and chronic metformin (biguanide) treatment increased the cytoplasmic redox state and decreased the mitochondrial redox state, the study considered that metformin may block one of the two main redox shuttle systems, the malate‚Äďaspartate and glycerophosphate shuttles. Guanides/biguanides did not alter the activity of purified, recombinant cytosolic glycerophosphate dehydrogenase (cGPD). In contrast, all guanides/biguanides inhibited mitochondrial GPD (mGPD) activity by30‚Äď50% in rat mitochondrial lysates. |
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Formal Description Interaction-ID: 60450 |
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| Drugbank entries | Show/Hide entries for Metformin |