Dataset Information

Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production.

ABSTRACT:

Background

Metformin is the most common pharmacological treatment for type 2 diabetes. It is considered safe but has been associated with the development of lactic acidosis under circumstances where plasma concentrations exceed therapeutic levels. Metformin-induced lactic acidosis has been linked to the drug's toxic effect on mitochondrial function. Current treatment strategies aim to remove the drug and correct for the acidosis. With a mortality of 20%, complementary treatment strategies are needed. In this study, it was investigated whether targeting mitochondria with pharmacological agents that bypass metformin-induced mitochondrial dysfunction can counteract the energetic deficit linked to toxic doses of metformin.

Methods

The redox agent methylene blue and the cell-permeable succinate prodrug NV118 were evaluated by measuring mitochondrial respiration and lactate production of human platelets exposed to metformin and co-treated with either of the two pharmacological bypass agents.

Results

The cell-permeable succinate prodrug NV118 increased mitochondrial respiration which was linked to phosphorylation by the ATP-synthase and alleviated the increase in lactate production induced by toxic doses of metformin. The redox agent methylene blue, in contrast, failed to mitigate the metformin-induced changes in mitochondrial respiration and lactate generation.

Conclusions

The cell-permeable succinate prodrug NV118 bypassed the mitochondrial dysfunction and counteracted the energy deficit associated with toxic doses of metformin. If similar effects of NV118 prove translatable to an in vivo effect, this pharmacological strategy presents as a promising complementary treatment for patients with metformin-induced lactic acidosis.

SUBMITTER: Piel S

PROVIDER: S-EPMC6070446 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production.

Piel Sarah S Ehinger Johannes K JK Chamkha Imen I Frostner Eleonor Åsander EÅ Sjövall Fredrik F Elmér Eskil E Hansson Magnus J MJ

Intensive care medicine experimental 20180801 1

<h4>Background</h4>Metformin is the most common pharmacological treatment for type 2 diabetes. It is considered safe but has been associated with the development of lactic acidosis under circumstances where plasma concentrations exceed therapeutic levels. Metformin-induced lactic acidosis has been linked to the drug's toxic effect on mitochondrial function. Current treatment strategies aim to remove the drug and correct for the acidosis. With a mortality of 20%, complementary treatment strategie ...[more]

PMID: 30069806

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Dataset Information

Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production.

Background

Methods

Results

Conclusions

Publications

Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production.

Similar Datasets

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