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

Piel, Sarah LU ; Ehinger, Johannes K LU ; Chamkha, Imen LU ; Frostner, Eleonor Åsander LU ; Sjövall, Fredrik LU ; Elmér, Eskil LU and Hansson, Magnus J LU (2018) In Intensive Care Medicine Experimental 6(1).
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:... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mitochondria, metformin, methylene blue, lactic acidosis, coupled respiration, succinate
in
Intensive Care Medicine Experimental
volume
6
issue
1
publisher
Springer Open
ISSN
2197-425X
DOI
10.1186/s40635-018-0186-1
language
English
LU publication?
yes
id
463703f3-06f0-495f-965b-a2a66b31e43b
date added to LUP
2018-09-26 10:05:48
date last changed
2019-02-26 12:35:22
@article{463703f3-06f0-495f-965b-a2a66b31e43b,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  articleno    = {22},
  author       = {Piel, Sarah and Ehinger, Johannes K and Chamkha, Imen and Frostner, Eleonor Åsander and Sjövall, Fredrik and Elmér, Eskil and Hansson, Magnus J},
  issn         = {2197-425X},
  keyword      = {mitochondria,metformin,methylene blue,lactic acidosis,coupled respiration,succinate},
  language     = {eng},
  month        = {08},
  number       = {1},
  publisher    = {Springer Open},
  series       = {Intensive Care Medicine Experimental},
  title        = {Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production},
  url          = {http://dx.doi.org/10.1186/s40635-018-0186-1},
  volume       = {6},
  year         = {2018},
}