Piel 2018 Intensive Care Med Exp

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Piel S, Ehinger JK, Chamkha I, Frostner EÅ, Sjövall F, Elmér E, Hansson MJ (2018) Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production. Intensive Care Med Exp 6:22.

» PMID: 30069806 Open Access

Piel S, Ehinger JK, Chamkha I, Frostner EAa, Sjoevall F, Elmer E, Hansson MJ (2018) Intensive Care Med Exp

Abstract: 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.

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.

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.

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.

Keywords: Cell-permeable succinate, Human platelets, Lactic acidosis, Metformin, Methylene blue, Mitochondrial respiration, Mitochondrial toxicity Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: US PA Philadelphia Kilbaugh T, SE Lund Elmer E


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Human  Tissue;cell: Platelet  Preparation: Intact cells 


Coupling state: LEAK  Pathway: S, ROX  HRR: Oxygraph-2k 

Labels, 2018-08