Piel 2014 Acta Physiol (Oxf): Difference between revisions
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{{Publication | {{Publication | ||
|title=Piel S, Ehinger JK, Elmรฉr E, Hansson Magnus J (2014) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial | |title=Piel S, Ehinger JK, Elmรฉr E, Hansson Magnus J (2014) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial Complex I inhibition. Acta Physiol (Oxf) 213:171-80. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/24801139 PMID: 24801139] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/24801139 PMID: 24801139] | ||
|authors=Piel S, Ehinger JK, Elmer | |authors=Piel S, Ehinger JK, Elmer Eskil, Hansson Magnus J | ||
|year=2014 | |year=2014 | ||
|journal=Acta Physiol (Oxf) | |journal=Acta Physiol (Oxf) | ||
|abstract=Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis. | |abstract=Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis. | ||
Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 | Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 mM) and phenformin (25-500 ฮผM) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH. | ||
Metformin induced respiratory inhibition at | Metformin induced respiratory inhibition at Complex I in peripheral blood mononuclear cells and platelets (IC<sub>50</sub> 0.45 mM and 1.2 mM respectively). Phenformin was about 20-fold more potent in Complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1 mM and higher. | ||
Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to | Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to Complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients. | ||
|keywords=Human, Drug screening, Metformin, Mitochondrial toxicity, Phenformin, Respirometry | |keywords=Human, Drug screening, Metformin, Mitochondrial toxicity, Phenformin, Respirometry | ||
|mipnetlab=SE Lund Elmer E | |mipnetlab=SE Lund Elmer E | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration | |area=Respiration, Pharmacology;toxicology | ||
|diseases=Diabetes | |diseases=Diabetes | ||
|organism=Human | |organism=Human | ||
|tissues=Blood cells, Other cell lines, Platelet | |tissues=Blood cells, Other cell lines, Platelet | ||
|preparations= | |preparations=Permeabilized cells, Intact cells | ||
|couplingstates=LEAK, ROUTINE, OXPHOS, | |couplingstates=LEAK, ROUTINE, OXPHOS, ET | ||
|pathways=N, S, CIV, NS, ROX | |pathways=N, S, CIV, NS, ROX | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=Metformin, MitoEAGLE blood cells data, | |||
}} | }} |
Latest revision as of 14:21, 12 May 2021
Piel S, Ehinger JK, Elmรฉr E, Hansson Magnus J (2014) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial Complex I inhibition. Acta Physiol (Oxf) 213:171-80. |
Piel S, Ehinger JK, Elmer Eskil, Hansson Magnus J (2014) Acta Physiol (Oxf)
Abstract: Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis.
Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 mM) and phenformin (25-500 ฮผM) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH.
Metformin induced respiratory inhibition at Complex I in peripheral blood mononuclear cells and platelets (IC50 0.45 mM and 1.2 mM respectively). Phenformin was about 20-fold more potent in Complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1 mM and higher.
Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to Complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients. โข Keywords: Human, Drug screening, Metformin, Mitochondrial toxicity, Phenformin, Respirometry
โข O2k-Network Lab: SE Lund Elmer E
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Diabetes
Organism: Human Tissue;cell: Blood cells, Other cell lines, Platelet Preparation: Permeabilized cells, Intact cells
Coupling state: LEAK, ROUTINE, OXPHOS, ET
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
Metformin, MitoEAGLE blood cells data