Difference between revisions of "Piel 2014 Acta Physiol (Oxf)"
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{{Publication | {{Publication | ||
|title=Piel S, Ehinger JK, Elmér E, Hansson MJ (2014) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol (Oxf) | |title=Piel S, Ehinger JK, Elmér E, Hansson MJ (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 E, Hansson MJ | |authors=Piel S, Ehinger JK, Elmer E, Hansson MJ |
Revision as of 16:13, 26 February 2015
Piel S, Ehinger JK, Elmér E, Hansson MJ (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 E, Hansson MJ (2014) Acta Physiol (Oxf)
Abstract: AIM: 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mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis.
METHODS: 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 μm) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH.
RESULTS: 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.
CONCLUSION: 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
• O2k-Network Lab: SE Lund Elmer E
Labels: MiParea: Respiration
Pathology: Diabetes
Organism: Human Tissue;cell: Blood cells Preparation: Intact cells, Permeabilized cells
Coupling state: LEAK, ROUTINE, OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.
HRR: Oxygraph-2k