Piel 2014 Acta Physiol (Oxf)

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Piel S, Ehinger JK, Elmér 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.

» PMID: 24801139

Piel S, Ehinger JK, Elmer E, 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mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis.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 μm) 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.

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, Other cell lines, Platelet  Preparation: Intact cells, Permeabilized cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k