Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration.
OBJECTIVE
The glucose-lowering drug metformin has been shown to inhibit complex I of the mitochondrial electron transport chain in skeletal muscle. To investigate this effect in vivo we studied skeletal muscle mitochondrial respiratory capacity and content from patients with type 2 diabetes treated with metformin (n = 14) or sulfonylurea (n = 8) and healthy control (n = 18) participants.


METHODS
Mitochondrial respiratory capacity was measured ex vivo in permeabilised muscle fibres obtained from the vastus lateralis muscle of all participants. The respiratory response to in vitro titration with metformin was measured in controls. Citrate synthase (CS) activity, and fasting plasma glucose, insulin and HbA(1c) levels were measured and body composition was determined.


RESULTS
Participants were matched for age, BMI and percentage body fat. Fasting plasma glucose concentrations were higher (p < 0.05) in those treated with sulfonylureas and metformin than in controls. CS activity was comparable between metformin-treated and control participants, but tended to be lower in those receiving sulfonylureas. Mitochondrial respiratory capacity with substrates for complex I and complex I and II was comparable in the groups, both when estimated per mg of tissue and when normalised to CS activity. In vitro metformin titration demonstrated a dose-dependent inhibitory effect on complex I and II in human skeletal muscle at suprapharmacological concentrations.


CONCLUSIONS
Metformin treatment does not inhibit mitochondrial complex I respiration in the electron transport chain in human skeletal muscle of patients with type 2 diabetes when measured ex vivo. Inhibition of complex I and II respiration in controls was demonstrated by metformin titration in vitro at doses well above those observed during metformin treatment.
Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen N, Denmark. stelar@sund.ku.dk
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Larsen
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Rabøl
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Hansen
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Madsbad
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Helge
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Dela
D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D016022:Case-Control Studies; D019069:Cell Respiration; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D042967:Electron Transport Complex I / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
D001786:Blood Glucose; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human