Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration

TY - JOUR

T1 - Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration

AU - Larsen, Steen

AU - Rabøl, R

AU - Hansen, C N

AU - Madsbad, S

AU - Helge, J W

AU - Dela, F

PY - 2012/2

Y1 - 2012/2

N2 - Aims/hypothesis: 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/interpretation: 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.

AB - Aims/hypothesis: 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/interpretation: 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.

KW - Blood Glucose

KW - Body Mass Index

KW - Case-Control Studies

KW - Cell Respiration

KW - Citrate (si)-Synthase

KW - Diabetes Mellitus, Type 2

KW - Electron Transport Complex I

KW - Hemoglobin A, Glycosylated

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin

KW - Male

KW - Metformin

KW - Middle Aged

KW - Models, Biological

KW - Muscle, Skeletal

KW - Oxygen Consumption

KW - Sulfonylurea Compounds

U2 - 10.1007/s00125-011-2340-0

DO - 10.1007/s00125-011-2340-0

M3 - Journal article

C2 - 22009334

SN - 0012-186X

VL - 55

SP - 443

EP - 449

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -