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

Abstract

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.

Skeletal muscle oxidative function in vivo and ex vivo in athletes with marked hypertrophy from resistance training

“…(17). In any case, the data obtained in the present study are similar to those obtained after substantially following the same protocol of the present study in the healthy control subjects of recent studies (9,23,30). In the present study, after adding cytochrome c to the measuring chamber, the increase in mitochondrial respiration was very small (ϳ2%).…”

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

“…The most common hypothesis is that metformin is able to partially inhibit complex I of the mitochondrial ETC, which in turn would lead to energy depletion and activation of AMPK (19)(20)(21). Recently this has been debated (16,22). One of the main arguments against metformin-mediated inhibition of complex I is the increased activity of pathways that generate energy after metformin treatment.…”

“…Metformin is generally believed to act through inhibition of complex I of the ETC (19)(20)(21), although some recent findings cast doubt on this (16,22). Treatment of C. elegans with rotenone, another complex I inhibitor, at a concentration that extends longevity, results in a decrease in total oxygen consumption (25).…”

“…In mammals, metformin is generally believed to act through the activation of AMPK, one of the main regulators of cellular energy homeostasis (2,(14)(15)(16), but recent research suggests the existence of AMPK-independent mechanisms as well (17,18). More upstream, metformin is thought to activate AMPK through partial inhibition of complex I of the electron transport chain (ETC) and a resultant increase in the AMP/ATP ratio (19)(20)(21), although again, not all data support this theory (16,22). Important players in metformin-induced lifespan extension in C. elegans are the liver kinase B1 ortholog PAR-4, the AMPK ortholog AMPactivated kinase-2 (AAK-2), and the skinhead-1 (SKN-1) transcription factor, which is involved in activating phase II detoxification mechanisms (5).…”

Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)*

“…These results challenge the role of LKB1-AMPK in mediating metformin suppression of hepatic gluconeogenesis (20). However, long term metformin administration did not affect the mitochondrial complex 1 activity both in the liver of mice and in the muscle of humans (21,22). In studies proposing an AMPKindependent mechanism, the authors employed metformin concentrations (1-2 mM) that were 10 -100-fold higher than maximal concentrations achieved in the hepatic portal vein after standard therapeutic dosing, and the high concentration of metformin used in these studies has raised safety concerns.…”