Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I

Abstract

Metformin and thiazolidinediones (TZDs) are believed to exert their antidiabetic effects via different mechanisms. As evidence suggests that both impair cell respiration in vitro, this study compared their effects on mitochondrial functions. The activity of complex I of the respiratory chain, which is known to be affected by metformin, was measured in tissue homogenates that contained disrupted mitochondria. In homogenates of skeletal muscle, metformin and TZDs reduced the activity of complex I (30 mmol/l metformin, ؊15 ؎ 2%; 100 mol/l rosiglitazone, ؊54 ؎ 7; and 100 mol/l pioglitazone, ؊12 ؎ 4; P < 0.05 each). Inhibition of complex I was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate ؉ malate as substrates for complex I (30 mmol/l metformin, ؊77 ؎ 1%; 100 mol/l rosiglitazone, ؊24 ؎ 4; and 100 mol/l pioglitazone, ؊18 ؎ 5; P < 0.05 each), whereas respiration with succinate feeding into complex II was unaffected. In line with inhibition of complex I, 24-h exposure of isolated rat soleus muscle to metformin or TZDs reduced cell respiration and increased anaerobic glycolysis (glucose oxidation: 270 mol/l metformin, ؊30 ؎ 9%; 9 mol/l rosiglitazone, ؊25 ؎ 8; and 9 mol/l pioglitazone, ؊45 ؎ 3; lactate release: 270 mol/l metformin, ؉84 ؎ 12; 9 mol/l rosiglitazone, ؉38 ؎ 6; and 9 mol/l pioglitazone, ؉64 ؎ 11; P < 0.05 each). As both metformin and TZDs inhibit complex I activity and cell respiration in vitro, similar mitochondrial actions could contribute to their antidiabetic effects. Diabetes

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

“…Although the primary role of AICAR is activating AMPK, AICAR has been reported to affect additional AMP-regulated enzymes in liver cells, such as glucokinase and fructose 1,6-bisphosphate [51]. Also, IL-6/gp130/janus kinase (JAK)/STAT signalling pathway is summarised as previously described by Heinrich et al [33] metformin is a non-specific AMPK activator with the potential to activate other enzymes regulated by the cellular energy status [27]. In this study, a correlation between the time frame and concentrations of AICAR and metformin activating AMPK and the fold-reduction in expression of acute-phase markers SAA1, SAA2 and haptoglobin in response to IL-6, was observed (Fig.…”

“…Metformin inhibits enzymatic activity of complex I of the respiratory chain and hence lowers the cellular ATP:ADP ratio, which leads to the activation of AMPK [27]. We assessed the ability of AICAR and metformin to activate Representative western blot analysis of two to four independent experiments using antibodies specific for phospho-AMPKα (Thr 172 ), AMPKα1, AMPKα2, total AMPKα, phospho-ACC (Ser 79 ), total ACC or LKB1.…”

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

“…Thus, additional studies are clearly needed to address both the safety and overall efficacy of Metformin (for both DM and overall health) in populations that may be at higher risk for lactic acidosis. A second theoretical reason for caution in the use of biguanides is that, in vitro, Metformin (and also TZDs) may inhibit of complex I of the mitochondrial respiratory chain; it is not clear whether the doses used in these studies are similar to those experienced by humans on Metformin therapy 23, 29. Metformin also inhibits mitochondrial glycerophosphate dehydrogenase 30…”

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“…A clue to the underlying mechanism is provided by the findings that pioglitazone reduces mitochondrial respiration and that the lactate content increases in parallel [9]. The triple event of increased glucose uptake and lactate release concomitant with decreased respiration has also been described in skeletal muscle [10]. Such a combination suggests a cause-effect relationship in which the increased glucose uptake may represent an adaptive response, producing ATP via a highly glucose-consuming pathway, which generates lactate.…”

“…Both the metabolic and inflammatory actions of thiazolidinediones have been attributed to changes in gene expression mediated by peroxisome proliferator-activated nuclear receptor (PPAR)-γ, of which thiazolidinediones are ligands [3]. However, several recent studies point to the existence of PPAR-independent effects of thiazolidinediones, such as the regulation of mitochondrial respiration [9][10][11][12]. Impaired mitochondrial activity has been related to insulin resistance [13] and correlated with the clinical state in Alzheimer's disease [14].…”