Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 20, 2026.

Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function

Amanda R Martins, Renato T Nachbar, Renata Gorjao and 7 more

Lipids in Health and Disease · 2012 · Review

doi:10.1186/1476-511x-11-30

Abstract

Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Insulin resistance is broadly defined as the reduction in insulin ability to stimulate glucose uptake from body peripheral tissues. At physiological conditions, insulin activates glucose uptake by stimulating the canonical IRS-PI3K-Akt pathway and by phosphorylating and inactivating Akt substrate 160 (AS160), a protein that, when activated, prevents glucose transporter (GLUT) 4 translocation to the membrane. Thus, by inhibiting AS160, insulin promotes the GLUT4 translocation from inner vesicules, promoting fusion to the plasma membrane and consequently glucose uptake.

Although insulin resistance is a key component of several chronic syndromes associated with obesity such as type 2 diabetes mellitus and metabolic syndrome, the involved factors and their underlying mechanisms linking excessive adiposity to insulin resistance were not completely elucidated yet. Evidence suggests that fatty acids, whose circulating levels are markedly increased in obesity and associated-diseases, might play a role in the development of skeletal muscle insulin resistance. In this sense, prolonged exposure of skeletal muscle and myocytes to high levels of fatty acids leads to severe insulin resistance. Among the different types of fatty acids, saturated long-chain fatty acids such as palmitic and stearic acids were demonstrated to be potent inducers of insulin resistance. Several mechanisms have been suggested by us and others to explain how saturated fatty acids impair insulin actions such as the Randle cycle, accumulation of intracellular lipid derivatives (diacylglycerol and ceramides), oxidative stress, modulation of gene transcription, inflammation and mitochondrial dysfunction. In the present review, we discuss evidence supporting the involvement of these mechanisms in the regulation of insulin sensitivity by saturated fatty acids and propose the mitochondrial dysfunction found in conditions of elevated fatty acid levels has a central role in the pathogenesis of insulin resistance.

Competition between fatty acids and glucose: the randle cycle

The first mechanistic explanation for the inverse relationship between fatty acids availability and glucose utilization was proposed by Randle et al.. In this study, it was shown that an elevation in fatty acids supply to diaphragm and isolated heart is associated with an increase in fatty acid oxidation and an impairment in glycolytic flux and glucose utilization, such effect being mediated by alosteric inhibition of glycolytic enzymes. More specifically, the proposed hypothesis was that increased fatty acid oxidation raises the production of acetyl-CoA resulting in inhibition of pyruvate dehydrogenase activity and elevation of citrate levels at the tricarboxylic acid cycle. Citrate together with an increased ATP/ADP ratio reduce the activity of phosphofructokinase and consequently glucose flux through the glycolytic pathway, resulting in glucose 6-phosphate accumulation, hexokinase II inhibition, increase in intracellular glucose content and, consequently, reduction in glucose uptake.

In accordance with Randle's hypothesis, elevation in circulating fatty acids levels by either intralipid/heparin or lipid infusion in rats, humans and type 2 diabetes mellitus patients is associated with impairments in glucose uptake, utilization and oxidation in insulin-sensitive tissues (heart, skeletal muscle and adipose tissue). Acutely, fatty acids lead to Randle cycle effect, increasing intracellular content of citrate and glucose-6-phosphate and decreasing glycolytic pathway flux. It has been also demonstrated that palmitate accutely increases glucose uptake in L6 myotubes by activating insulin signaling pathways (Akt and ERK1/2).

However, in contrast to Randle's hypothesis, in which intracellular glucose accumulation must precede the inhibition of glucose uptake, further studies demonstrated that the insulin resistance induced by fatty acids is primarily associated with impaired glucose uptake rather than changes in hexose metabolism. In studies involving lipid infusion associated with other techniques including glucose and insulin clamp and nuclear magnetic resonance a rapid reduction in glycolysis (previous to 2 hours) followed by impaired glucose disposal and glycogen synthesis (between 4-6 hours) was observed. Roden et al. demonstrated that the reduction in muscle glycogen synthesis is preceded by a decrease in intramuscular glucose 6-phosphate, suggesting that the increase in plasma fatty acid concentration initially induces insulin resistance by inhibiting glucose transport or its phosphorylation. Other studies also demonstrated that lipid infusion decreases intracellular glucose and glucose 6-phosphate content, due to inhibition of glucose uptake by skeletal muscle. These studies demonstrated that Randle cycle does not completely explain the effects of FFA on glucose metabolism indicating that other mechanisms are also involved in the FFA-induced insulin resistance.

Inhibition of skeletal muscle insulin signaling by saturated fatty acids

In addition to its important effects on glucose metabolism directly, saturated fatty acids were demonstrated to affect insulin intracellular signaling pathways in skeletal muscle and myocytes. Studies have demonstrated a marked reduction in IRS-1 tyrosine phosphorylation, IRS-1 and -2-associated PI3-kinase activity, and Akt phosphorylation and activity in skeletal muscle after lipid infusion in euglycemic-hyperinsulinemic clamp. Along with a direct effect of saturated fatty acids on skeletal muscle insulin signaling, palmitic acid was shown to decrease insulin receptor expression and activity and phosphorylation of IRS-1 and -2 at tyrosine residues, Akt and GSK-3, as reviewed by Schmitz-Peiffer et al. in isolated soleus muscle, primary culture of rat myocytes, pmi28 myotubes, C2C12 and L6 myocytes. Similarly to skeletal muscle, palmitic acid inhibits Akt phosphorylation and activity in rat perfused heart and in HL-1 cells, an immortalized cardiomyocyte like cell lineage.

Several mechanisms have been postulated to account for the inhibition of insulin signaling by saturated fatty acids, including the activation of various kinases such as PKCs, IKK β, JNK, and p38 MAP kinase. These kinases have been postulated to catalyze the phosphorylation of serine residues in IRS-1 inhibiting its activity and directing it for degradation by the proteasome. Such effects culminate with a reduction in the phosphorylation of tyrosine residues of IRS-1 by insulin, blocking its downstream signal transduction. Other serine/threonine kinase activated in high-fat diet-induced or palmitate-induced insulin resistance is mammalian target of rapamycin (mTOR), but the mechanisms involved are unknown yet.

Lipotoxic intramyocellular lipid accumulation induced by fatty acids

When the amount of circulating lipids chronically exceeds white adipose tissue ability for uptake and storage, like obesity, fatty acids accumulate in other tissues with limited capacity for lipid storage such as liver and skeletal muscles. Such abnormal ectopic lipid accumulation (lipotoxicity) is strongly associated with insulin resistance.

Fatty acids accumulate intracellularly in myocytes mainly as long-chain fatty acyl-CoA, monoacylglcyerol, diacylglycerol, phosphatidic acid, triacylglycerol and ceramides. Among these fatty acid derivatives, high intramyocellular levels of diacylglycerol, triacylglycerol, and ceramides are directly associated with insulin resistance. Corroborating with this hypothesis, high fat feeding is associated with an increase in intramyocellular content of diacylglycerol and triacylglycerol and insulin resistance, such effects being abolished by inhibition of muscle lipid accumulation due to genetic deletion of lipoprotein lipase, fatty acid transporters (CD36 and FATP1), and diacylglycerol acyl transferase-1 (DGAT-1). Diacylglycerol accumulation is associated with the activation of subgroup of novel kinases, members of the large protein kinase C (PKC) family. Among the novel kinases, diacylglycerol directly activates PKCθ that catalyzes the phosphorylation of serine-307 residue at IRS-1, reducing its tyrosine phosphorylation and activation by insulin.

Consistent with this, Schmitz-Peiffer et al. reported increased concentration of DAG in rodent's muscle and activation of PKCs induced by high-fat diet. Similarly, infusion of lipid and heparin caused insulin resistance in muscles that was associated with accumulation of intracellular DAG and specific activation of PKCθ. Insulin resistance in this model was due to lipid-induced defects in the insulin signaling pathway that was caused by a reduction in tyrosine phosphorylation of IRS1, increasing its phosphorylation in serine-307 residue. However, there are still no evidence to explain how the activation of novel PKCs might relate to serine phosphorylation of IRS1, and which kinases might have a role in the pathway, as reviewed by Samuel et al..

In addition to diacylglycerol accumulation, high-fat diet or palmitate treatment increases production of ceramide and sphingosines in skeletal muscle cells, which is associated with glucose intolerance and insulin resistance. Evidence suggests that ceramide and phosphatidic acid mediate the deleterious effects of palmitic acid on insulin signaling in cultured myotubes and insulin mediated Akt and GSK phosphorylation in C2C12 myotubes. Ceramides also affects insulin signaling by two distinct mechanisms involving the activation of Akt dephosphorylation at threonine 308 and inhibition of its translocation to the plasma membrane, such effects being dependent on ceramides activation of protein phosphatase 2A (PP2A) and PKCζ, respectively. In addition, glycosylceramide, a glycosyl derivative of ceramides was shown to inhibit insulin receptor activity inducing insulin resistance. Recently, it has been demonstrated that increased lysophosphatidylcholine content, a phosphatidic acid, in L6 myotubes treated with palmitate also leads to JNK activation and IRS-1 Ser307 phosphorylation, contributing to the development of muscle insulin resistance.

Activation of inflammatory signaling pathways by saturated fatty acids

Saturated fatty acids activate inflammatory signaling pathways directly through interaction with members of Toll-like receptor (TLR) family and indirectly through the secretion of cytokines including TNF-α, IL-1β and IL-6. TLRs are an evolutionarily ancient pattern-recognition class of receptors that facilitate the detection of microbes. Saturated fatty acids activate TLR-4 in skeletal muscle promoting c-Jun NH(2)-terminal kinase (JNK) and Iκb kinase (IKK) complex activation, which results in degradation of the inhibitor of κB (IκBα) and nuclear factor-κB (NFκB) activation. Activation of JNK and IKKβ by saturated fatty acids is associated with a marked inhibition of insulin action due to the phosphorylation of serine residues on the insulin IRS-1 and inhibition of its stimulatory phosphorylation of tyrosine residues by the insulin receptor. Corroborating with an important contribution of TLR-4 to muscle insulin resistance, mice containing a loss of function by mutation of this receptor are partially protected from fat-induced inflammation and insulin resistance. In addition, diabetic and obese mice have increased skeletal muscle IKK and JNK activities, whose pharmacological and genetic inhibition leads to an improvement in insulin sensitivity and glucose tolerance.

Coletta and Mandarino demonstrated that changes in genes and proteins from inflammatory pathway contribute to the mitochondrial dysfunction observed in insulin resistant muscle and it can lead to decreased fat oxidation, ectopic fat accumulation, insulin signaling abnormalities and finally insulin resistance. These authors indicate that this mechanism is compatible with and complementary to other hypotheses regarding the vicious cycle connecting inflammation, mitochondrial changes, lipid accumulation and insulin signaling defects. The novel aspect of this mechanism is that it connects inflammatory processes with changes in insulin sensitivity by means of altered mechanosignal transduction due to fibrotic changes.

Fatty acids were also demonstrated to reduce mitochondrial function through induction of pro-inflammatory cytokines. Saturated fatty acids, palmitic and stearic acids, stimulate the secretion of TNF-α, IL-1β and IL-6 in human leukocytes. Wen et al. showed increased IL-1β production and release by palmitic acid in macrophages through activation of the NLRP3-ASC inflammasome. The pro-inflammatory cytokines have been associated to impaired mitochondrial function, establishing a link between fatty acids and mitochondrial dysfunction. Indeed, some studies reported reduced mitochondrial function in cells exposed to TNF-α, IL-1β or IL-6.

Alteration in gene expression by saturated fatty acids

Evidence has been obtained that fatty acids modulate expression of genes involved in glucose and lipid metabolism. Schmid et al. demonstrated that C57BL/6 mice submitted to high-fat diet present reduced expression of enolase, a glycolytic enzyme, and ATP synthase in skeletal muscle. In addition, other enzymes of the glycolytic pathway have been shown to be modulated by fatty acids, such as pyruvate dehydrogenase kinase isozyme 1 (PDK-1), whose expression is increased in pancreatic islets incubated with saturated fatty acids, and lactate dehydrogenase A (LDHA), which was downregulated in white adipose tissue from high-fat-fed animals. Moreover, increased intramyocellular lipid content has been associated with down-regulation of PGC-1α and of other genes encoding protein mitochondrial respiratory complexes I, II, III, and IV, resulting in impaired mitochondrial biogenesis and function. Some studies identified transcription factors that recognize conserved motifs at the promoters of mitochondrial oxidative phosphorylation genes, such as nuclear respiratory factor (NRF)-1 and GA-binding protein (GABP) (also known as NRF-2). Studies showed that the peroxisome proliferator activator receptors (PPARs) control mitochondrial gene subsets, modulating fatty acid oxidation (FAO) and uncoupling. Later, studies showed that PGC-1α is a transcriptional coactivator of NRF-1, GABP, and PPARs, demonstrating the ability of PGC-1α to integrate physiological signals and to increase mitochondrial biogenesis and oxidative function. Thus, a reduction of PGC-1α content in conditions of high fatty acid levels might be associated with impairment of mitochondrial function. In addition, insulin-resistant subjects have reduced expression of mitochondrial genes, such as cytochrome c oxidase and complexes I and III subunits of the electron transport chain. Activities of carnitine palmitoyltransferase-1 (CPT-1) and other key mitochondrial enzymes, such as citrate synthase and β-hydroxyacyl-CoA dehydrogenase, have also been found decreased in skeletal muscle from obese and type 2 diabetic individuals. These changes in gene expression and enzyme activities induced by fatty acids contribute to the reduced mitochondrial oxidative capacity consequently leading to mitochondrial dysfunction.

Increase in reactive oxygen species by saturated fatty acids

Type 2 diabetes mellitus, obesity and the metabolic syndrome are strongly correlated with increased skeletal muscle content of reactive oxygen species (ROS). All conditions cited above contribute to an oxidative environment, modulating insulin sensitivity either by increasing insulin signaling or impairing glucose tolerance. The mechanisms by which this occurs are often multifactorial and complex, involving several cell signaling pathways.

Production of ROS can occur in response to diverse stimuli including: (1) intracellular factors, such as nutrient metabolism, endoplasmic reticulum stress, and detoxification of various xenobiotics; (2) extracellular factors like signaling through plasma membrane receptors, such as hormones and growth factors and by pro-inflammatory cytokines; and (3) physical-environmental factors (e.g. ultraviolet irradiation). When moderately produced, ROS are involved in important physiological processes that lead to desired cellular responses. However, high ROS production is negatively associated with different biological signaling pathways. ROS can react with multiple cellular components, such as proteins, lipids and nucleic acids, generating reversible or irreversible oxidative modifications. Pathophysiological processes mediated by ROS are more likely to induce irreversible modifications in cellular components, a reasonable definition of the term oxidative stress.

Control of vascular tone, cell adhesion, immune responses, and growth factors and hormone action are examples of ROS participation in normal physiology. Conversely, a negative role of ROS has been implicated in ageing-related diseases, malignant transformation, atherosclerosis, neurodegenerative diseases, obesity, and diabetes. Insulin signaling can be also impaired by oxidative stress, but the mechanisms involved are not fully understood. Studies have been demonstrated that ROS lead to impaired insulin response by inducing IRS serine/threonine phosphorylation, decreasing GLUT4 gene transcription, and decreasing mitochondrial activity.

Chronic elevation in plasma lipids levels and excessive intramyocellular fatty acid disposal are characterized by increased ROS and reactive nitrogen species (RNS) production. Diet-induced obese mice have an increased expression of inducible nitric oxide synthase (iNOS) and RNS generation in skeletal muscle such effects being associated with impaired insulin sensitivity, since mice with iNOS disruption in muscle are protected from insulin resistance induced by obesity. Diabetic patients present elevated ROS production in endothelial cells through NADPH oxidase activation, a mechanism mediated by PKC. NADPH-oxidase complex is also found in skeletal muscles, raising the possibility that a similar mechanism occurs under elevated FA availability. Our group recently demonstrated that palmitate induces superoxide production in cultured skeletal muscle cells via NADPH oxidase activation, at least in part. Some evidence also links xanthine oxidase (XO) as a source of increased ROS generation in diabetes and obesity. XO protein and activity is found increased in muscle arterioles and livers from animal models of type 1 diabetes and diet-induced obesity.

Animals treated either with high-fat diet or oxidant drugs such as buthionine sulfoximine (BSO), an inhibitor of gluthatione synthase, have increased skeletal muscle ROS production, oxidative stress and are insulin-resistant. On the other hand, animals food restricted or treated with antioxidant drugs such as N-acetyl-cysteine (NAC), lipoic acid, vitamin E, and taurine, have reduced oxidative stress and improved insulin sensitivity. In addition, mice overexpressing SOD2 have decreased ROS levels, improved hepatic insulin sensitivity, normalization of blood glucose and insulin levels, and reduced activation of cellular stress signalling pathways. These data suggest that mitochondrial ROS is important for the development of insulin resistance.

The involvement of oxidative stress in insulin resistance was also observed in studies performed in myocytes. In L6 muscle cells, H2O2 reduced insulin-stimulated glucose uptake and glutathione content, effects that were prevented by preincubation with the antioxidant lipoic acid. Rat soleus muscle exposed to nitric oxide (NO) donors have decreased insulin-stimulated glucose uptake and glycogen synthesis, effects that were associated with reduced insulin-stimulated phosphorylation of IR, IRS-1, and Akt.

Since mitochondria is the main site of ROS production in skeletal muscle, mitochondrion DNA, protein and lipids components are exposed to high levels of these metabolites suffering structural modification and damage which at long term can result in impaired function of this organelle.

Mitochondrial dysfunction or reduced mitochondrial biogenesis and density can lead to a decrease in mitochondrial fatty acids oxidation, which results in increased levels of fatty acil-CoA and DAG that can activate stress-related Ser/Thr kinase activity and inhibit glucose transport, as reviewed by Lowell and Shulman.

In the case of stress-activated kinases, oxidative stress also contributes to impair insulin signaling by increased uncoupling protein-2 (UCP-2) activity. When these proteins are activated, it results in a heat generation that does not contribute to ATP production. UCP-2 negatively regulates glucose-stimulated insulin secretion by reducing the ATP production, which is key to provide energy for almost all cellular processes. In addition, UCP-2-/- mice demonstrate enhanced insulin secretory capacity after a high-fat diet due to improved β-cell functions in a type 2 diabetes animal model.

Mitochondrial uncoupling is a powerful tool to control ROS formation and consequently to preserve mitochondrial function. It can be hypothesized that fatty-acid induced uncoupling decrease mitochondrial ROS production and thus it can prevent mitochondrial lipotoxicity. In fact, UCP-3 is upregulated using high-fat diets, fasting, etomoxir treatment (which inhibits the mitochondrial fatty acid oxidation) and lipid infusion, all conditions being associated with excessive lipid accumulation in skeletal muscle. On the other hand, when fat oxidative capacity is improved, like with endurance training, weight loss, or lowering circulatory fatty acids there is a decrease in UCP-3. Interestingly, UCPs are activated by fatty acids and/or its peroxidation products, reducing mitochondrial ROS production. So, it can be suggested that UCP-3 is involved in the protection against mitochondrial lipotoxicity by decreasing ROS production when activated by FA, as reviewed by Schrauwen et al..

In summary, oxidative stress seems to play an important role in mitochondrial dysfunction, which can further exacerbate stress signals and reduce ATP production. The pathways leading to insulin resistance may be synergistic and mitochondrial dysfunction can create a feedback loop, adding to the overall oxidative stress environment.

Impairment of skeletal muscle mitochondrial function by saturated fatty acids

Several studies have shown that mitochondrial content, mitochondrial function, and oxidative capacity are decreased in insulin-resistant obese and type 2 diabetic individuals suggesting that mitochondrial dysfunction might play an important role in the pathophysiology of insulin resistance. Corroborating with this hypothesis, impaired mitochondrial function and reduced fatty acid oxidative capacity were found in isolated primary myocytes, isolated rectus abdominal muscle strips and muscle homogenates from insulin-resistant obese and type 2 diabetic patients. Moreover, mitochondrial density is reduced in insulin-resistant skeletal muscle from children, offspring of people with type 2 diabetes, suggesting that impaired mitochondrial oxidative capacity can be an inherited defect and an early marker for the development of insulin resistance. Some studies have also reported alterations (mutations, polymorphisms, and epigenetics) in the mitochondrial DNA in conditions of insulin resistance, such as obesity, type 2 diabetes, and metabolic syndrome.

Evidence points for an important role of fatty acids in the genesis of the mitochondrial dysfunction associated with obesity and type 2 diabetes mellitus. In this sense, lipid infusion or administration of high-fat diet to health human and rodents were associated with impaired mitochondrial function characterized by a reduction in ATP synthesis, oxygen consumption and oxidative phosphorylation. These findings were corroborated by in vitro studies in which treatment of cultured skeletal muscle cells with palmitic acid increased ROS production, impaired fatty acid oxidation and decreased PGC-1 expression. Studies from our group demonstrated that saturated fatty acids directly induces mitochondrial dysfunction in C2C12 skeletal muscle cells, as evidenced by reduced ATP synthesis and mitochondrial polarization.

Mitochondrial dysfunction plays a central role in the fatty acid-induced insulin resistance

As discussed above, several mechanisms have been proposed to explain the insulin resistance induced by saturated fatty acids. All these mechanisms operate in coordinated, integrated manner linking fatty acids availability to skeletal muscle insulin resistance. To account for this multifactorial characteristic of saturated fatty acid actions, we propose herein an integrative model centered on mitochondrial dysfunction as an important factor in the genesis of insulin resistance induced by fatty acids (Figure 1).

In physiological conditions, fatty acids are normally and rapidly oxidized with low ROS production, little intracellular lipid accumulation and preservation of insulin sensitivity (Figure 1A). In pathological conditions, chronic elevation in circulating fatty acid levels reduces the expression of genes involved in mitochondrial biogenesis oxidative capacity and increase production of ROS, impairing mitochondrial biogenesis and function (Figure 1B). As a consequence, oxidative capacity is impaired and mitochondrial mass is reduced, increasing still further ROS production, leading to accumulation of fatty acid-derived metabolites such as diacylglycerol and ceramides.

ROS and lipid metabolites have been positively associated with insulin resistance and activation of several kinases, such as NFκB, p38 MAP kinase, JNK, and some novel and atypical PKC isoforms, as PKC-ζ and -ε, in skeletal muscle. These kinases impair the insulin signaling pathway by inducing serine/threonine phosphorylation in IRS-1. Under this condition, insulin-stimulated tyrosine phosphorylation of IRS-1 is inhibited, impairing activation of downstream signaling pathways and decreasing glucose uptake and metabolism in response to the hormone (Figure 2).

Concluding remarks

We discussed herein the mechanisms involved in insulin resistance in skeletal muscle cells induced by high availability of FFA. Several mechanisms have been proposed, such as Randle cycle, inhibition of insulin signaling pathway, regulation of gene expression and enzymatic activities, increase in ROS and RNS production, and impairment in mitochondrial function. Although numerous studies have been performed in order to investigate each one of these mechanisms, the conclusive proposition has not been defined yet. Evidence suggests that these mechanisms are not exclusive and there are several data in the literature pointing out that more than one mechanism is involved in the insulin resistance induced by FFA. We proposed herein a unifying hypothesis that places the importance of mitochondria in the establishment of FFA-induced insulin resistance.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

ARM, RTN, and RHL participated of the acquisition, analysis, and interpretation of the data from literature. RG, MAV, and WTF organized the structure of the manuscript and had substantial contribution to the conception and design. MFCB and LRS were involved in the drafting of the manuscript and figures. SMH and RC critically revised the text and figures for the final version of the manuscript. All authors read and approved the final manuscript.

References 146

  1. 1.

    Sakamoto K Holman GD Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 trafficAm J Physiol Endocrinol Metab2008 2952937

    Not in our library10.1152/ajpendo.90331.2008

  2. 2.

    Hirabara SM Silveira LR Abdulkader F Carvalho CR Procopio J Curi R Time-dependent effects of fatty acids on skeletal muscle metabolismCell Physiol2007 210715

    Not in our library10.1002/jcp.20811

  3. 3.

    Silveira LR Fiamoncini J Hirabara SM Procópio J Cambiaghi TD Pinheiro CH Lopes LR Curi R Updating the effects of fatty acids on skeletal muscleJ Cell Physiol2008 217112

    Not in our library10.1002/jcp.21514

  4. 4.

    Ragheb R Shanab GM Medhat AM Seoudi DM Adeli K Fantus IG Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: evidence for PKC activation and oxidative stress-activated signaling pathwaysBiochem Biophys Res Commun2009 389211216

    Not in our library10.1016/j.bbrc.2009.08.106

  5. 5.

    Hirabara SM Curi R Maechler P Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cellsJ Cell Physiol2010 222187194

    Not in our library10.1002/jcp.21936

  6. 6.

    Shulman GI Cellular mechanisms of insulin resistanceJ Clin Invest2000 106171176

    Not in our library10.1172/jci10583

  7. 7.

    Roden M How free fatty acids inhibit glucose utilization in human skeletal muscleNews Physiol Sci2004 199296

    Not in our library10.1152/nips.01459.2003

  8. 8.

    Griffin ME Marcucci MJ Cline GW Bell K Barucci N Lee D Goodyear LJ Kraegen EW White MF Shulman GI Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascadeDiabetes1999 4812701274

    Not in our library10.2337/diabetes.48.6.1270

  9. 9.

    Yu C Chen Y Cline GW Zhang D Zong H Wang Y Bergeron R Kim JK Cushman SW Cooney GJ Atcheson B White MF Kraegen EW Shulman GI Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscleJ Biol Chem2002 2775023050236

    Not in our library10.1074/jbc.m200958200

  10. 10.

    Yuzefovych L Wilson G Rachek L Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stressAm J Physiol Endocrinol Metab2010 29910961105

    Not in our library10.1152/ajpendo.00238.2010

  11. 11.

    Hirabara SM Carvalho CRO Mendonça JR Piltcher Haber E Fernandes LC Curi R Palmitate acutely raises glycogen synthesis in rat soleus muscle by a mechanism that requires its metabolization (Randle cycle)FEBS Lett2003 541109114

    Not in our library10.1016/s0014-5793(03)00316-8

  12. 12.

    Hirabara SM Silveira LR Alberici LC Leandro CV Lambertucci RH Polimeno GC Cury Boaventura MF Procopio J Vercesi AE Curi R Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscleBiochim Biophys Acta2006 17575766

    Not in our library10.1016/j.bbabio.2005.11.007

  13. 13.

    Randle PJ Garland PB Hales CN Newsholme EA The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitusLancet1963 1785789

    Not in our library10.1016/s0140-6736(63)91500-9

  14. 14.

    Roden M Price TB Perseghin G Petersen KF Rothman DL Cline GW Shulman GI Mechanism of free fatty acid-induced insulin resistance in humansJ Clin Invest1996 9728592865

    Not in our library10.1172/jci118742

  15. 15.

    Carvalho-Filho MA Ueno M Hirabara SM Seabra AB Carvalheira JB de Oliveira MG Velloso LA Curi R Saad MJ S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistanceDiabetes2005 54959967

    Not in our library10.2337/diabetes.54.4.959

  16. 16.

    Brehm A Krssak M Schmid AI Nowotny P Waldhäusl W Roden M Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscleDiabetes2006 55136140

    Not in our library

  17. 17.

    Randle PJ Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 yearsDiabetes Metab Rev1998 14263283

    Not in our library10.1002/(sici)1099-0895(199812)14:4<263::aid-dmr233>3.0.co;2-c

  18. 18.

    Dresner A Laurent D Marcucci M Griffin ME Dufour S Cline GW Slezak LA Andersen DK Hundal RS Rothman DL Petersen KF Shulman GI Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activityJ Clin Invest1999 103253259

    Not in our library10.1172/jci5001

  19. 19.

    Jenkins AB Storlien LH Chisholm DJ Kraegen EW Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivoJ Clin Invest1988 82293299

    Not in our library10.1172/jci113586

  20. 20.

    Johnson AB Argyraki M Thow JC Cooper BG Fulcher G Taylor R Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal manClin Sci1992 82219226

    Not in our library10.1042/cs0820219

  21. 21.

    Boden G Chen X Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetesJ Clin Invest1995 9612611268

    Not in our library10.1172/jci118160

  22. 22.

    Pu J Peng G Li L Na H Liu Y Liu P Palmitic acid acutely stimulates glucose uptake via activation of Akt and ERK1/2 in skeletal muscle cellsJ Lipid Res2011 5213191327

    Not in our library10.1194/jlr.m011254

  23. 23.

    Rothman DL Shulman RG Shulman GI 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitusJ Clin Invest1992 8910691075

    Not in our library10.1172/jci115686

  24. 24.

    Hawley JA Burke LM Angus DJ Fallon KE Martin DT Febbraio MA Effect of altering substrate availability on metabolism and performance during intense exerciseBr J Nutr2000 84829838

    Not in our library10.1017/s0007114500002440

  25. 25.

    Savage DB Petersen KF Shulman GI Disordered lipid metabolism and the pathogenesis of insulin resistancePhysiol Rev2007 87507520

    Not in our library10.1152/physrev.00024.2006

  26. 26.

    Kim JY Hickner RC Cortright RL Dohm GL Houmard JA Lipid oxidation is reduced in obese human skeletal muscleAm J Physiol Endocrinol Metab2000 27910391044

    Not in our library10.1152/ajpendo.2000.279.5.e1039

  27. 27.

    Dey D Mukherjee M Basu D Datta M Roy SS Bandyopadhyay A Bhattacharya S Inhibition of insulin receptor gene expression and insulin signaling by fatty acid: interplay of PKC isoforms thereinCell Physiol Biochem2005 16217228

    Not in our library10.1159/000089847

  28. 28.

    Storz P Döppler H Wernig A Pfizenmaier K Müller G Cross-talk mechanisms in the development of insulin resistance of skeletal muscle cells palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptakeEur J Biochem1999 2661725

    Not in our library10.1046/j.1432-1327.1999.00809.x

  29. 29.

    Thompson AL Lim-Fraser MY Kraegen EW Cooney GJ Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitroAm J Physiol Endocrinol Metab2000 279577584

    Not in our library10.1152/ajpendo.2000.279.3.e577

  30. 30.

    Cazzolli R Carpenter L Biden TJ Schmitz-Peiffer C A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitateDiabetes2001 5022102218

    Not in our library10.2337/diabetes.50.10.2210

  31. 31.

    Hajduch E Balendran A Batty IH Litherland GJ Blair AS Downes CP Hundal HS Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cellsDiabetologia2001 44173183

    Not in our library10.1007/s001250051596

  32. 32.

    Schmitz-Peiffer C Signalling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupplyCell Signal2000 12583594

    Not in our library10.1016/s0898-6568(00)00110-8

  33. 33.

    Soltys CL Buchholz L Gandhi M Clanachan AS Walsh K Dyck JR Phosphorylation of cardiac protein kinase B is regulated by palmitateAm J Physiol Heart Circ Physiol2002 28310561064

    Not in our library10.1152/ajpheart.00275.2002

  34. 34.

    Paz K Hemi R LeRoith D Karasik A Elhanany E Kanety H Zick Y A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylationJ Biol Chem1997 2722991129918

    Not in our library10.1074/jbc.272.47.29911

  35. 35.

    Zhande R Mitchell JJ Wu J Sun XJ Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1Mol Cell Biol2002 2210161026

    Not in our library10.1128/mcb.22.4.1016-1026.2002

  36. 36.

    Tirosh A Potashnik R Bashan N Rudich A Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocationJ Biol Chem1999 2741059510602

    Not in our library10.1074/jbc.274.15.10595

  37. 37.

    Bloch-Damti A Bashan N Proposed mechanisms for the induction of insulin resistance by oxidative stressAntioxid Redox Signal2005 715531567

    Not in our library10.1089/ars.2005.7.1553

  38. 38.

    Evans JL Maddux BA Goldfine ID The molecular basis for oxidative stress-induced insulin resistanceAntioxid Redox Signal2005 710401052

    Not in our library10.1089/ars.2005.7.1040

  39. 39.

    Khamzina L Veilleux A Bergeron S Marette A Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistanceEndocrinology2005 14614731481

    Not in our library10.1210/en.2004-0921

  40. 40.

    Rivas DA Yaspelkis BB Hawley JA Lessard SJ Lipid-induced mTOR activation in rat skeletal muscle reversed by exercise and 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosideJ Endocrinol2009 202441451

    Not in our library10.1677/joe-09-0202

  41. 41.

    Consitt LA Bell JA Houmard JA Intramuscular lipid metabolism, insulin action, and obesityIUBMB Life2009 614755

    Not in our library10.1002/iub.142

  42. 42.

    Samuel VT Fructose induced lipogenesis: from sugar to fat to insulin resistanceTrends Endocrinol Metab2011 226065

    Not in our library10.1016/j.tem.2010.10.003

  43. 43.

    Cooney GJ Thompson AL Furler SM Ye J Kraegen EW Muscle long-chain acyl CoA esters and insulin resistanceAnn N Y Acad Sci2002 967196207

    Not in our library10.1111/j.1749-6632.2002.tb04276.x

  44. 44.

    Itani SI Ruderman NB Schmieder F Boden G Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alphaDiabetes2002 5120052011

    Not in our library10.2337/diabetes.51.7.2005

  45. 45.

    Summers SA Ceramides in insulin resistance and lipotoxicityProg Lipid Res2006 454272

    Not in our library10.1016/j.plipres.2005.11.002

  46. 46.
    Hepatic triacylglycerol accumulation and insulin resistance · 2009
    Not checked
  47. 47.

    Choi JS Koh IU Jung MH Song J Effects of three different conjugated linoleic acid preparations on insulin signalling, fat oxidation and mitochondrial function in rats fed a high-fat dietBr J Nutr2007 98264275

    Not in our library10.1017/s000711450770497x

  48. 48.

    Wang H Knaub LA Jensen DR Young Jung D Hong EG Ko HJ Coates AM Goldberg IJ de la Houssaye BA Janssen RC McCurdy CE Rahman SM Soo Choi C Shulman GI Kim JK Friedman JE Eckel RH Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissuesDiabetes2009 58116124

    Not in our library10.2337/db07-1839

  49. 49.

    Liu L Yu S Khan RS Ables GP Bharadwaj KG Hu Y Huggins LA Eriksson JW Buckett LK Turnbull AV Ginsberg HN Blaner WS Huang LS Goldberg IJ DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscleJ Lipid Res2011 52732744

    Not in our library10.1194/jlr.m011395

  50. 50.

    Schmitz-Peiffer C Browne CL Oakes ND Watkinson A Chisholm DJ Kraegen EW Biden TJ Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the highfat-fed ratDiabetes1997 46169178

    Not in our library10.2337/diab.46.2.169

  51. 51.

    Samuel VT Petersen KF Shulman GI Lipid-induced insulin resistance: unravelling the mechanismLancet2010 37522672277

    Not in our library10.1016/s0140-6736(10)60408-4

  52. 52.

    Chavez JA Holland WL Bär J Sandhoff K Summers SA Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signalingJ Biol Chem2005 2802014820153

    Not in our library10.1074/jbc.m412769200

  53. 53.

    Hu W Bielawski J Samad F Merrill AH Jr Cowart LA Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activityJ Lipid Res2009 5018521862

    Not in our library10.1194/jlr.m800635-jlr200

  54. 54.

    Chavez JA Summers SA Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubesArch Biochem Biophys2003 419101109

    Not in our library10.1016/j.abb.2003.08.020

  55. 55.

    Summers SA Sphingolipids and insulin resistance: the five WsCurr Opin Lipidol2010 21128135

    Not in our library10.1097/mol.0b013e3283373b66

  56. 56.

    Holland WL Summers SA Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolismEndocr Rev2008 29381402

    Not in our library10.1210/er.2007-0025

  57. 57.

    Lipina C Hundal HS Sphingolipids: agents provocateurs in the pathogenesis of insulin resistanceDiabetologia2011 5415961607

    Not in our library10.1007/s00125-011-2127-3

  58. 58.

    Han MS Lim YM Quan W Kim JR Chung KW Kang M Kim S Park SY Han JS Park SY Cheon HG Dal Rhee S Park TS Lee MS Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistanceJ Lipid Res2011 5212341246

    Not in our library10.1194/jlr.m014787

  59. 59.

    Hotamisligil GS Inflammation and metabolic disordersNature2006 444860867

    Not in our library10.1038/nature05485

  60. 60.

    Håversen L Danielsson KN Fogelstrand L Wiklund O Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophagesAtherosclerosis2009 202382393

    Not in our library10.1016/j.atherosclerosis.2008.05.033

  61. 61.

    Wen H Gris D Lei Y Jha S Zhang L Huang MT Brickey WJ Ting JP Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signalingNat Immunol2011 12408415

    Not in our library10.1038/ni.2022

  62. 62.

    Hotamisligil GS Shargill NS Spiegelman BM Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistanceScience1993 2598791

    Not in our library10.1126/science.7678183

  63. 63.

    Hotamisligil GS Inflammation and endoplasmic reticulum stress in obesity and diabetesInt J Obes (Lond)2008 325254

    Not in our library10.1038/ijo.2008.238

  64. 64.

    Tsukumo DM Carvalho-Filho MA Carvalheira JB Prada PO Hirabara SM Schenka AA Araújo EP Vassallo J Curi R Velloso LA Saad MJ Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistanceDiabetes2007 5619861998

    Not in our library10.2337/db06-1595

  65. 65.

    Hirosumi J Tuncman G Chang L Görgün CZ Uysal KT Maeda K Karin M Hotamisligil GS A central role for JNK in obesity and insulin resistanceNature2002 420333336

    Not in our library10.1038/nature01137

  66. 66.

    Kaneto H Nakatani Y Kawamori D Miyatsuka T Matsuoka TA Matsuhisa M Yamasaki Y Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistanceInt J Biochem Cell Biol2006 38782793

    Not in our library10.1016/j.biocel.2006.01.004

  67. 67.

    Solinas G Naugler W Galimi F Lee MS Karin M Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substratesProc Natl Acad Sci USA2006 1031645416459

    Not in our library10.1073/pnas.0607626103

  68. 68.

    Coletta DK Mandarino LJ Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondriaAm J Physiol Endocrinol Metab2011 301749755

    Not in our library10.1152/ajpendo.00363.2011

  69. 69.

    Bunn RC Cockrell GE Ou Y Thrailkill KM Lumpkin CK Jr Fowlkes JL Palmitate and insulin synergistically induce IL-6 expression in human monocytesCardiovasc Diabetol2010 973

    Not in our library10.1186/1475-2840-9-73

  70. 70.

    Ji C Chen X Gao C Jiao L Wang J Xu G Fu H Guo X Zhao Y IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytesJ Bioenerg Biomembr2011 43367375

    Not in our library10.1007/s10863-011-9361-8

  71. 71.

    Yasuhara R Miyamoto Y Akaike T Akuta T Nakamura M Takami M Morimura N Yasu K Kamijo R Interleukin-1beta induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent mannerBiochem J2005 389315323

    Not in our library10.1042/bj20041996

  72. 72.

    Schmid GM Converset V Walter N Sennitt MV Leung KY Byers H Ward M Hochstrasser DF Cawthorne MA Sanchez JC Effect of high-fat diet on the expression of proteins in muscle, adipose tissues, and liver of C57BL/6 miceProteomics2004 422702282

    Not in our library10.1002/pmic.200300810

  73. 73.

    Xu J Han J Epstein PN Liu YQ Regulation of PDK mRNA by high fatty acid and glucose in pancreatic isletsBiochem Biophys Res Commun2006 344827833

    Not in our library10.1016/j.bbrc.2006.03.211

  74. 74.

    López IP Milagro FI Martí A Moreno-Aliaga MJ Martínez JA De Miguel C Gene expression changes in rat white adipose tissue after a high-fat diet determined by differential displayBiochem Biophys Res Commun2004 318234239

    Not in our library10.1016/j.bbrc.2004.04.018

  75. 75.

    Sparks LM Xie H Koza RA Mynatt R Hulver MW Bray GA Smith SR A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscleDiabetes2005 5419261933

    Not in our library10.2337/diabetes.54.7.1926

  76. 76.

    Petersen KF Dufour S Befroy D Garcia R Shulman GI Impaired mitochondrial activity in the insulin-resistant offspring of patientswith type 2 diabetesN Engl J Med2004 350664671

    Not in our library10.1056/nejmoa031314

  77. 77.

    Scarpulla RC Transcriptional paradigms in mammalian mitochondrial biogenesis and functionPhysiol Rev2008 88611638

    Not in our library10.1152/physrev.00025.2007

  78. 78.

    Evans RM Barish GD Wang YX PPARs and the complex journey to obesityNat Med2004 10355361

    Not in our library10.1038/nm1025

  79. 79.

    Puigserver P Wu Z Park CW Graves R Wright M Spiegelman BM A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesisCell1998 92829839

    Not in our library10.1016/s0092-8674(00)81410-5

  80. 80.

    Wu Z Puigserver P Andersson U Zhang C Adelmant G Mootha V Troy A Cinti S Lowell B Scarpulla RC Spiegelman BM Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1Cell1999 98115124

    Not in our library10.1016/s0092-8674(00)80611-x

  81. 81.

    Heilbronn LK Gan SK Turner N Campbell LV Chisholm DJ Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjectsJ Clin Endocrinol Metab2007 9214671473

    Not in our library10.1210/jc.2006-2210

  82. 82.

    Simoneau JA Kelley DE Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDMJ Appl Physiol1997 83166171

    Not in our library10.1152/jappl.1997.83.1.166

  83. 83.

    Hulver MW Berggren JR Cortright RN Dudek RW Thompson RP Pories WJ MacDonald KG Cline GW Shulman GI Dohm GL Houmard JA Skeletal muscle lipid metabolism with obesityAm J Physiol Endocrinol Metab2003 284741747

    Not in our library10.1152/ajpendo.00514.2002

  84. 84.

    Abdul-Ghani MA Muller FL Liu Y Chavez AO Balas B Zuo P Chang Z Tripathy D Jani R Molina-Carrion M Monroy A Folli F Van Remmen H DeFronzo RA Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistanceAm J Physiol Endocrinol Metab2008 295678685

    Not in our library10.1152/ajpendo.90287.2008

  85. 85.

    Bonnard C Durand A Peyrol S Chanseaume E Chauvin MA Morio B Vidal H Rieusset J Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant miceJ Clin Invest2008 118789800

    Not in our library10.1172/jci32601

  86. 86.

    Kumashiro N Tamura Y Uchida T Ogihara T Fujitani Y Hirose T Mochizuki H Kawamori R Watada H Impact of oxidative stress and peroxisome proliferator-activated receptor gamma coactivator-1alpha in hepatic insulin resistanceDiabetes2008 5720832091

    Not in our library10.2337/db08-0144

  87. 87.

    Rains JL Jain SK Oxidative stress, insulin signaling, and diabetesFree Radic Biol Med2011 50567575

    Not in our library10.1016/j.freeradbiomed.2010.12.006

  88. 88.

    Bashan N Kovsan J Kachko I Ovadia H Rudich A Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen speciesPhysiol Rev2009 892771

    Not in our library10.1152/physrev.00014.2008

  89. 89.

    Gomez-Mendikute A Cajaraville MP Comparative effects of cadmium, copper, paraquat and benzo[a]pyrene on the actin cytoskeleton and production of reactive oxygen species (ROS) in mussel haemocytesToxicol Vitr2003 17539546

    Not in our library10.1016/s0887-2333(03)00093-6

  90. 90.

    Haynes CM Titus EA Cooper AA Degradation of misfolded proteins prevents ER-derived oxidative stress and cell deathMolecular cell2004 15767776

    Not in our library10.1016/j.molcel.2004.08.025

  91. 91.

    He YY Hader DP UV-B-induced formation of reactive oxygen species and oxidative damage of the cyanobacterium Anabaena sp.: protective effects of ascorbic acid and N-acetyl-L-cysteineJ Photochem Photobiol B Biol2002 66115124

    Not in our library10.1016/s1011-1344(02)00231-2

  92. 92.

    Gutterman DD Miura H Liu Y Redox modulation of vascular tone: focus of potassium channel mechanisms of dilationArterioscler Thromb Vasc Biol2005 25671678

    Not in our library10.1161/01.atv.0000158497.09626.3b

  93. 93.

    Taddei ML Parri M Mello T Catalano A Levine AD Raugei G Ramponi G Chiarugi P Integrin-mediated cell adhesion and spreading engage different sources of reactive oxygen speciesAntioxid redox Signaling2007 9469481

    Not in our library10.1089/ars.2006.1392

  94. 94.

    Lee HC Wei YH Oxidative stress, mitochondrial DNA mutation, and apoptosis in agingExp Biol Med2007 232592606

    Not in our library

  95. 95.

    Madamanchi NR Vendrov A Runge MS Oxidative stress and vascular diseaseArterioscler Thromb Vasc Biol2005 252938

    Not in our library10.1161/01.atv.0000150649.39934.13

  96. 96.

    Morino K Petersen KF Dufour S Befroy D Frattini J Shatzkes N Neschen S White MF Bilz S Sono S Pypaert M Shulman GI Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parentsJ Clin Invest2005 11535873593

    Not in our library10.1172/jci25151

  97. 97.

    Duval C Cámara Y Hondares E Sibille B Villarroya F Overexpression of mitochondrial uncoupling protein-3 does not decrease production of the reactive oxygen species, elevated by palmitate in skeletal muscle cellsFEBS Lett2007 581955961

    Not in our library10.1016/j.febslet.2007.01.085

  98. 98.

    Lambertucci RH Hirabara SM Silveira L dos R Levada-Pires AC Curi R Pithon-Curi TC Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cellsJ Cell Physiol2008 216796804

    Not in our library10.1002/jcp.21463

  99. 99.
    Endotoxin mediated-iNOS induction causes insulin resistance via ONOO⁻ induced tyrosine nitration of IRS-1 in skeletal muscle. · 2010
    Not checked
  100. 100.

    Perreault M Marette A Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscleNat Med2001 711381143

    Not in our library10.1038/nm1001-1138

  101. 101.

    Dallaire P Bellmann K Laplante M Gélinas S Centeno-Baez C Penfornis P Peyot ML Latour MG Lamontagne J Trujillo ME Scherer PE Prentki M Deshaies Y Marette A Obese mice lacking inducible nitric oxide synthase are sensitized to the metabolic actions of peroxisome proliferator-activated receptor-gamma agonismDiabetes2008 5719992011

    Not in our library10.2337/db08-0540

  102. 102.

    Inoguchi T Li P Umeda F Yu HY Kakimoto M Imamura M Aoki T Etoh T Hashimoto T Naruse M Sano H Utsumi H Nawata H High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cellsDiabetes2000 4919391945

    Not in our library10.2337/diabetes.49.11.1939

  103. 103.

    Desco MC Asensi M Marquez R Martinez-Valls J Vento M Pallardo FV Sastre J Vina J Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinolDiabetes2002 5111181124

    Not in our library10.2337/diabetes.51.4.1118

  104. 104.

    Erdei N Toth A Pasztor ET Papp Z Edes I Koller A Bagi Z High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anionAm J Physiol Heart Circulatory Physiol2006 291H2107H2115

    Not in our library10.1152/ajpheart.00389.2006

  105. 105.

    Ogihara T Asano T Katagiri H Sakoda H Anai M Shojima N Ono H Fujishiro M Kushiyama A Fukushima Y Kikuchi M Noguchi N Aburatani H Gotoh Y Komuro I Fujita T Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinaseDiabetologia2004 47794805

    Not in our library10.1007/s00125-004-1391-x

  106. 106.

    Blouet C Mariotti F Mikogami T Tome D Huneau JF Meal cysteine improves postprandial glucose control in rats fed a high-sucrose mealJ Nutr Biochem2007 18519524

    Not in our library10.1016/j.jnutbio.2006.10.002

  107. 107.

    Maddux BA Goldfine ID Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunitDiabetes2000 491319

    Not in our library10.2337/diabetes.49.1.13

  108. 108.

    Haber CA Lam TK Yu Z Gupta N Goh T Bogdanovic E Giacca A Fantus IG N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stressAm J Physiol Endocrinol Metab2003 285744753

    Not in our library10.1152/ajpendo.00355.2002

  109. 109.

    Zhai L Ballinger SW Messina JL Role of reactive oxygen species in injury-induced insulin resistanceMol Endocrinol2011 25492502

    Not in our library10.1210/me.2010-0224

  110. 110.

    Maddux BA See W Lawrence JC Jr Goldfine AL Goldfine ID Evans JL Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acidDiabetes2001 50404410

    Not in our library10.2337/diabetes.50.2.404

  111. 111.

    Schrauwen P Hesselink MK Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetesDiabetes2004 5314121417

    Not in our library10.2337/diabetes.53.6.1412

  112. 112.

    Indo HP Davidson M Yen HC Suenaga S Tomita K Nishii T Higuchi M Koga Y Ozawa T Majima HJ Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damageMitochondrion2007 7106118

    Not in our library10.1016/j.mito.2006.11.026

  113. 113.

    Lowell BB Shulman GI Mitochondrial dysfunction and type 2 diabetesScience2005 307384387

    Not in our library10.1126/science.1104343

  114. 114.

    Rousset S Alves-Guerra MC Mozo J Miroux B Cassard-Doulcier AM Bouillaud F Ricquier D The biology of mitochondrial uncoupling proteinsDiabetes2004 53130135

    Not in our library10.2337/diabetes.53.2007.s130

  115. 115.

    Fisler JS Warden CH Uncoupling proteins, dietary fat and the metabolic syndromeNutr Metab (Lond)2006 338

    Not in our library10.1186/1743-7075-3-38

  116. 116.

    Joseph JW Koshkin V Zhang CY Wang J Lowell BB Chan CB Wheeler MB Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat dietDiabetes2002 5132113219

    Not in our library10.2337/diabetes.51.11.3211

  117. 117.

    Hesselink MK Greenhaff PL Constantin-Teodosiu D Hultman E Saris WH Nieuwlaat R Schaart G Kornips E Schrauwen P Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivoJ Clin Invest2003 111479486

    Not in our library10.1172/jci16653

  118. 118.

    Weigle DS Selfridge LE Schwartz MW Seeley RJ Cummings DE Havel PJ Kuijper JL BeltrandelRio H Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fastingDiabetes1998 47298302

    Not in our library10.2337/diab.47.2.298

  119. 119.

    Millet L Vidal H Andreelli F Larrouy D Riou JP Ricquier D Laville M Langin D Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humansJ Clin Invest1997 10026652670

    Not in our library10.1172/jci119811

  120. 120.

    Schrauwen P Hinderling V Hesselink MK Schaart G Kornips E Saris WH Westerterp-Plantenga M Langhans W Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporterFASEB J2002 1616881690

    Not in our library10.1096/fj.02-0275fje

  121. 121.

    Samec S Seydoux J Dulloo AG Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate?FASEB J1998 12715724

    Not in our library10.1096/fasebj.12.9.715

  122. 122.

    Hoeks J Hesselink MK Sluiter W Schaart G Willems J Morrisson A Clapham JC Saris WH Schrauwen P The effect of high-fat feeding on intramuscular lipid and lipid peroxidation levels in UCP3-ablated miceFEBS Lett2006 58013711375

    Not in our library10.1016/j.febslet.2006.01.059

  123. 123.

    Russell AP Gastaldi G Bobbioni-Harsch E Arboit P Gobelet C Dériaz O Golay A Witztum JL Giacobino JP Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids?FEBS Lett2003 551104106

    Not in our library10.1016/s0014-5793(03)00875-5

  124. 124.

    Schrauwen P Troost FJ Xia J Ravussin E Saris WH Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjectsInt J Obes Relat Metab Disord1999 23966972

    Not in our library10.1038/sj.ijo.0801026

  125. 125.

    Mingrone G Rosa G Greco AV Manco M Vega N Hesselink MK Castagneto M Schrauwen P Vidal H Decreased uncoupling protein expression and intramyocytic triglyceride depletion in formerly obese subjectsObes Res2003 11632640

    Not in our library10.1038/oby.2003.91

  126. 126.

    Hoeks J van Baak MA Hesselink MK Hul GB Vidal H Saris WH Schrauwen P Effect of beta1- and beta2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humansAm J Physiol Endocrinol Metab2003 285E775E782

    Not in our library10.1152/ajpendo.00175.2003

  127. 127.

    Samec S Seydoux J Dulloo AG Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs: is there a role for circulating free fatty acids?Diabetes1998 4716931698

    Not in our library10.2337/diabetes.47.11.1693

  128. 128.

    Echtay KS Esteves TC Pakay JL Jekabsons MB Lambert AJ Portero-Otín M Pamplona R Vidal-Puig AJ Wang S Roebuck SJ Brand MD A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncouplingEMBO J2003 2241034110

    Not in our library10.1093/emboj/cdg412

  129. 129.

    Nabben M Hoeks J Briedé JJ Glatz JF Moonen-Kornips E Hesselink MK Schrauwen P The effect of UCP3 overexpression on mitochondrial ROS production in skeletal muscle of young versus aged miceFEBS Lett2008 58241474152

    Not in our library10.1016/j.febslet.2008.11.016

  130. 130.

    Schrauwen P Schrauwen-Hinderling V Hoeks J Hesselink MK Mitochondrial dysfunction and lipotoxicityBiochim Biophys Acta2010 1801266271

    Not in our library10.1016/j.bbalip.2009.09.011

  131. 131.

    Holloway GP Thrush AB Heigenhauser GJ Tandon NN Dyck DJ Bonen A Spriet LL Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese womenAm J Physiol Endocrinol Metab2007 29217821789

    Not in our library10.1152/ajpendo.00639.2006

  132. 132.

    Schrauwen-Hinderling VB Kooi ME Hesselink MK Jeneson JA Backes WH van Echteld CJ van Engelshoven JM Mensink M Schrauwen P Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjectsDiabetologia2007 50113120

    Not in our library10.1007/s00125-006-0475-1

  133. 133.

    Ukropcova B McNeil M Sereda O de Jonge L Xie H Bray GA Smith SR Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donorJ Clin Invest2005 11519341941

    Not in our library10.1172/jci24332

  134. 134.

    Lim S Park KS Kim MS Cho BY Lee HK Relationship between various surrogate indices of insulin resistance and mitochondrial DNA content in the peripheral blood of 18 healthy volunteersMitochondrion2001 17177

    Not in our library10.1016/s1567-7249(01)00003-4

  135. 135.

    Guo LJ Oshida Y Fuku N Takeyasu T Fujita Y Kurata M Sato Y Ito M Tanaka M Mitochondrial genome polymorphisms associated with type-2 diabetes or obesityMitochondrion2005 51533

    Not in our library10.1016/j.mito.2004.09.001

  136. 136.

    Juo SHH Lu MY Bai RK Liao YC Trieu RB Yu ML Wong LJC A common mitochondrial polymorphism 10398A > G is associated metabolic syndrome in a Chinese populationMitochondrion2010 10294299

    Not in our library10.1016/j.mito.2010.01.001

  137. 137.

    Wallace DC Fan W Energetics, epigenetics, mitochondrial geneticsMitochondrion2010 101231

    Not in our library10.1016/j.mito.2009.09.006

  138. 138.

    Chanseaume E Malpuech-Brugère C Patrac V Bielicki G Rousset P Couturier K Salles J Renou JP Boirie Y Morio B Diets high in sugar, fat, and energy induce muscle typespecific adaptations in mitochondrial functions in ratsJ Nutr2006 13621942200

    Not in our library10.1093/jn/136.8.2194

  139. 139.

    Szendroedi J Schmid AI Meyerspeer M Cervin C Kacerovsky M Smekal G Graser-Lang S Groop L Roden M Impaired mitochondrial function and insulin resistance of skeletal muscle in mitochondrial diabetesDiabetes Care2009 32677679

    Not in our library10.2337/dc08-2078

  140. 140.

    Coll T Jové M Rodríguez-Calvo R Eyre E Palomer X Sánchez RM Merlos M Laguna JC Vázquez-Carrera M Palmitate-mediated downregulation of peroxisome proliferator-activated receptorgamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activationDiabetes2006 5527792787

    Not in our library10.2337/db05-1494

  141. 141.

    Pimenta AS Gaidhu MP Habib S So M Fediuc S Mirpourian M Musheev M Curi R Ceddia RB Prolonged exposure to palmitate impairs fatty acid oxidation despite activation of AMP-activated protein kinase in skeletal muscle cellsJ Cell Physiol2008 217478485

    Not in our library10.1002/jcp.21520

  142. 142.

    Jove M Laguna JC Vázquez-Carrera M Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cellsBiochim Biophys Acta2005 17345261

    Not in our library10.1016/j.bbalip.2005.02.002

  143. 143.

    Bloch-Damti A Potashnik R Gual P Le Marchand-Brustel Y Tanti JF Rudich A Bashan N Differential effects of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stressDiabetologia2006 4924632473

    Not in our library10.1007/s00125-006-0349-6

  144. 144.

    Watt MJ Steinberg GR Chen ZP Kemp BE Febbraio MA Fatty acids stimulate AMP-activated protein kinase and enhance fatty acid oxidation in L6 myotubesJ Physiol2006 574139147

    Not in our library10.1113/jphysiol.2006.107318

  145. 145.

    Krebs M Roden M Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculatureDiabetes Obes Metab2005 7621632

    Not in our library10.1111/j.1463-1326.2004.00439.x

  146. 146.

    Talukdar I Szeszel-Fedorowicz W Salati LM Arachidonic acid inhibits the insulin induction of glucose-6-phosphate dehydrogenase via p38 MAP kinaseJ Biol Chem2005 2804066040667

    Not in our library10.1074/jbc.m505531200

Cited by papers we hold 3

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.