scholarly journals The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

2016 ◽  
Vol 40 (5) ◽  
pp. 1207-1220 ◽  
Author(s):  
Agnieszka U. Blachnio-Zabielska ◽  
Marta Chacinska ◽  
Mikkel H. Vendelbo ◽  
Piotr Zabielski
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
De Novo ◽  
Synthesis Rate ◽  
Standard Diet ◽  
Bioactive Lipids ◽  
Skeletal Muscle Insulin Resistance ◽  
Lipid Species

Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U13C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

scholarly journals Effect of metformin on bioactive lipid metabolism in insulin-resistant muscle

2017 ◽  
Vol 233 (3) ◽  
pp. 329-340 ◽  
Author(s):  
Piotr Zabielski ◽  
Marta Chacinska ◽  
Karol Charkiewicz ◽  
Marcin Baranowski ◽  
Jan Gorski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Acyl Chain ◽  
Principal Component ◽  
Synthesis Rate ◽  
Bioactive Lipids ◽  
Insulin Resistant ◽  
Isotope Tracer ◽  
Lipid Species

Intramuscular accumulation of bioactive lipids leads to insulin resistance and type 2 diabetes (T2D). There is lack of consensus concerning which of the lipid mediators has the greatest impact on muscle insulin action in vivo. Our aim was to elucidate the effects of high-fat diet (HFD) and metformin (Met) on skeletal muscle bioactive lipid accumulation and insulin resistance (IR) in rats. We employed a [U-13C]palmitate isotope tracer and mass spectrometry to measure the content and fractional synthesis rate (FSR) of intramuscular long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Eight weeks of HFD-induced intramuscular accumulation of LCACoA, DAG and Cer accompanied by both systemic and skeletal muscle IR. Metformin treatment improved insulin sensitivity at both systemic and muscular level by the augmentation of Akt/PKB and AS160 phosphorylation and decreased the content of DAG and Cer and their respective FSR. Principal component analysis (PCA) of lipid variables revealed that altered skeletal muscle IR was associated with lipid species containing 18-carbon acyl-chain, especially with C18:0-Cer, C18:1-Cer, 18:0/18:2-DAG and 18:2/18:2-DAG, but not palmitate-derived lipids. It is concluded that the insulin-sensitizing action of metformin in skeletal muscle is associated with decreased 18-carbon acyl-chain-derived bioactive lipids.

scholarly journals Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

2020 ◽  
Vol 21 (17) ◽  
pp. 6358 ◽  
Author(s):  
Benjamin Lair ◽  
Claire Laurens ◽  
Bram Van Den Bosch ◽  
Cedric Moro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Acyl Chain ◽  
The Body ◽  
Glucose Disposal ◽  
Tissue Lipid ◽  
Lipid Species ◽  
Chain Composition

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

scholarly journals Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides

2020 ◽  
Vol 21 (4) ◽  
pp. 1514 ◽  
Author(s):  
Paul T. Reidy ◽  
Ziad S. Mahmassani ◽  
Alec I. McKenzie ◽  
Jonathan J. Petrocelli ◽  
Scott A. Summers ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Muscle Contraction ◽  
Contractile Activity ◽  
Skeletal Muscle Insulin Resistance ◽  
Ceramide Content ◽  
Subcellular Compartmentalization ◽  
Skeletal Muscle Insulin Sensitivity

Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity.

scholarly journals The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

2009 ◽  
Vol 31 (1) ◽  
pp. 25-51 ◽  
Author(s):  
Ines Pagel-Langenickel ◽  
Jianjun Bao ◽  
Liyan Pang ◽  
Michael N. Sack
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

scholarly journals Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

2017 ◽  
Vol 233 (1) ◽  
pp. R15-R42 ◽  
Author(s):  
Sergio Di Meo ◽  
Susanna Iossa ◽  
Paola Venditti
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Early Event ◽  
Ros Production ◽  
Obese People ◽  
Skeletal Muscle Insulin Resistance ◽  
Mitochondrial Alterations

At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to ‘toxic’ lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

scholarly journals Skeletal muscle ceramides do not contribute to physical inactivity-induced insulin resistance

2018 ◽  
Author(s):  
Zephyra Appriou ◽  
Kevin Nay ◽  
Nicolas Pierre ◽  
Dany Saligaut ◽  
Luz Lefeuvre-Orfila ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Physical Inactivity ◽  
De Novo ◽  
Akt Phosphorylation ◽  
Develop Type ◽  
Inflammatory State ◽  
Ceramide Content

Physical inactivity increases the risk to develop type 2 diabetes, a disease characterized by a state of insulin resistance. By promoting inflammatory state, ceramides are especially recognized to alter insulin sensitivity in skeletal muscle. The present study was designed to analyze, in mice, whether muscle ceramides contribute to physical inactivity-induced insulin resistance. For this purpose, we used the wheel lock model to induce a sudden reduction of physical activity, in combination with myriocin treatment, an inhibitor of de novo ceramide synthesis. Mice were assigned to 3 experimental groups: voluntary wheel access group (Active), a wheel lock group (Inactive) and wheel lock group treated with myriocin (Inactive-Myr). We observed that 10 days of physical inactivity induces hyperinsulinemia and increase HOMA-IR. The muscle ceramide content were not modified by physical inactivity and myriocin. Thus, muscle ceramides do not play a role in physical inactivity-induced insulin resistance. In skeletal muscle, insulin-stimulated Akt phosphorylation and inflammatory pathway were not affected by physical inactivity whereas a reduction of GLUT4 content was observed. Based on these results, physical inactivity-induced insulin resistance seems related to a reduction in GLUT4 content rather than defects in insulin signaling. We observed in inactive mice that myriocin treatment improved glucose tolerance, insulin-stimulated Akt, AMPK activation and GLUT4 content in skeletal muscle. Such effects occur regardless of changes in muscle ceramide content. These findings highlight that myriocin could be a promising drug to improve glucose tolerance and insulin sensitivity.

scholarly journals Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes

Diabetes ◽  
2000 ◽  
Vol 49 (2) ◽  
pp. 263-271 ◽  
Author(s):  
S. E. Nikoulina ◽  
T. P. Ciaraldi ◽  
S. Mudaliar ◽  
P. Mohideen ◽  
L. Carter ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Potential Role ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance
Sign in / Sign up

Export Citation Format

Share Document