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 A PIP3phosphatase SKIP links endoplasmic reticulum stress in skeletal muscle to insulin resistance

2015 ◽  
pp. MCB.00921-15 ◽  
Author(s):  
Takeshi Ijuin ◽  
Tetsuya Hosooka ◽  
Tadaomi Takenawa
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Glucose Disposal ◽  
Inositol Polyphosphate ◽  
Insulin Dependent ◽  
Activating Transcription Factor

Insulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin dependent-glucose disposal, it is unclear if ER stress in those tissue contributes to insulin resistance. In this study, we show that skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress, and was higher in the skeletal muscle isolated from high fat diet-fed mice anddb/dbmice than that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.

scholarly journals Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

2020 ◽  
Vol 21 (16) ◽  
pp. 5738
Author(s):  
Xiong Weng ◽  
De Lin ◽  
Jeffrey T. J. Huang ◽  
Roland H. Stimson ◽  
David H. Wasserman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Resistant ◽  
Global View ◽  
Novel Association ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.

Abstract 1185: Role Of Sphingosine-1-Phosphate (S1P) In Insulin Signaling.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Suzanne M Nicholl ◽  
Elisa Roztocil ◽  
Mark G Davies
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Receptor Expression ◽  
Serine Phosphorylation ◽  
Glucose Disposal ◽  
Sphingosine 1 Phosphate ◽  
Low Glucose

A failure to increase glucose disposal into peripheral tissues in response to insulin leads to impaired insulin signaling and an inability to uptake glucose leading to the onset of insulin resistance, a major contributing factor to diabetes. We examined the role of sphingosine-1-phosphate (S1P) in insulin signaling and its ability to regulate glucose uptake in skeletal muscle cells. S1P, a sphingolipid found in abundance in the circulation, has been implicated in not only mediating crosstalk with other signaling pathways but has also been implicated in insulin resistance. We hypothesize that S1P interacts with post-receptor insulin signaling to increase glucose disposal in an in vitro model of insulin resistance using differentiated mouse skeletal C2C12 myotubes. Our data demonstrates that S1P (10μM) increases basal glucose levels similar to that observed in response to insulin (100nM) under conditions of low glucose (** p < 0.005: n = 3). Conversely, high glucose conditions completely inhibit both insulin and S1P stimulated glucose uptake (*p < 0.01:n = 3). Pre-incubation with S1P does not augment insulin-induced glucose uptake (***p < 0.001:n = 3), suggesting that S1P does not act via a separate signaling pathway. This is confirmed by our data demonstrating that S1P-induced glucose uptake is abrogated by Cytochalasin B (*p < 0.001:n = 3). In addition, the PI3-K inhibitors, LY294002 and Wortmannin, the Akt inhibitor, AKT2 and the p38MAPK inhibitor, SB203580 significantly inhibited glucose uptake in response to S1P, demonstrating their importance in S1P-induced glucose uptake (*p < 0.05:n = 3). S1P2 and S1P3 receptor expression were upregulated in response to insulin (~2-fold over basal) under low glucose conditions suggesting that insulin may regulate S1P signaling via one or both of these receptors. S1P increased serine phosphorylation of IRS1, both at serine 307 and serines 636/639 maximally after 15 minutes of stimulation. This data has important clinical implications in patients with metabolic syndrome who have impaired skeletal muscle glucose disposal due to insulin resistance and will help guide present and future therapy for patients who have this rapidly growing disease.

scholarly journals The influence of sleep and sleep loss upon food intake and metabolism

2007 ◽  
Vol 20 (2) ◽  
pp. 195-212 ◽  
Author(s):  
Cibele Aparecida Crispim ◽  
Ioná Zalcman ◽  
Murilo Dáttilo ◽  
Heloisa Guarita Padilha ◽  
Ben Edwards ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Feedback Regulation ◽  
Modern Society ◽  
Blood Lipid ◽  
Sleep Time ◽  
Sleep Loss ◽  
The Body ◽  
Negative Feedback Regulation

The present review investigates the role of sleep and its alteration in triggering metabolic disorders. The reduction of the amount of time sleeping has become an endemic condition in modern society and the current literature has found important associations between sleep loss and alterations in nutritional and metabolic aspects. Studies suggest that individuals who sleep less have a higher probability of becoming obese. It can be related to the increase of ghrelin and decrease of leptin levels, generating an increase of appetite and hunger. Sleep loss has been closely associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and diabetes, and this disturbance may reflect decreased efficacy of the negative-feedback regulation of the hypothalamic–pituitary–adrenal axis. The period of sleep is also associated with an increase of blood lipid concentrations, which can be intensified under conditions of reduced sleep time, leading to disorders in fat metabolism. Based on a review of the literature, we conclude that sleep loss represents an important risk factor for weight gain, insulin resistance, type 2 diabetes and dyslipidaemia. Therefore, an adequate sleep pattern is fundamental for the nutritional balance of the body and should be encouraged by professionals in the area.

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 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 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 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

scholarly journals ROLE OF VIKARVIGHATBHAVA AND VIKARVIGHATABHAVA IN MANIFESTATION OF DIABETES

2019 ◽  
Vol 7 (01) ◽  
Author(s):  
Namrata Goray ◽  
Dr. Maheshkumar Harit ◽  
Vd.Vinay Pawar
Keyword(s):  
Insulin Resistance ◽  
Ecological Factors ◽  
The Body ◽  
Exercise Regime ◽  
Daily Exercise ◽  
Diet And Exercise ◽  
Strict Diet ◽  
Sedentary Life Style

Abstract: Background: The consequence of variation in ecological factors, intensity of the morbid humors and susceptibility of the body elements influences suppression or incidence of the disease by Vikar vighat bhava and Vikar vighat abhava respectively. Owing to the occurrence of pathological changes, along with vitiation of morbific factor like, increased kleda (excessive fluidity) and shithilata (diminished viscous essential) and due to frequent indulgent etiological factors, the body fluid, combined with humors and adipose tissue, acquires the pathological character of Prameha(diabetes). Objective: The present study was done to conceptualize the role of Vikar vighat bhava and Vikar vighat abhava in resistance and development respectively, of Prameha with all its symptoms. Methods: Conceptual literary search done by referring literature on exercise, Ayurveda texts, and research papers from peer-reviewed journals to explore the role of Vikar vighat bhava and Vikar vighat abhava in manifestation and therapy of Prameha. Result: The vikar vighat abhava like avoidance of exercise, swapnasukha (sleeping for long hours), asyasukha (sedentary life style) and kaphakar aahar (diet increasing and vitiating kapha) leads Aghnimandya (decreased digestive power and metabolism) which is the reason for obesity, hyperlipidemia and development of insulin resistance. Whereas Vikar vighat bhava like losing weight, optimal diet and exercise regime, helps to reduce insulin resistance and prediabetes, thus preventing or delaying type 2 diabetes. Conclusion: The Vikar vighat bhava like strict diet i.e Ystvaharam sharirasyadhatusamyakarm and daily exercise i.e sevate vividhanschy anyacheshtah can keep check on the diabetes. The dietary and exercise regime along with increase in immunity will help more in pre diabetic conditions. Key words: Vikar vighat bhava, vikar vighat abhava, prameha.

Sign in / Sign up

Export Citation Format

Share Document