scholarly journals Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

2015 ◽  
Vol 35 (2) ◽  
pp. 541-552 ◽  
Author(s):  
Thomas K. Sin ◽  
Benjamin Y. Yung ◽  
Parco M. Siu
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Pyruvate Dehydrogenase ◽  
Glycolytic Enzyme ◽  
Negative Regulator ◽  
Sirtuin 1 ◽  
Diabetic Patients ◽  
Muscle Aging

Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH). In contrast, how aging would regulate acetylation/deacetylation machineries and glucose utilization in skeletal muscle through the Foxo1/PDH axis remains largely undetermined. Accumulating body of evidence have shown that resveratrol, a natural polyphenol in grapes and red wine, activates the longevity-related protein sirtuin 1 (SIRT1) and augments insulin sensitivity in addition to its well-documented effects on mitochondrial energetics. The present review summarizes the role of Foxo1/SIRT1 in insulin signaling in skeletal muscle and proposes the insight that activation of SIRT1 deacetylase activity to deacetylate and suppress the Foxo1-induced transactivation of PDK4 may represent an anti-hyperglycemic mechanism of resveratrol in aging skeletal muscle.

scholarly journals CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2259-2269 ◽  
Author(s):  
Jun Liu ◽  
Ben Zhou ◽  
Menghong Yan ◽  
Rui Huang ◽  
Yuangao Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Sirtuin 1 ◽  
C2c12 Myotubes ◽  
Constant Darkness ◽  
Circadian Misalignment ◽  
Mouse Skeletal Muscle

Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of ClockΔ19/Δ19 mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.

scholarly journals Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1αin Skeletal Muscle

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Fengxia Liang ◽  
Rui Chen ◽  
Atsushi Nakagawa ◽  
Makoto Nishizawa ◽  
Shinichi Tsuda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Fasting Blood Glucose ◽  
Low Frequency ◽  
Tolerance Test ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obesity And Diabetes

Electroacupuncture (EA) has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1) and induced gene expression of peroxisome proliferator-activated receptor coactivator (PGC-), nuclear respiratory factor 1 (NRF1), and acyl-CoA oxidase (ACOX). These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-, thus resulting in improved insulin signal.

scholarly journals Placental Restriction Reduces Insulin Sensitivity and Expression of Insulin Signaling and Glucose Transporter Genes in Skeletal Muscle, But Not Liver, in Young Sheep

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2142-2151 ◽  
Author(s):  
Miles J. De Blasio ◽  
Kathryn L. Gatford ◽  
M. Lyn Harland ◽  
Jeffrey S. Robinson ◽  
Julie A. Owens
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Postnatal Growth ◽  
Whole Body ◽  
Poor Growth ◽  
Hepatic Expression ◽  
Metabolic Genes

Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (−43%, P < 0.001) and skeletal muscle expression of INSR (−36%), IRS1 (−28%), AKT2 (−44%), GLUT4 (−88%), GSK3α (−35%), and GYS1 (−31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.

scholarly journals Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation

2009 ◽  
Vol 297 (1) ◽  
pp. E67-E75 ◽  
Author(s):  
Andrew J. Hoy ◽  
Amanda E. Brandon ◽  
Nigel Turner ◽  
Matthew J. Watt ◽  
Clinton R. Bruce ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Synthesis ◽  
Pyruvate Dehydrogenase Kinase ◽  
Cumulative Exposure ◽  
Synthesis Rate ◽  
Lipid Infusion

Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (∼300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.

P734Research on the mechamism of renal sympathetic denervation in the treatment of insulin resistance

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Xu ◽  
C Lu
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Sham Group ◽  
Sympathetic Denervation ◽  
Renal Sympathetic Denervation ◽  
Control Group ◽  
Diabetic Patients ◽  
Renal Sympathetic

Abstract Background Insulin resistance is the main pathogenesis of type 2 diabetes. In order to better control the blood glucose of diabetic patients, the key is to improve the insulin sensitivity. With the in-depth study on the mechanism of insulin resistance, sympathetic nerve is an important part of it, but the specific mechanism is not clear. Objective This experiment aims to observe the effects of RDN on insulin resistance and skeletal muscle mitochondrial function in spontaneous diabetes ZDF rats. Methods 6 SPF healthy male ZDF (fa/+) rats were selected as control group, 12 healthy males ZDF (fa/fa) rats were randomly divided into sham group and RDN group. In the sham group and RDN group, the rats were treated with sham operation or bilateral renal sympathetic denervation respectively. Insulin sensitivity was tested in all rats with Hyperinsulinemic-euglycemic clamp test 2 weeks after RDN. The skeletal muscle ATPsyn, COXIV, UCP3 and SOD2 were tested by Western-blot method. Results The result showed that 2 weeks after RDN, the blood glucose level of the RDN group decreased significantly (P=0.000) when compared with the sham group. The glucose infusion rate (GIR) in sham and RDN group decreased significantly when compared with the control group (P=0.000). After RDN, the GIR in RDN group increased significantly. ATPsyn, COXIV which were the key enzyme of oxidative metabolism in skeletal muscle mitochondria decreased significantly in the sham and RDN group when compared with control group (P=0.001). However, parameters improved dramatically after RDN (P=0.001). Table 1. Comparision of Baseline in each group 2 weeks after RDN Control (n=6) Sham (n=6) RDN (n=6) Pa Pb Pc Weight (g) 311.1±8.5 410.8±10.7 377.9±15.3 0.000 0.001 0.002 BBG (mmol/L) 5.97±0.16 21.42±1.45 7.91±0.54 0.000 0.001 0.000 BISN (ng/mL) 100.67±4.18 162.17±3.13 134.67±2.50 0.000 0.001 0.001 TG (mmol/L) 2.71±0.28 6.90±0.24 4.88±0.23 0.000 0.001 0.002 TC (mmol/L) 2.38±0.17 6.98±0.15 5.40±0.09 0.000 0.000 0.000 HDL-C (mmol/L) 7.92±0.44 2.95±0.22 5.35±0.19 0.000 0.000 0.000 LDL-C (mmol/L) 3.72±0.37 4.12±0.17 3.98±0.17 0.001 0.000 0.000 aCompared with Control Group and Sham Group. bCompared with RDN Group and Sham Group. cCompared with Sham Group and RDN Group. Relative results Conclusion Our results showed that RDN improved the insulin sensitivity in diabetes rats. The mechanism may be related to the decrease of oxidative stress and function improvement in skeletal muscle mitochondrial by RDN.

scholarly journals The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

2021 ◽  
Vol 46 (6) ◽  
pp. 1350-1358
Author(s):  
Fruzsina Bagaméry ◽  
Kamilla Varga ◽  
Kitti Kecsmár ◽  
István Vincze ◽  
Éva Szökő ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Metabolism ◽  
Relative Significance ◽  
Differentiated Cells ◽  
Mature Neuron ◽  
The Right ◽  
The Impact

AbstractRecently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

scholarly journals SAT0111 THE RELATIONSHIP BETWEEN THE ADMINISTRATION OF IL-6 INHIBITORS AND INSULIN RESISTANCE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 989.3-989
Author(s):  
A. Jitaru ◽  
C. Pomirleanu ◽  
M. M. Leon-Constantin ◽  
F. Mitu ◽  
C. Ancuta
Keyword(s):  
Rheumatoid Arthritis ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Beneficial Effect ◽  
Disease Activity ◽  
Interleukin 6 ◽  
Normal Weight ◽  
Diabetic Patients ◽  
Model Assessment ◽  
Inflammatory Status

Background:Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, due not only to the traditional risk factors (hypertension, insulin resistance/diabetes, obesity, smoking), but to the inflammatory status as well. The blockade of interleukin-6 (IL-6) can regulate the glucose metabolism, reducing the glucose level and insulin resistance (IR). This beneficial effect is seen more in patients with normal values of body mass index (BMI), compared to the obese population.Objectives:Given the mentioned existing data, we aim to demonstrate the positive effect of IL-6 inhibitors in active RA patients with normal or increased BMI.Methods:We recruited 56 consecutive patients with definite and active RA, non-responders/partial responders to conventional synthetic Drug Modifying Anti-Rheumatic Drugs (csDMARDs)/biological therapy. For a period of 52 weeks, patients received subcutaneous Tocilizumab (TCZ) in a dose of 162mg once a week, according to European League Anti Rheumatism (EULAR) recommendation and National Protocol. We assessed demographics, RA-related parameters (clinical, inflammatory and immune) and metabolic markers, as well as the peripheral response to insulin, quantified by Homeostasis Model Assessment for insulin resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI). We did not include in the study the patients known with diabetes mellitus (DM) and those undergoing glucocorticoids.Results:After 52 weeks of treatment, most of the patients showed a statistically significant reduction of HOMA-IR (3.61 ± 1.21 at the onset vs. 2.45 ± 1.46 at the end of the study, p<0.001), while QUICKI registered a slight increase (0.32 ± 0.01 at the onset vs. 0.33 ± 0.01 at the end of the study, p<0.001). Also, the decrease in insulin and glucose levels were more obvious in patients with normal BMI, strictly related to disease activity.Conclusion:Long-term administration of TCZ in active RA is associated with a significant reduction of disease activity and IR, especially in normal weight patients. This confirms that obesity, as a CV risk factor, represents one of the main causes of IR.References:[1]Castañeda S, Remuzgo-Martínez S, López-Mejías R et al. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis.Clin Exp Rheumatol. 2019; 37(3):465-473.[2]Lehrskov LL, Christensen RH. The role of interleukin-6 in glucose homeostasis and lipid metabolism.Semin Immunopathol. 2019; 41(4):491-499.[3]Ursini F, Russo E, Ruscitti P, Giacomelli R, De Sarro G. The effect of non-TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis.Autoimmun Rev. 2018 Apr;17(4):399-404.Disclosure of Interests:Alexandra Jitaru: None declared, Cristina Pomirleanu: None declared, Maria-Magdalena Leon-Constantin: None declared, Florin Mitu: None declared, CODRINA ANCUTA Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly, Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly

scholarly journals Effect of carvedilol versus nebivolol on insulin resistance among non-diabetic, non-ischemic cardiomyopathy with heart failure

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Yasser Gaber Metwally ◽  
Heba Kamal Sedrak ◽  
Inass Fahiem Shaltout
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Ischemic Cardiomyopathy ◽  
Diabetic Patients ◽  
Promising Strategy ◽  
Improve Insulin Resistance ◽  
First Choice ◽  
The Difference

Abstract Background Although B-blockers provide unequivocal benefits in heart failure (HF) management, some B-blockers worsen insulin resistance. It will be a promising strategy to recruit such a B blocker that did not worsen or can even improve insulin resistance (IR). So, this study aimed to assess the effect of two of the third-generation B-blockers (carvedilol versus nebivolol) on insulin sensitivity state in non-diabetic patients with non-ischemic cardiomyopathy with heart failure. Results Out of 43 patients enrolled, 58.1% represented the carvedilol group while 41.9% represented the nebivolol group. Nebivolol improves insulin resistance-related variables (fasting glucose, fasting insulin, and HOMA-IR; P < 0.001, 0.01, and 0.01 respectively). The percentage of change at homeostasis model of assessment (HOMA-IR), indicative of insulin sensitivity status, between baseline versus at 3-months follow-up level of intra-group comparison was increased by 4.58% in the carvedilol arm whereas it was decreased by 11.67% in the nebivolol arm, and the difference on the intragroup level of comparison was significant (P < 0.001 and 0.01 respectively). Conclusion Nebivolol improves insulin resistance-related variables .Nebivolol may be recommended as the B blocker of the first choice for those with non-ischemic cardiomyopathy heart failure with evident insulin resistance; however, larger scaled prospective multicenter randomized trials are needed for confirming our favorable results.

scholarly journals Exercise, heat shock proteins and insulin resistance

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160529 ◽  
Author(s):  
Ashley E. Archer ◽  
Alex T. Von Schulze ◽  
Paige C. Geiger
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Metabolic Effects ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Exercise Induced ◽  
Shock Proteins

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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