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Peter Schjerling - One of the best experts on this subject based on the ideXlab platform.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
The Journal of Physiology, 2020Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:KEY POINTS Muscle-specific genetic ablation of p21-activated kinase (PAK)2, but not whole-body PAK1 knockout, impairs Glucose tolerance in mice. Insulin-stimulated Glucose Uptake partly relies on PAK2 in glycolytic extensor digitorum longus muscle By contrast to previous reports, PAK1 is dispensable for insulin-stimulated Glucose Uptake in mouse muscle. ABSTRACT The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated Glucose transporter 4 translocation in mouse skeletal muscle. Therefore, the present study aimed to examine the role of PAK1 in insulin-stimulated muscle Glucose Uptake. The pharmacological inhibitor of group I PAKs, IPA-3 partially reduced (-20%) insulin-stimulated Glucose Uptake in isolated mouse soleus muscle (P < 0.001). However, because there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 KO and in mice with combined whole-body PAK1 KO and muscle-specific PAK2 KO. By contrast, Glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle, insulin-stimulated Glucose Uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (-18%) or in combination with PAK1 KO (-12%) (P < 0.05). In conclusion, Glucose tolerance and insulin-stimulated Glucose Uptake partly rely on PAK2 in glycolytic mouse muscle, whereas PAK1 is dispensable for whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
bioRxiv, 2019Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:Abstract Objective Skeletal muscle Glucose Uptake is essential for maintaining whole-body Glucose homeostasis and accounts for the majority of Glucose disposal in response to insulin. The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle. Interestingly, PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle and PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation. However, the relative contribution of PAK1 and PAK2 to insulin-stimulated Glucose Uptake in mature skeletal muscle is unresolved. The aim of the present investigation was to determine the requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle. Methods Glucose Uptake was measured in isolated skeletal muscle incubated with a pharmacological inhibitor (IPA-3) of group I PAKs and in muscle from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results The whole-body respiratory exchange ratio was largely unaffected by lack of PAK1 and/or PAK2. Whole-body Glucose tolerance was mildly impaired in PAK2 mKO, but not PAK1 KO mice. IPA-3 partially reduced (−20%) insulin-stimulated Glucose Uptake in mouse soleus muscle. In contrast to a previous study of GLUT4 translocation in PAK1 KO mice, PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle. On the contrary, Glucose Uptake was slightly reduced in response to insulin in glycolytic extensor digitorum longus muscle lacking PAK2, alone (−18%) or in combination with PAK1 KO (−12%). Conclusions Insulin-stimulated Glucose Uptake partly relies on PAK2, but not PAK1, in mouse skeletal muscle. Thus, the present study challenges that group I PAKs, and especially PAK1, are major regulators of whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle.
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rac1 governs exercise stimulated Glucose Uptake in skeletal muscle through regulation of glut4 translocation in mice
The Journal of Physiology, 2016Co-Authors: Lykke Sylow, Lisbeth L V Moller, Peter Schjerling, Thomas E Jensen, Maximilian Kleinert, Amira Klip, Ida L Nielsen, Thorkil Ploug, Philip J Bilan, Erik A RichterAbstract:Key point Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is Glucose taken up from the blood. The GTPase Rac1 can be activated by muscle contraction and has been found to be necessary for insulin-stimulated Glucose Uptake, although its role in exercise-stimulated Glucose Uptake is unknown. We show that Rac1 regulates the translocation of the Glucose transporter GLUT4 to the plasma membrane in skeletal muscle during exercise. We find that Rac1 knockout mice display significantly reduced Glucose Uptake in skeletal muscle during exercise. Abstract Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is Glucose taken up from the blood. Despite extensive efforts, the signalling mechanisms vital for Glucose Uptake during exercise are not yet fully understood, although the GTPase Rac1 is a candidate molecule. The present study investigated the role of Rac1 in muscle Glucose Uptake and substrate utilization during treadmill exercise in mice in vivo. Exercise-induced Uptake of radiolabelled 2-deoxyGlucose at 65% of maximum running capacity was blocked in soleus muscle and decreased by 80% and 60% in gastrocnemius and tibialis anterior muscles, respectively, in muscle-specific inducible Rac1 knockout (mKO) mice compared to wild-type littermates. By developing an assay to quantify endogenous GLUT4 translocation, we observed that GLUT4 content at the sarcolemma in response to exercise was reduced in Rac1 mKO muscle. Our findings implicate Rac1 as a regulatory element critical for controlling Glucose Uptake during exercise via regulation of GLUT4 translocation.
Laurie J Goodyear - One of the best experts on this subject based on the ideXlab platform.
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exercise and type 2 diabetes molecular mechanisms regulating Glucose Uptake in skeletal muscle
Advances in Physiology Education, 2014Co-Authors: Kristin I Stanford, Laurie J GoodyearAbstract:Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle Glucose Uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of Glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase Glucose Uptake in skeletal muscle.
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stretch stimulated Glucose Uptake in skeletal muscle is mediated by reactive oxygen species and p38 map kinase
The Journal of Physiology, 2009Co-Authors: Melissa A Chambers, Laurie J Goodyear, Jennifer S Moylan, Jeffrey D Smith, Michael B ReidAbstract:Alternatives to the canonical insulin-stimulated pathway for Glucose Uptake are exercise- and exogenous reactive oxygen species (ROS)-stimulated Glucose Uptake. We proposed a model wherein mechanical loading, i.e. stretch, stimulates production of ROS to activate AMP-activated kinase (AMPK) to increase Glucose Uptake. Immunoblotting was used to measure protein phosphorylation; the fluorochrome probe 2′7′-dichlorofluorescin diacetate was used to measure cytosolic oxidant activity and 2-deoxy-d[1,2-3H]Glucose was used to measure Glucose Uptake. The current studies demonstrate that stretch increases ROS, AMPKα phosphorylation and Glucose transport in murine extensor digitorum longus (EDL) muscle (+121%, +164% and +184%, respectively; P 0.16). We also demonstrate that stretch-stimulated Glucose Uptake persists in the presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294001 (P 0.99). These data indicate that stretch-stimulated Glucose Uptake in skeletal muscle is mediated by a ROS- and p38 MAPK-dependent mechanism that appears to be AMPKα2- and PI3-K-independent.
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calmodulin binding domain of as160 regulates contraction but not insulin stimulated Glucose Uptake in skeletal muscle
Diabetes, 2007Co-Authors: Henning F Kramer, Eric B Taylor, Carol A Witczak, Nobuharu L Fujii, Michael F Hirshman, Laurie J GoodyearAbstract:OBJECTIVE— Insulin and contraction increase skeletal muscle Glucose Uptake through distinct and additive mechanisms. However, recent reports have demonstrated that both signals converge on the Akt substrate of 160 kDa (AS160), a protein that regulates GLUT4 translocation. Although AS160 phosphorylation is believed to be the primary factor affecting its activity, AS160 also possesses a calmodulin-binding domain (CBD). This raises the possibility that contraction-stimulated increases in Ca 2+ /calmodulin could also modulate AS160 function. RESEARCH DESIGN AND METHODS— To evaluate the AS160 CBD in skeletal muscle, empty-vector, wild-type, or CBD-mutant AS160 cDNAs were injected into mouse muscles followed by in vivo electroporation. One week later, AS160 was overexpressed by ∼14-fold over endogenous protein. RESULTS— Immunoprecipitates of wild-type and CBD-mutant AS160 were incubated with biotinylated calmodulin in the presence of Ca 2+ . Wild-type AS160, but not the CBD-mutant AS160, associated with calmodulin. Next, we measured insulin- and contraction-stimulated Glucose Uptake in vivo. Compared with empty-vector and wild-type AS160, insulin-stimulated Glucose Uptake was not altered in muscles expressing CBD-mutant AS160. In contrast, contraction-stimulated Glucose Uptake was significantly decreased in CBD-mutant–expressing muscles. This inhibitory effect on Glucose Uptake was not associated with aberrant contraction-stimulated AS160 phosphorylation. Interestingly, AS160 expressing both calmodulin-binding and Rab-GAP (GTPase-activating protein) domain point mutations (CBD + R/K) fully restored contraction-stimulated Glucose Uptake. CONCLUSIONS— Our results suggest that the AS160 CBD directly regulates contraction-induced Glucose Uptake in mouse muscle and that calmodulin provides an additional means of modulating AS160 Rab-GAP function independent of phosphorylation. These findings define a novel AS160 signaling component, unique to contraction and not insulin, leading to Glucose Uptake in skeletal muscle.
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as160 regulates insulin and contraction stimulated Glucose Uptake in mouse skeletal muscle
Journal of Biological Chemistry, 2006Co-Authors: Henning F Kramer, Eric B Taylor, Carol A Witczak, Nobuharu L Fujii, Michael F Hirshman, Laurie J GoodyearAbstract:Insulin and contraction are potent stimulators of GLUT4 translocation and increase skeletal muscle Glucose Uptake. We recently identified the Rab GTPase-activating protein (GAP) AS160 as a putative point of convergence linking distinct upstream signaling cascades induced by insulin and contraction in mouse skeletal muscle. Here, we studied the functional implications of these AS160 signaling events by using an in vivo electroporation technique to overexpress wild type and three AS160 mutants in mouse tibialis anterior muscles: 1) AS160 mutated to prevent phosphorylation on four regulatory phospho-Akt-substrate sites (4P); 2) AS160 mutated to abolish Rab GTPase activity (R/K); and 3) double mutant AS160 containing both 4P and R/K mutations (2M). One week following gene injection, protein expression for all AS160 isoforms was elevated over 7-fold. To determine the effects of AS160 on insulin- and contraction-stimulated Glucose Uptake in transfected muscles, we measured [3H]2-deoxyGlucose Uptake in vivo following intravenous Glucose administration and in situ muscle contraction, respectively. Insulin-stimulated Glucose Uptake was significantly inhibited in muscles overexpressing 4P mutant AS160. However, this inhibition was completely prevented by concomitant disruption of AS160 Rab GAP activity. Transfection with 4P mutant AS160 also significantly impaired contraction-stimulated Glucose Uptake, as did overexpression of wild type AS160. In contrast, overexpressing mutant AS160 lacking Rab GAP activity resulted in increases in both sham and contraction-stimulated muscles. These data suggest that AS160 regulates both insulin- and contraction-stimulated Glucose metabolism in mouse skeletal muscle in vivo and that the effects of mutant AS160 on the actions of insulin and contraction are not identical. Our findings directly implicate AS160 as a critical convergence factor for independent stimulators of skeletal muscle Glucose Uptake.
Lisbeth L V Moller - One of the best experts on this subject based on the ideXlab platform.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
The Journal of Physiology, 2020Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:KEY POINTS Muscle-specific genetic ablation of p21-activated kinase (PAK)2, but not whole-body PAK1 knockout, impairs Glucose tolerance in mice. Insulin-stimulated Glucose Uptake partly relies on PAK2 in glycolytic extensor digitorum longus muscle By contrast to previous reports, PAK1 is dispensable for insulin-stimulated Glucose Uptake in mouse muscle. ABSTRACT The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated Glucose transporter 4 translocation in mouse skeletal muscle. Therefore, the present study aimed to examine the role of PAK1 in insulin-stimulated muscle Glucose Uptake. The pharmacological inhibitor of group I PAKs, IPA-3 partially reduced (-20%) insulin-stimulated Glucose Uptake in isolated mouse soleus muscle (P < 0.001). However, because there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 KO and in mice with combined whole-body PAK1 KO and muscle-specific PAK2 KO. By contrast, Glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle, insulin-stimulated Glucose Uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (-18%) or in combination with PAK1 KO (-12%) (P < 0.05). In conclusion, Glucose tolerance and insulin-stimulated Glucose Uptake partly rely on PAK2 in glycolytic mouse muscle, whereas PAK1 is dispensable for whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
bioRxiv, 2019Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:Abstract Objective Skeletal muscle Glucose Uptake is essential for maintaining whole-body Glucose homeostasis and accounts for the majority of Glucose disposal in response to insulin. The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle. Interestingly, PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle and PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation. However, the relative contribution of PAK1 and PAK2 to insulin-stimulated Glucose Uptake in mature skeletal muscle is unresolved. The aim of the present investigation was to determine the requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle. Methods Glucose Uptake was measured in isolated skeletal muscle incubated with a pharmacological inhibitor (IPA-3) of group I PAKs and in muscle from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results The whole-body respiratory exchange ratio was largely unaffected by lack of PAK1 and/or PAK2. Whole-body Glucose tolerance was mildly impaired in PAK2 mKO, but not PAK1 KO mice. IPA-3 partially reduced (−20%) insulin-stimulated Glucose Uptake in mouse soleus muscle. In contrast to a previous study of GLUT4 translocation in PAK1 KO mice, PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle. On the contrary, Glucose Uptake was slightly reduced in response to insulin in glycolytic extensor digitorum longus muscle lacking PAK2, alone (−18%) or in combination with PAK1 KO (−12%). Conclusions Insulin-stimulated Glucose Uptake partly relies on PAK2, but not PAK1, in mouse skeletal muscle. Thus, the present study challenges that group I PAKs, and especially PAK1, are major regulators of whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle.
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rac1 governs exercise stimulated Glucose Uptake in skeletal muscle through regulation of glut4 translocation in mice
The Journal of Physiology, 2016Co-Authors: Lykke Sylow, Lisbeth L V Moller, Peter Schjerling, Thomas E Jensen, Maximilian Kleinert, Amira Klip, Ida L Nielsen, Thorkil Ploug, Philip J Bilan, Erik A RichterAbstract:Key point Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is Glucose taken up from the blood. The GTPase Rac1 can be activated by muscle contraction and has been found to be necessary for insulin-stimulated Glucose Uptake, although its role in exercise-stimulated Glucose Uptake is unknown. We show that Rac1 regulates the translocation of the Glucose transporter GLUT4 to the plasma membrane in skeletal muscle during exercise. We find that Rac1 knockout mice display significantly reduced Glucose Uptake in skeletal muscle during exercise. Abstract Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is Glucose taken up from the blood. Despite extensive efforts, the signalling mechanisms vital for Glucose Uptake during exercise are not yet fully understood, although the GTPase Rac1 is a candidate molecule. The present study investigated the role of Rac1 in muscle Glucose Uptake and substrate utilization during treadmill exercise in mice in vivo. Exercise-induced Uptake of radiolabelled 2-deoxyGlucose at 65% of maximum running capacity was blocked in soleus muscle and decreased by 80% and 60% in gastrocnemius and tibialis anterior muscles, respectively, in muscle-specific inducible Rac1 knockout (mKO) mice compared to wild-type littermates. By developing an assay to quantify endogenous GLUT4 translocation, we observed that GLUT4 content at the sarcolemma in response to exercise was reduced in Rac1 mKO muscle. Our findings implicate Rac1 as a regulatory element critical for controlling Glucose Uptake during exercise via regulation of GLUT4 translocation.
Rasmus Kjobsted - One of the best experts on this subject based on the ideXlab platform.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
The Journal of Physiology, 2020Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:KEY POINTS Muscle-specific genetic ablation of p21-activated kinase (PAK)2, but not whole-body PAK1 knockout, impairs Glucose tolerance in mice. Insulin-stimulated Glucose Uptake partly relies on PAK2 in glycolytic extensor digitorum longus muscle By contrast to previous reports, PAK1 is dispensable for insulin-stimulated Glucose Uptake in mouse muscle. ABSTRACT The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated Glucose transporter 4 translocation in mouse skeletal muscle. Therefore, the present study aimed to examine the role of PAK1 in insulin-stimulated muscle Glucose Uptake. The pharmacological inhibitor of group I PAKs, IPA-3 partially reduced (-20%) insulin-stimulated Glucose Uptake in isolated mouse soleus muscle (P < 0.001). However, because there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 KO and in mice with combined whole-body PAK1 KO and muscle-specific PAK2 KO. By contrast, Glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle, insulin-stimulated Glucose Uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (-18%) or in combination with PAK1 KO (-12%) (P < 0.05). In conclusion, Glucose tolerance and insulin-stimulated Glucose Uptake partly rely on PAK2 in glycolytic mouse muscle, whereas PAK1 is dispensable for whole-body Glucose homeostasis and insulin-stimulated muscle Glucose Uptake.
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insulin stimulated Glucose Uptake partly relies on p21 activated kinase pak 2 but not pak1 in mouse skeletal muscle
bioRxiv, 2019Co-Authors: Lisbeth L V Moller, Merna Jaurji, Rasmus Kjobsted, Giselle A Joseph, Agnete B Madsen, Jonas R Knudsen, Annemarie Lundsgaard, Nicoline R Andersen, Peter SchjerlingAbstract:Abstract Objective Skeletal muscle Glucose Uptake is essential for maintaining whole-body Glucose homeostasis and accounts for the majority of Glucose disposal in response to insulin. The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle. Interestingly, PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle and PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation. However, the relative contribution of PAK1 and PAK2 to insulin-stimulated Glucose Uptake in mature skeletal muscle is unresolved. The aim of the present investigation was to determine the requirement for PAK1 and PAK2 in whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle. Methods Glucose Uptake was measured in isolated skeletal muscle incubated with a pharmacological inhibitor (IPA-3) of group I PAKs and in muscle from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results The whole-body respiratory exchange ratio was largely unaffected by lack of PAK1 and/or PAK2. Whole-body Glucose tolerance was mildly impaired in PAK2 mKO, but not PAK1 KO mice. IPA-3 partially reduced (−20%) insulin-stimulated Glucose Uptake in mouse soleus muscle. In contrast to a previous study of GLUT4 translocation in PAK1 KO mice, PAK1 KO muscles displayed normal insulin-stimulated Glucose Uptake in vivo and in isolated muscle. On the contrary, Glucose Uptake was slightly reduced in response to insulin in glycolytic extensor digitorum longus muscle lacking PAK2, alone (−18%) or in combination with PAK1 KO (−12%). Conclusions Insulin-stimulated Glucose Uptake partly relies on PAK2, but not PAK1, in mouse skeletal muscle. Thus, the present study challenges that group I PAKs, and especially PAK1, are major regulators of whole-body Glucose homeostasis and insulin-stimulated Glucose Uptake in skeletal muscle.
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AMPK and TBC1D1 Regulate Muscle Glucose Uptake After, but Not During, Exercise and Contraction
Diabetes, 2019Co-Authors: Rasmus Kjobsted, Julie Roll, Nicolas Jørgensen, Jesper Birk, Marc Foretz, Benoit Viollet, Alexandra Chadt, Hadi Al-hasani, Jørgen Wojtaszewski, Julie L.w. RollAbstract:Exercise increases Glucose Uptake in skeletal muscle independently of insulin signaling. This makes exercise an effective stimulus to increase Glucose Uptake in insulin-resistant skeletal muscle. AMPK has been suggested to regulate muscle Glucose Uptake during exercise/contraction, but findings from studies of various AMPK transgenic animals have not reached consensus on this matter. Comparing methods used in these studies reveals a hitherto unappreciated difference between those studies reporting a role of AMPK and those that do not. This led us to test the hypothesis that AMPK and downstream target TBC1D1 are involved in regulating muscle Glucose Uptake in the immediate period after exercise/contraction but not during exercise/contraction. Here we demonstrate that Glucose Uptake during exercise/contraction was not compromised in AMPK-deficient skeletal muscle, whereas reversal of Glucose Uptake toward resting levels after exercise/contraction was markedly faster in AMPK-deficient muscle compared with wild-type muscle. Moreover, muscle Glucose Uptake after contraction was positively associated with phosphorylation of TBC1D1, and skeletal muscle from TBC1D1-deficient mice displayed impaired Glucose Uptake after contraction. These findings reconcile previous observed discrepancies and redefine the role of AMPK activation during exercise/contraction as being important for maintaining Glucose permeability in skeletal muscle in the period after, but not during, exercise/contraction.
Evangelia Tsiani - One of the best experts on this subject based on the ideXlab platform.
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carnosol increases skeletal muscle cell Glucose Uptake via ampk dependent glut4 Glucose transporter translocation
International Journal of Molecular Sciences, 2018Co-Authors: Filip Vlavcheski, David C Baron, Ioannis A Vlachogiannis, Rebecca E K Macpherson, Evangelia TsianiAbstract:Skeletal muscle is a major insulin-target tissue and plays an important role in Glucose homeostasis. Insulin action in muscle activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 Glucose transporters to the plasma membrane and increased Glucose Uptake. Impaired insulin action in muscle results in insulin resistance and type 2 diabetes mellitus (T2DM). Activation of the energy sensor AMP-activated kinase (AMPK) increases muscle Glucose Uptake and the use of AMPK activators is viewed as an effective strategy to combat insulin resistance. Rosemary extract (RE) has been shown to stimulate muscle AMPK and Glucose Uptake, but the exact components responsible for these effects are unknown. In the current study, we investigated the effect of carnosol, a RE polyphenol, in L6 rat muscle cells. Carnosol stimulated Glucose Uptake in L6 myotubes in a dose- and time-dependent manner, did not affect Akt, increased AMPK phosphorylation and plasma membrane GLUT4 levels. The carnosol-stimulated Glucose Uptake and GLUT4 translocation was significantly reduced by the AMPK inhibitor compound C (CC). Our study is the first to show an AMPK-dependent increase in muscle Glucose Uptake by carnosol. Carnosol has potential as a Glucose homeostasis regulating agent and deserves further study.
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naringenin a citrus flavonoid increases muscle cell Glucose Uptake via ampk
Biochemical and Biophysical Research Communications, 2010Co-Authors: Katarzyna Zygmunt, Jordan Macneil, Brandon Faubert, Evangelia TsianiAbstract:Abstract Naringenin, a flavonoid found in high concentrations in grapefruit, has been reported to have antioxidant, antiatherogenic, and anticancer effects. Effects on lipid and Glucose metabolism have also been reported. Naringenin is structurally similar to the polyphenol resveratrol, that has been reported to activate the SIRT1 protein deacetylase and to have antidiabetic properties. In the present study we examined the direct effects of naringenin on skeletal muscle Glucose Uptake and investigated the mechanism involved. Naringenin stimulated Glucose Uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 75 μM naringenin for 2 h (192.8 ± 24%, p
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naringenin a citrus flavonoid increases muscle cell Glucose Uptake via ampk
Biochemical and Biophysical Research Communications, 2010Co-Authors: Katarzyna Zygmunt, Jordan Macneil, Brandon Faubert, Evangelia TsianiAbstract:Naringenin, a flavonoid found in high concentrations in grapefruit, has been reported to have antioxidant, antiatherogenic, and anticancer effects. Effects on lipid and Glucose metabolism have also been reported. Naringenin is structurally similar to the polyphenol resveratrol, that has been reported to activate the SIRT1 protein deacetylase and to have antidiabetic properties. In the present study we examined the direct effects of naringenin on skeletal muscle Glucose Uptake and investigated the mechanism involved. Naringenin stimulated Glucose Uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 75 microM naringenin for 2 h (192.8+/-24%, p<0.01), a response comparable to maximum insulin response (190.1+/-13%, p<0.001). Similar to insulin, naringenin did not increase Glucose Uptake in myoblasts indicating that GLUT4 Glucose transporters may be involved in the naringenin-stimulated Glucose Uptake. In addition, naringenin did not have a significant effect on basal or insulin-stimulated Akt phosphorylation while significantly increased AMPK phosphorylation/activation. Furthermore, silencing of AMPK, using siRNA approach, abolished the naringenin-stimulated Glucose Uptake. The SIRT1 inhibitors nicotinamide and EX527 did not have an effect on naringenin-stimulated AMPK phosphorylation and Glucose Uptake. Our data show that naringenin increases Glucose Uptake by skeletal muscle cells in an AMPK-dependent manner.
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stimulation of muscle cell Glucose Uptake by resveratrol through sirtuins and ampk
Biochemical and Biophysical Research Communications, 2008Co-Authors: Danna M Breen, Toran Sanli, Adria Giacca, Evangelia TsianiAbstract:Although recent studies in vitro and in vivo indicate that the polyphenol resveratrol (RSV) has anti-diabetic properties, the exact mechanisms involved are not known. In the present study, we examined the effects of RSV and the mechanism of regulation of Glucose Uptake in skeletal muscle cells. In L6 myotubes RSV (100 microM) induced maximum stimulation of Glucose (2DG) Uptake (201+/-8.90% of control, p<0.001), an effect that was similar to insulin action. RSV-stimulated Glucose Uptake was abolished by AMPK inhibition. In the presence of the sirtuin inhibitor nicotinamide, RSV-stimulated 2DG Uptake and AMPK phosphorylation were abolished. RSV did not stimulate significant translocation of GLUT4 or GLUT1 transporters. However, treatment with indinavir, a GLUT4 specific inhibitor, blocked RSV-stimulated Glucose Uptake. We propose that RSV elevates Glucose Uptake in muscle cells through a mechanism that involves sirtuins and AMPK and possibly stimulation of GLUT4 transporter intrinsic activity.