scholarly journals BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β2-adrenoceptors without causing classical receptor desensitization

2019 ◽  
Vol 316 (5) ◽  
pp. R666-R677 ◽  
Author(s):  
Saori Mukaida ◽  
Masaaki Sato ◽  
Anette I. Öberg ◽  
Nodi Dehvari ◽  
Jessica M. Olsen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Ex Vivo ◽  
Partial Agonist ◽  
Receptor Desensitization ◽  
Glut4 Translocation ◽  
Adrenoceptor Agonist

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2-adrenoceptors, with a similar potency and efficacy to that of the nonselective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit β-arrestin1/2 to the β2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

Abstract 158: A Tether Containing a UBX Domain (TUG) Mediates Glucose Transporter Translocation in the Ischemic Heart

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Ji Li ◽  
Yina Ma ◽  
Jonathan Bogan
Keyword(s):  
Cell Surface ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Ex Vivo ◽  
Ischemia And Reperfusion ◽  
Ampk Activation ◽  
Glut4 Translocation ◽  
Heart Perfusion ◽  
Intracellular Vesicles

Introduction: The adaptive metabolic regulation of glucose and fatty acid in the heart plays a critical role in limiting cardiac damage caused by ischemia and reperfusion (I/R). TUG (tether containing a UBX domain, for GLUT4) can be cleaved to mobilize glucose transporter GLUT4 from intracellular vesicles to the cell surface in skeletal muscle and adipose in response to insulin stimulation. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role in response to ischemic insults by modulating GLUT4 translocation. Hypothesis: TUG is one of the downstream targets of AMPK in the heart. TUG could be phosphorylated by ischemic AMPK and cleaved to dissociate with GLUT4 and increase GLUT4 translocation in the ischemic heart. Methods: In vivo regional ischemia by ligation of left anterior coronary artery and ex vivo isolated mouse heart perfusion Langendorff system were used to test the hypothesis. Results: Antithrombin (AT) is an endogenous AMPK agonist in the heart and used to define the role of TUG in regulating GLUT4 trafficking during ischemia and reperfusion in the heart. AT showed its cardioprotective function through recovering cardiac pumping function and activating AMPK. The results showed that AMPK activation by AT treatment was through LKB1 and Sesn2 complex. Furthermore, the ex vivo heart perfusion data demonstrated that AT administration significantly increase GLUT4 translocation, glucose uptake, glycolysis and glucose oxidation during ischemia and reperfusion (p<0.05 vs . vehicle). Moreover, AT treatment increased abundance of a TUG cleavage product (42 KD) in response to I/R. The TUG protein was clearly phosphorylated by activated AMPK in HL-1 cardiomyocytes. The in vivo myocardial ischemia results demonstrated that ischemic AMPK activation triggers TUG cleavage and significantly increases GLUT4 translocation to the cell surface. Moreover, an augmented interaction between AMPK and TUG was observed during ischemia. Conclusions: Cardiac AMPK activation stimulates TUG cleavage and causes the dissociation between TUG and GLUT4 in the intracellular vesicles. TUG is a critical mediator that modulates cardiac GLUT4 translocation to cell surface and enhances glucose uptake by AMPK signaling pathway.

Effect of exercise training on glucose homeostasis in normal and insulin-deficient diabetic rats

1988 ◽  
Vol 65 (2) ◽  
pp. 844-851 ◽  
Author(s):  
L. J. Goodyear ◽  
M. F. Hirshman ◽  
S. M. Knutson ◽  
E. D. Horton ◽  
E. S. Horton
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Plasma Glucose ◽  
Citrate Synthase ◽  
Diabetic Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

The effect of 8-wk of treadmill training on plasma glucose, insulin, and lipid concentrations, oral glucose tolerance, and glucose uptake in the perfused hindquarter of normal and streptozocin-treated, diabetic Sprague-Dawley rats was studied. Diabetic rats with initial plasma glucose concentrations of 200-450 mg/dl and control rats were divided into trained and sedentary subgroups. Training resulted in lower plasma free fatty acid concentrations and increased triceps muscle citrate synthase activity in both the control and diabetic rats; triglyceride concentrations were lowered by training only in the diabetic animals. Oral glucose tolerance and both basal and insulin-stimulated glucose uptake in hindquarter skeletal muscle were impaired in the diabetic rats, and plasma glucose concentrations (measured weekly) gradually increased during the experiment. Training did not improve the hyperglycemia, impaired glucose tolerance, or decreased skeletal muscle glucose uptake in the diabetic rats, nor did it alter these parameters in the normal control animals. In considering our results and those of previous studies in diabetic rats, we propose that exercise training may improve glucose homeostasis in animals with milder degrees of diabetes but fails to cause improvement in the more severely insulin-deficient, diabetic rat.

scholarly journals SUN-670 P300 and CBP Are Necessary for Skeletal Muscle Insulin-Stimulated Glucose Uptake

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Vitor Fernandes Martins ◽  
Samuel LaBarge ◽  
Kristoffer Svensson ◽  
Jennifer M Cunliffe ◽  
Dion Banoian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Ex Vivo ◽  
Binding Protein ◽  
Whole Body ◽  
Oral Glucose ◽  
Skeletal Muscle Insulin Sensitivity

Abstract Introduction: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. Methods: We used Cre-LoxP methodology to generate mice with a tamoxifen-inducible, conditional knock out of Ep300 and/or Crebbp in skeletal muscle. At 13-15 weeks of age, the knockout was induced via oral gavage of tamoxifen and oral glucose tolerance, ex vivo skeletal muscle insulin sensitivity, and microarray and proteomics analysis were done. Results: Loss of both p300 and CBP in adult mouse skeletal muscle rapidly and severely impairs whole body glucose tolerance and skeletal muscle insulin sensitivity. Furthermore, giving back a single allele of either p300 or CBP rescues both phenotypes. Moreover, the severe insulin resistance in the p300/CBP double knockout mice is accompanied by significant changes in both mRNA and protein expression of transcript/protein networks critical for insulin signaling, GLUT4 trafficking, and metabolism. Lastly, in human skeletal muscle samples, p300 and CBP protein levels correlate significantly and negatively with markers of insulin resistance. Conclusions: p300 and CBP are jointly required for maintaining whole body glucose tolerance and insulin sensitivity in skeletal muscle.

scholarly journals Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching

2013 ◽  
Vol 305 (1) ◽  
pp. E119-E131 ◽  
Author(s):  
Ognian C. Ikonomov ◽  
Diego Sbrissa ◽  
Khortnal Delvecchio ◽  
Han-Zhong Feng ◽  
Gregory D. Cartee ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Glucose Intolerance ◽  
Fat Mass ◽  
Gene Disruption ◽  
Glut4 Translocation ◽  
Fat Cell

The evolutionarily conserved kinase PIKfyve that synthesizes PtdIns5P and PtdIns(3,5)P2 has been implicated in insulin-regulated GLUT4 translocation/glucose entry in 3T3-L1 adipocytes. To decipher PIKfyve's role in muscle and systemic glucose metabolism, here we have developed a novel mouse model with Pikfyve gene disruption in striated muscle (MPIfKO). These mice exhibited systemic glucose intolerance and insulin resistance at an early age but had unaltered muscle mass or proportion of slow/fast-twitch muscle fibers. Insulin stimulation of in vivo or ex vivo glucose uptake and GLUT4 surface translocation was severely blunted in skeletal muscle. These changes were associated with premature attenuation of Akt phosphorylation in response to in vivo insulin, as tested in young mice. Starting at 10–11 wk of age, MPIfKO mice progressively accumulated greater body weight and fat mass. Despite increased adiposity, serum free fatty acid and triglyceride levels were normal until adulthood. Together with the undetectable lipid accumulation in liver, these data suggest that lipotoxicity and muscle fiber switching do not contribute to muscle insulin resistance in MPIfKO mice. Furthermore, the 80% increase in total fat mass resulted from increased fat cell size rather than altered fat cell number. The observed profound hyperinsulinemia combined with the documented increases in constitutive Akt activation, in vivo glucose uptake, and gene expression of key enzymes for fatty acid biosynthesis in MPIfKO fat tissue suggest that the latter is being sensitized for de novo lipid anabolism. Our data provide the first in vivo evidence that PIKfyve is essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle.

scholarly journals Postexercise improvement in glucose uptake occurs concomitant with greater γ3-AMPK activation and AS160 phosphorylation in rat skeletal muscle

2018 ◽  
Vol 315 (5) ◽  
pp. E859-E871 ◽  
Author(s):  
Haiyan Wang ◽  
Edward B. Arias ◽  
Mark W. Pataky ◽  
Laurie J. Goodyear ◽  
Gregory D. Cartee
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Ex Vivo ◽  
Contractile Activity ◽  
Exercise Session ◽  
Ampk Activation ◽  
Rat Skeletal Muscle ◽  
Ampk Activity ◽  
Exercise Induced

A single exercise session can increase insulin-stimulated glucose uptake (GU) by skeletal muscle, concomitant with greater Akt substrate of 160 kDa (AS160) phosphorylation on Akt-phosphosites (Thr642 and Ser588) that regulate insulin-stimulated GU. Recent research using mouse skeletal muscle suggested that ex vivo 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or electrically stimulated contractile activity-inducing increased γ3-AMPK activity and AS160 phosphorylation on a consensus AMPK-motif (Ser704) resulted in greater AS160 Thr642 phosphorylation and GU by insulin-stimulated muscle. Our primary goal was to determine whether in vivo exercise that increases insulin-stimulated GU in rat skeletal muscle would also increase γ3-AMPK activity and AS160 site-selective phosphorylation (Ser588, Thr642, and Ser704) immediately postexercise (IPEX) and/or 3 h postexercise (3hPEX). Epitrochlearis muscles isolated from sedentary and exercised (2-h swim exercise; studied IPEX and 3hPEX) rats were incubated with 2-deoxyglucose to determine GU (without insulin at IPEX; without or with insulin at 3hPEX). Muscles were also assessed for γ1-AMPK activity, γ3-AMPK activity, phosphorylated AMPK (pAMPK), and phosphorylated AS160 (pAS160). IPEX versus sedentary had greater γ3-AMPK activity, pAS160 (Ser588, Thr642, Ser704), and GU with unaltered γ1-AMPK activity. 3hPEX versus sedentary had greater γ3-AMPK activity, pAS160 Ser704, and GU with or without insulin; greater pAS160 Thr642 only with insulin; and unaltered γ1-AMPK activity. These results using an in vivo exercise protocol that increased insulin-stimulated GU in rat skeletal muscle are consistent with the hypothesis that in vivo exercise-induced enhancement of γ3-AMPK activation and AS160 Ser704 IPEX and 3hPEX are important for greater pAS160 Thr642 and enhanced insulin-stimulated GU by skeletal muscle.

scholarly journals Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle

2021 ◽  
Author(s):  
Philipp Rhein ◽  
Eric M Desjardins ◽  
Ping Rong ◽  
Danial Ahwazi ◽  
Nicolas Bonhoure ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Ex Vivo ◽  
Fiber Type ◽  
Whole Body ◽  
Glucose Clearance

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and also potentially in BAT. Here, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed if γ3 plays a role in adipose thermogenesis and browning. Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo, as well as blood glucose clearance in response to small molecule AMPK activators that target nucleotide-binding domain of γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics and function. Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and integrity, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose lowering in vivo and glucose uptake specifically in glycolytic muscles ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice. Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for thermogenesis and browning of iWAT.

scholarly journals Cysteine- and glycine-rich protein 3 regulates glucose homeostasis in skeletal muscle

2018 ◽  
Vol 315 (2) ◽  
pp. E267-E278 ◽  
Author(s):  
Angelina Hernandez-Carretero ◽  
Natalie Weber ◽  
Samuel A. LaBarge ◽  
Veronika Peterka ◽  
Nhu Y Thi Doan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Glycine Rich Protein ◽  
Resistant State ◽  
Insulin Resistant State

Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.

scholarly journals Insulin-stimulated glucose uptake partly relies on p21-activated kinase (PAK)-2, but not PAK1, in mouse skeletal muscle

2019 ◽  
Author(s):  
Lisbeth L. V. Møller ◽  
Merna Jaurji ◽  
Rasmus Kjøbsted ◽  
Giselle A. Joseph ◽  
Agnete B. Madsen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Whole Body ◽  
Glucose Disposal ◽  
Glut4 Translocation ◽  
Resistant Mouse ◽  
Mouse Skeletal Muscle ◽  
Group I ◽  
P21 Activated Kinase

AbstractObjectiveSkeletal 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.MethodsGlucose 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.ResultsThe 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%).ConclusionsInsulin-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.

scholarly journals Cacao liquor procyanidin extract improves glucose tolerance by enhancing GLUT4 translocation and glucose uptake in skeletal muscle

2012 ◽  
Vol 1 ◽  
Author(s):  
Yoko Yamashita ◽  
Masaaki Okabe ◽  
Midori Natsume ◽  
Hitoshi Ashida
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Dependent Manner ◽  
Glut4 Translocation ◽  
Food Material ◽  
Carbohydrate Ingestion ◽  
The Metabolic Syndrome ◽  
Increased Risk

AbstractHyperglycaemia and insulin resistance are associated with the increased risk of the metabolic syndrome and other severe health problems. The insulin-sensitive GLUT4 regulates glucose homoeostasis in skeletal muscle and adipose tissue. In this study, we investigated whether cacao liquor procyanidin (CLPr) extract, which contains epicatechin, catechin and other procyanidins, improves glucose tolerance by promoting GLUT4 translocation and enhances glucose uptake in muscle cells. Our results demonstrated that CLPr increased glucose uptake in a dose-dependent manner and promoted GLUT4 translocation to the plasma membrane of L6 myotubes. Oral administration of a single dose of CLPr suppressed the hyperglycaemic response after carbohydrate ingestion, which was accompanied by enhanced GLUT4 translocation in ICR mice. These effects of CLPr were independent of α-glucosidase inhibition in the small intestine. CLPr also promoted GLUT4 translocation in skeletal muscle of C57BL/6 mice fed a CLPr-supplemented diet for 7 d. These results indicate that CLPr is a beneficial food material for improvement of glucose tolerance by promoting GLUT4 translocation to the plasma membrane of skeletal muscle.

Sign in / Sign up

Export Citation Format

Share Document