scholarly journals Exercise, GLUT4, and Skeletal Muscle Glucose Uptake

2013 ◽  
Vol 93 (3) ◽  
pp. 993-1017 ◽  
Author(s):  
Erik A. Richter ◽  
Mark Hargreaves
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Glucose Uptake ◽  
Nuclear Export ◽  
Glucose Transporter ◽  
Glucose Disposal ◽  
Facilitated Diffusion ◽  
Molecular Signaling ◽  
Glut4 Translocation ◽  
Glut4 Expression

Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca2+, and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.

scholarly journals MicroRNAs-Mediated Regulation of Skeletal Muscle GLUT4 Expression and Translocation in Insulin Resistance

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
João Victor Esteves ◽  
Francisco Javier Enguita ◽  
Ubiratan Fabres Machado
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glycemic Control ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Regulation Of Gene Expression ◽  
Glut4 Translocation ◽  
Therapeutic Approaches ◽  
Glut4 Expression ◽  
Solute Carrier

The solute carrier family 2 facilitated glucose transporter member 4 (GLUT4) plays a key role in the insulin-induced glucose uptake by muscle and adipose tissues. In prediabetes and diabetes, GLUT4 expression/translocation has been detected as reduced, participating in mechanisms that impair glycemic control. Recently, a class of short endogenous noncoding RNAs named microRNAs (miRNAs) has been increasingly described as involved in the posttranscriptional epigenetic regulation of gene expression. The present review focuses on miRNAs potentially involved in the expression of GLUT4 expression, and proteins related to GLUT4 and translocation in skeletal muscle, seeking to correlate them with insulin resistance and diabetes. So far, miR-21a-5p, miR-29a-3p, miR-29c-3p, miR-93-5p, miR-106b-5p, miR-133a-3p, miR-133b-3p, miR-222-3p, and miR-223-3p have been reported to directly and/or indirectly regulate the GLUT4 expression; and their expression is altered under diabetes-related conditions. Besides, some miRNAs that have been linked to the expression of proteins involved in GLUT4 translocation machinery in muscle could also impact glucose uptake. That makes these miRNAs promising targets for preventive and/or therapeutic approaches, which could improve glycemic control, thus deserving future new investigations.

scholarly journals AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle

2019 ◽  
Vol 316 (5) ◽  
pp. E931-E939 ◽  
Author(s):  
Jin-Ho Koh ◽  
Chad R. Hancock ◽  
Dong-Ho Han ◽  
John O. Holloszy ◽  
K. Sreekumaran Nair ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glut4 Expression ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise ◽  
Glucose Transporter Type 4

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), or peroxisome proliferator-activated receptor β (PPARβ) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPARβ can regulate GLUT4 expression without PGC-1α. We also found AMPK and PPARβ are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPARβ are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPARβ via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPARβ. Furthermore, exercise training increases the cooperation of AMPK and PPARβ to regulate glucose uptake. In conclusion, cooperation between AMPK and PPARβ via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.

Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Atul S. Deshmukh
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Disposal ◽  
Facilitated Diffusion ◽  
Primary Target ◽  
Insulin Resistant ◽  
Transporter Protein ◽  
Signaling Events

AbstractSkeletal muscle is the largest tissues in the human body and is considered the primary target for insulin-stimulated glucose disposal. In skeletal muscle, binding of the insulin to insulin receptor (IR) initiates a signaling cascade that results in the translocation of the insulin-sensitive glucose transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle.

scholarly journals Inhibition of the Protein Tyrosine Phosphatase SHP-1 Increases Glucose Uptake in Skeletal Muscle Cells by Augmenting Insulin Receptor Signaling and GLUT4 Expression

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4581-4588 ◽  
Author(s):  
Sébastien Bergeron ◽  
Marie-Julie Dubois ◽  
Kerstin Bellmann ◽  
Michael Schwab ◽  
Nancy Larochelle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Glucose Uptake ◽  
Protein Tyrosine Phosphatase ◽  
Insulin Action ◽  
Tyrosine Phosphatase ◽  
Glycogen Synthesis ◽  
Glut4 Translocation ◽  
Protein Tyrosine ◽  
Glut4 Expression

The protein tyrosine phosphatase (PTPase) Src-homology 2-domain-containing phosphatase (SHP)-1 was recently reported to be a novel regulator of insulin's metabolic action. In order to examine the role of this PTPase in skeletal muscle, we used adenovirus (AdV)-mediated gene transfer to express an interfering mutant of SHP-1 [dominant negative (DN)SHP-1; mutation C453S] in L6 myocytes. Expression of DNSHP-1 increased insulin-induced Akt serine-threonine kinase phosphorylation and augmented glucose uptake and glycogen synthesis. Pharmacological inhibition of glucose transporter type 4 (GLUT4) activity using indinavir and GLUT4 translocation assays revealed an important role for this transporter in the increased insulin-induced glucose uptake in DNSHP-1-expressing myocytes. Both GLUT4 mRNA and protein expression were also found to be increased by DNSHP-1 expression. Furthermore, AdV-mediated delivery of DNSHP-1 in skeletal muscle of transgenic mice overexpressing Coxsackie and AdV receptor also enhanced GLUT4 protein expression. Together, these findings confirm that SHP-1 regulates muscle insulin action in a cell-autonomous manner and further suggest that the PTPase negatively modulates insulin action through down-regulation of both insulin signaling to Akt and GLUT4 translocation, as well as GLUT4 expression.

scholarly journals Is the canine corpus luteum an insulin-sensitive tissue?

2016 ◽  
Vol 231 (3) ◽  
pp. 223-233 ◽  
Author(s):  
Liza Margareth Medeiros de Carvalho Sousa ◽  
Renata dos Santos Silva ◽  
Vanessa Uemura da Fonseca ◽  
Rafael Magdanelo Leandro ◽  
Thiago Senna Di Vincenzo ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Corpus Luteum ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Glucose Disposal ◽  
Luteal Cell ◽  
Luteal Function ◽  
Luteal Cells ◽  
Glut4 Expression

This study aimed to determine in the canine corpus luteum throughout the dioestrus (1) the influence of insulin on glucose uptake; (2) the regulation of genes potentially involved; and (3) the influence of hypoxia on glucose transporter expression and steroidogenesis, after treatment with cobalt chloride (CoCl2). Glucose uptake by luteal cells increased 2.7 folds (P < 0.05) in response to insulin; a phenomenon related to increased expression of glucose transporter (GLUT) 4 and phosphorylation of protein kinase B (AKT). The gene expression of insulin receptor and SLC2A4 (codifier of GLUT4) genes after insulin stimulation increased on day 20 post ovulation (p.o.) and declined on day 40 p.o. (P < 0.05). Regarding potentially involved molecular mechanisms, the nuclear factor kappa B gene RELA was upregulated on days 30/40 p.o., when SLC2A4 mRNA was low, and the interleukin 6 (IL6) gene was upregulated in the first half of dioestrus, when SLC2A4 mRNA was high. CoCl2 in luteal cell cultures increased the hypoxia-inducible factor HIF1A/HIF1A and the SLC2A4/GLUT4 expression, and decreased progesterone (P4) production and hydroxyl-delta-5-steroid dehydrogenase 3 beta (HSD3B) mRNA expression (P < 0.05). This study shows that the canine luteal cells are responsive to insulin, which stimulates glucose uptake in AKT/GLUT4-mediated pathway; that may be related to local activity of RELA and IL6. Besides, the study reveals that luteal cells under hypoxia activate HIF1A-modulating luteal function and insulin-stimulated glucose uptake. These data indicate that insulin regulates luteal cells’ glucose disposal, participating in the maintenance and functionality of the corpus luteum.

scholarly journals A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes

2019 ◽  
Vol 20 (21) ◽  
pp. 5443 ◽  
Author(s):  
Takenaka ◽  
Nakao ◽  
Matsui ◽  
Satoh
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Specific Inhibitor ◽  
Small Gtpase ◽  
Glut4 Translocation ◽  
Insulin Dependent ◽  
Mouse Adipocytes ◽  
Phosphoinositide 3 Kinase

Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, the small GTPase Rac1 plays an important role downstream of Akt2 in the regulation of insulin-stimulated glucose uptake. However, the role for Rac1 in adipocytes remains controversial. Here, we show that Rac1 is required for insulin-dependent GLUT4 translocation also in adipocytes. A Rac1-specific inhibitor almost completely suppressed GLUT4 translocation induced by insulin or a constitutively activated mutant of phosphoinositide 3-kinase or Akt2. Constitutively activated Rac1 also enhanced GLUT4 translocation. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was abrogated by inhibition of phosphoinositide 3-kinase or Akt2. On the other hand, constitutively activated Akt2 caused Rac1 activation, and insulin-induced Rac1 activation was suppressed by an Akt2-specific inhibitor. Moreover, GLUT4 translocation induced by a constitutively activated mutant of Akt2 or Rac1 was diminished by knockdown of another small GTPase RalA. RalA was activated by a constitutively activated mutant of Akt2 or Rac1, and insulin-induced RalA activation was suppressed by an Akt2- or Rac1-specific inhibitor. Collectively, these results suggest that Rac1 plays an important role in the regulation of insulin-dependent GLUT4 translocation downstream of Akt2, leading to RalA activation in adipocytes.

scholarly journals Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

2017 ◽  
Vol 59 (3) ◽  
pp. 257-268 ◽  
Author(s):  
Raquel S Campello ◽  
Luciana A Fátima ◽  
João Nilton Barreto-Andrade ◽  
Thais F Lucas ◽  
Rosana C Mori ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Subcellular Distribution ◽  
Glucose Transporter ◽  
Biological Effects ◽  
Glut4 Translocation ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Glut4 Expression ◽  
Protein Kinase Akt

Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17β-estradiol (E2) modulates SLC2A4/GLUT4 expression, but the involved mechanisms are unclear. Although E2 exerts biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E2 regulates GLUT4 through an extranuclear ESR1 mechanism. Thus, we investigated the effects of E2 upon (1) subcellular distribution of ESRs and the proto-oncogene tyrosine-protein kinases (SRC) involvement; (2) serine/threonine-protein kinase (AKT) activation; (3) Slc2a4/GLUT4 expression and (4) GLUT4 subcellular distribution and glucose uptake in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were cultivated or not with E2 for 24 h, and additionally treated or not with ESR1-selective agonist (PPT), ESR1-selective antagonist (MPP) or selective SRC inhibitor (PP2). Subcellular distribution of ESR1, ESR2 and GLUT4 was analyzed by immunocytochemistry; Slc2a4 mRNA and GLUT4 were quantified by qPCR and Western blotting, respectively; plasma membrane GLUT4 translocation and glucose uptake were analyzed under insulin stimulus for 20 min or not. E2 induced (1) translocation of ESR1, but not of ESR2, from nucleus to plasma membrane and AKT phosphorylation, effects mimicked by PPT and blocked by MPP and PP2; (2) increased Slc2a4/GLUT4 expression and (3) increased insulin-stimulated GLUT4 translocation and glucose uptake. In conclusion, E2 treatment promoted a SRC-mediated nucleus-plasma membrane shuttle of ESR1, and increased AKT phosphorylation, Slc2a4/GLUT4 expression and plasma membrane GLUT4 translocation; consequently, improving insulin-stimulated glucose uptake. These results unravel mechanisms through which estrogen improves insulin sensitivity.

scholarly journals A Novel Xanthene Derivative, DS20060511, Attenuates Glucose Intolerance by Inducing Skeletal Muscle-specific GLUT4 Translocation in Diabetic Mice

2020 ◽  
Author(s):  
Shinji Furuzono ◽  
Tetsuya Kubota ◽  
Junki Taura ◽  
Masahiro Konishi ◽  
Asuka Naito ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Surface ◽  
Glucose Uptake ◽  
Muscle Cell ◽  
Glucose Intolerance ◽  
Actin Polymerization ◽  
Glucose Transporter ◽  
Skeletal Muscle Cell ◽  
Diabetic Mice ◽  
Glut4 Translocation

Abstract Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. We found a novel xanthene compound, DS20060511, which induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the skeletal muscle. DS20060511 induced GLUT4 translocation and glucose uptake into differentiated L6-miytubes and into the skeletal muscles of live mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 surface translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle specific-GLUT4 translocation enhancer to facilitate glucose utilization. Further studies with DS20060511 would help to develop a novel antidiabetic medicine.

scholarly journals Atrophy of White Adipose Tissue Accompanied with Decreased Insulin-Stimulated Glucose Uptake in Mice Lacking the Small GTPase Rac1 Specifically in Adipocytes

2021 ◽  
Vol 22 (19) ◽  
pp. 10753
Author(s):  
Kiko Hasegawa ◽  
Nobuyuki Takenaka ◽  
Kenya Tanida ◽  
Man Piu Chan ◽  
Mizuki Sakata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Physiological Role ◽  
Small Gtpase ◽  
Mrna Levels ◽  
Glut4 Translocation ◽  
White Adipocytes ◽  
Phosphoinositide 3 Kinase

Insulin stimulates glucose uptake in adipose tissue and skeletal muscle by inducing plasma membrane translocation of the glucose transporter GLUT4. Although the small GTPase Rac1 is a key regulator downstream of phosphoinositide 3-kinase (PI3K) and the protein kinase Akt2 in skeletal muscle, it remains unclear whether Rac1 also regulates glucose uptake in white adipocytes. Herein, we investigated the physiological role of Rac1 in white adipocytes by employing adipocyte-specific rac1 knockout (adipo-rac1-KO) mice. Subcutaneous and epididymal white adipose tissues (WATs) in adipo-rac1-KO mice showed significant reductions in size and weight. Actually, white adipocytes lacking Rac1 were smaller than controls. Insulin-stimulated glucose uptake and GLUT4 translocation were abrogated in rac1-KO white adipocytes. On the other hand, GLUT4 translocation was augmented by constitutively activated PI3K or Akt2 in control, but not in rac1-KO, white adipocytes. Similarly, to skeletal muscle, the involvement of another small GTPase RalA downstream of Rac1 was demonstrated. In addition, mRNA levels of various lipogenic enzymes were down-regulated in rac1-KO white adipocytes. Collectively, these results suggest that Rac1 is implicated in insulin-dependent glucose uptake and lipogenesis in white adipocytes, and reduced insulin responsiveness due to the deficiency of Rac1 may be a likely explanation for atrophy of WATs.

scholarly journals Local myostatin inhibition improves skeletal muscle glucose uptake in insulin-resistant high-fat diet-fed mice

2020 ◽  
Vol 319 (1) ◽  
pp. E163-E174
Author(s):  
Wouter Eilers ◽  
David Chambers ◽  
Mark Cleasby ◽  
Keith Foster
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Muscle Hypertrophy ◽  
Glucose Transporter ◽  
Whole Body ◽  
Glucose Disposal ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Myostatin Inhibition

Myostatin inhibition is thought to improve whole body insulin sensitivity and mitigate the development of insulin resistance in models of obesity. However, although myostatin is known to be a major regulator of skeletal muscle mass, the direct effects of myostatin inhibition in muscle on glucose uptake and the mechanisms that may underlie this are still unclear. We investigated the effect of local myostatin inhibition by adeno-associated virus-mediated overexpression of the myostatin propeptide on insulin-stimulated skeletal muscle glucose disposal in chow-fed or high fat diet-fed mice and evaluated the molecular pathways that might mediate this. We found that myostatin inhibition improved glucose disposal in obese high fat diet-fed mice alongside the induction of muscle hypertrophy but did not have an impact in chow-fed mice. This improvement was not associated with greater glucose transporter or peroxisome proliferator-activated receptor-γ coactivator-1α expression or 5′ AMP-activated protein kinase activation as previously suggested. Instead, transcriptomic analysis suggested that the improvement in glucose disposal was associated with significant enrichment in genes involved in fatty acid metabolism and translation of mitochondrial genes. Thus, myostatin inhibition improves muscle insulin-stimulated glucose disposal in obese high fat diet-fed mice independent of muscle hypertrophy, potentially involving previously unidentified pathways.

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