Red rice koji extract alleviates hyperglycemia by increasing glucose uptake and glucose transporter type 4 levels in skeletal muscle in two diabetic mouse models

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.

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ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.00603.2020 ◽

2021 ◽

Author(s):

Hye Kyoung Sung ◽

Patricia L. Mitchell ◽

Sean Gross ◽

Andre Marette ◽

Gary Sweeney

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Glucose Transporter ◽

Muscle Cells ◽

Temporal Analysis ◽

Skeletal Muscle Cells ◽

Adiponectin Receptor ◽

Metabolic Effects

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment both increased glucose uptake itself and enhanced insulin-stimulated glucose uptake. In the model of high glucose/high insulin (HGHI)-induced insulin resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting assessing Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high sucrose fed mice also improve glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

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Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1997.273.3.c1082 ◽

1997 ◽

Vol 273 (3) ◽

pp. C1082-C1087 ◽

Cited By ~ 46

Author(s):

A. D. Lee ◽

P. A. Hansen ◽

J. Schluter ◽

E. A. Gulve ◽

J. Gao ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Transport ◽

Glucose Transporter ◽

Inhibitory Effect ◽

Phosphate Concentration ◽

Intrinsic Activity ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Glut 4

beta-Adrenergic stimulation has been reported to inhibit insulin-stimulated glucose transport in adipocytes. This effect has been attributed to a decrease in the intrinsic activity of the GLUT-4 isoform of the glucose transporter that is mediated by phosphorylation of GLUT-4. Early studies showed no inhibition of insulin-stimulated glucose transport by epinephrine in skeletal muscle. The purpose of this study was to determine the effect of epinephrine on GLUT-4 phosphorylation, and reevaluate the effect of beta-adrenergic stimulation on insulin-activated glucose transport, in skeletal muscle. We found that 1 microM epinephrine, which raised adenosine 3',5'-cyclic monophosphate approximately ninefold, resulted in GLUT-4 phosphorylation in rat skeletal muscle but had no inhibitory effect on insulin-stimulated 3-O-methyl-D-glucose (3-MG) transport. In contrast to 3-MG transport, the uptakes of 2-deoxyglucose and glucose were markedly inhibited by epinephrine treatment. This inhibitory effect was presumably mediated by stimulation of glycogenolysis, which resulted in an increase in glucose 6-phosphate concentration to levels known to severely inhibit hexokinase. We conclude that 1) beta-adrenergic stimulation decreases glucose uptake by raising glucose 6-phosphate concentration, thus inhibiting hexokinase, but does not inhibit insulin-stimulated glucose transport and 2) phosphorylation of GLUT-4 has no effect on glucose transport in skeletal muscle.

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Carnosol Increases Skeletal Muscle Cell Glucose Uptake via AMPK-Dependent GLUT4 Glucose Transporter Translocation

International Journal of Molecular Sciences ◽

10.3390/ijms19051321 ◽

2018 ◽

Vol 19 (5) ◽

pp. 1321 ◽

Cited By ~ 17

Author(s):

Filip Vlavcheski ◽

David Baron ◽

Ioannis Vlachogiannis ◽

Rebecca MacPherson ◽

Evangelia Tsiani

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Muscle Cell ◽

Glucose Transporter ◽

Skeletal Muscle Cell ◽

Cell Glucose

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Octaphlorethol A, a novel phenolic compound isolated from a brown alga, Ishige foliacea, increases glucose transporter 4-mediated glucose uptake in skeletal muscle cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.03.036 ◽

2012 ◽

Vol 420 (3) ◽

pp. 576-581 ◽

Cited By ~ 34

Author(s):

Seung-Hong Lee ◽

Sung-Myung Kang ◽

Seok-Chun Ko ◽

Dae-Ho Lee ◽

You-Jin Jeon

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Phenolic Compound ◽

Brown Alga ◽

Glucose Transporter ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Glucose Transporter 4

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The effects of muscle contraction and insulin on glucose-transporter translocation in rat skeletal muscle

Biochemical Journal ◽

10.1042/bj2970539 ◽

1994 ◽

Vol 297 (3) ◽

pp. 539-545 ◽

Cited By ~ 48

Author(s):

J T Brozinick ◽

G J Etgen ◽

B B Yaspelkis ◽

J L Ivy

Keyword(s):

Skeletal Muscle ◽

Plasma Membrane ◽

Muscle Contraction ◽

Glucose Uptake ◽

Protein Concentration ◽

Glucose Transporter ◽

Cytochalasin B ◽

Protein Distribution ◽

Sprague Dawley ◽

Glut 4

The effect of electrically induced muscle contraction, insulin (10 m-units/ml) and electrically-induced muscle contraction in the presence of insulin on insulin-regulatable glucose-transporter (GLUT-4) protein distribution was studied in female Sprague-Dawley rats during hindlimb perfusion. Plasma-membrane cytochalasin B binding increased approximately 2-fold, whereas GLUT-4 protein concentration increased approximately 1.5-fold above control with contractions, insulin, or insulin + contraction. Microsomal-membrane cytochalasin B binding and GLUT-4 protein concentration decreased by approx. 30% with insulin or insulin + contraction, but did not significantly decrease with contraction alone. The rate of muscle glucose uptake was assessed by determining the rate of 2-deoxy[3H]glucose accumulation in the soleus, plantaris, and red and white portions of the gastrocnemius. Both contraction and insulin increased glucose uptake significantly and to the same degree in the muscles examined. Insulin + contraction increased glucose uptake above that of insulin or contraction alone, but this effect was only statistically significant in the soleus, plantaris and white gastrocnemius. The combined effects of insulin + contraction of glucose uptake were not fully additive in any of the muscles investigated. These results suggest that (1) insulin and muscle contraction are mobilizing two separate pools of GLUT-4 protein, and (2) the increase in skeletal-muscle glucose uptake due to insulin + contraction is not due to an increase in plasma-membrane GLUT-4 protein concentration above that observed for insulin or contraction alone.

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CaMKKα stimulates skeletal muscle glucose uptake independent of increases in glucose transporter expression

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1154.17 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

J. Matthew Hinkley ◽

Carol A Witczak

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Transporter ◽

Skeletal Muscle Glucose Uptake ◽

Transporter Expression

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

International Journal of Molecular Sciences ◽

10.3390/ijms20215443 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5443 ◽

Cited By ~ 5

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.

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Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00297.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. C377-C385 ◽

Cited By ~ 67

Author(s):

Jonas T. Treebak ◽

Eric B. Taylor ◽

Carol A. Witczak ◽

Ding An ◽

Taro Toyoda ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transporter ◽

Vastus Lateralis ◽

Phosphorylation Site ◽

Rab Gtpase ◽

Vastus Lateralis Muscle ◽

Phosphorylation Sites ◽

Amp Activated Protein Kinase

TBC1D4 (also known as AS160) regulates glucose transporter 4 (GLUT4) translocation and glucose uptake in adipocytes and skeletal muscle. Its mode of action involves phosphorylation of serine (S)/threonine (T) residues by upstream kinases resulting in inactivation of Rab-GTPase-activating protein (Rab-GAP) activity leading to GLUT4 mobilization. The majority of known phosphorylation sites on TBC1D4 lie within the Akt consensus motif and are phosphorylated by insulin stimulation. However, the 5′-AMP-activated protein kinase (AMPK) and other kinases may also phosphorylate TBC1D4, and therefore we hypothesized the presence of additional phosphorylation sites. Mouse skeletal muscles were contracted or stimulated with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), and muscle lysates were subjected to mass spectrometry analyses resulting in identification of novel putative phosphorylation sites on TBC1D4. The surrounding amino acid sequence predicted that S711 would be recognized by AMPK. Using a phosphospecific antibody against S711, we found that AICAR and contraction increased S711 phosphorylation in mouse skeletal muscle, and this increase was abolished in muscle-specific AMPKα2 kinase-dead transgenic mice. Exercise in human vastus lateralis muscle also increased TBC1D4 S711 phosphorylation. Recombinant AMPK, but not Akt1, Akt2, or PKCζ, phosphorylated purified muscle TBC1D4 on S711 in vitro. Interestingly, S711 was also phosphorylated in response to insulin in an Akt2- and rapamycin-independent, but a wortmannin-sensitive, manner, suggesting this site is regulated by one or more additional upstream kinases. Despite increased S711 phosphorylation with AICAR, contraction, and insulin, mutation of S711 to alanine did not alter glucose uptake in response to these stimuli. S711 is a novel TBC1D4 phosphorylation site regulated by AMPK in skeletal muscle.

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Insulin, Muscle Glucose Uptake, and Hexokinase: Revisiting the Road Not Taken

Physiology ◽

10.1152/physiol.00034.2021 ◽

2021 ◽

Author(s):

David H. Wasserman

Keyword(s):

Skeletal Muscle ◽

Cell Membrane ◽

Glucose Uptake ◽

Glucose Transporter ◽

Hexokinase Ii ◽

The Road ◽

Glucose Phosphorylation ◽

Skeletal Muscle Glucose Uptake ◽

Cell Membrane Transport ◽

Glucose Transporter Glut4

Research conducted over the last 50 years has provided insight into the mechanisms by which insulin stimulates glucose transport across the skeletal muscle cell membrane. Transport alone, however, does not result in net glucose uptake as freeglucose equilibrates across the cell membrane and is not metabolized. Glucose uptake requires that glucose is phosphorylated by hexokinases. Phosphorylated glucosecannot leave the cell and is the substrate for metabolism. It is indisputable that glucose phosphorylation is essential for glucose uptake. Major advances have been made in defining the regulation of the insulin-stimulated glucose transporter, GLUT4, in skeletalmuscle. By contrast, the insulin-regulated hexokinase, hexokinase II parallels RobertFrost's Road Not Taken. Here the case is made that an understanding of glucosephosphorylation by hexokinase II is necessary to define the regulation of skeletal muscle glucose uptake in health and insulin resistance. Results of studies from different physiological disciplines that have elegantly described how hexokinase II can beregulated are summarized to provide a framework for potential application to skeletal muscle. Mechanisms by which hexokinase II is regulated in skeletal muscle await rigorous examination.

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