scholarly journals Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control

2019 ◽  
Vol 5 (4) ◽  
pp. eaav4116
Author(s):  
Qiaoli Chen ◽  
Ping Rong ◽  
Sangsang Zhu ◽  
Xinyu Yang ◽  
Qian Ouyang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transporter ◽  
Postprandial Glucose ◽  
Lipid Homeostasis ◽  
Dual Purpose ◽  
Diet Induced Obesity ◽  
Glucose And Lipid Homeostasis ◽  
Lipid Control ◽  
Glucose Transporter Glut4 ◽  
Muscle Insulin Action

How insulin stimulates postprandial uptake of glucose and long-chain fatty acids (LCFAs) into skeletal muscle and the mechanisms by which these events are dampened in diet-induced obesity are incompletely understood. Here, we show that RalGAPα1 is a critical regulator of muscle insulin action and governs both glucose and lipid homeostasis. A high-fat diet increased RalGAPα1 protein but decreased its insulin-responsive Thr735-phosphorylation in skeletal muscle. A RalGAPα1Thr735Ala mutation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice. In contrast, skeletal muscle–specific deletion of RalGAPα1 improved postprandial glucose and lipid control. Mechanistically, these mutations of RalGAPα1 affected translocation of insulin-responsive glucose transporter GLUT4 and fatty acid translocase CD36 via RalA to affect glucose and lipid homeostasis. These data indicated RalGAPα1 as a dual-purpose target, for which we developed a peptide-blockade for improving muscle insulin sensitivity. Our findings have implications for drug discovery to combat metabolic disorders.

scholarly journals RalA controls glucose homeostasis by regulating glucose uptake in brown fat

2018 ◽  
Vol 115 (30) ◽  
pp. 7819-7824 ◽  
Author(s):  
Yuliya Skorobogatko ◽  
Morgan Dragan ◽  
Claudia Cordon ◽  
Shannon M. Reilly ◽  
Chao-Wei Hung ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Brown Fat ◽  
Specific Chemical ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Chemical Inhibitors ◽  
Glucose Transporter Glut4

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.

In vivo effect of Trigonella foenum graecum on the expression of pyruvate kinase, phosphoenolpyruvate carboxykinase, and distribution of glucose transporter (GLUT4) in alloxan-diabetic rats

2006 ◽  
Vol 84 (6) ◽  
pp. 647-654 ◽  
Author(s):  
Sameer Mohammad ◽  
Asia Taha ◽  
Kamal Akhtar ◽  
R.N.K. Bamezai ◽  
Najma Zaheer Baquer
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Kinase ◽  
Plasma Glucose ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Transporter ◽  
Diabetic Rats ◽  
Altered Expression ◽  
Glucose Levels ◽  
Glucose Transporter Glut4

Plasma glucose levels are maintained by a precise balance between glucose production and its use. Liver pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK), 2 key enzymes of glycolysis and gluconeogenesis, respectively, play a crucial role in this glucose homeostasis along with skeletal muscle glucose transporter (GLUT4). In the diabetic state, this balance is disturbed owing to the absence of insulin, the principal factor controlling this regulation. In the present study, alloxan-diabetic animals having high glucose levels of more than 300 mmol/L have been taken and the administration of Trigonella seed powder (TSP) to the diabetic animals was assessed for its effect on the expression of PK and PEPCK in liver and GLUT4 distribution in skeletal muscle of alloxan-diabetic rats. TSP treatment to the diabetic animals resulted in a marked decrease in the plasma glucose levels. Trigonella treatment partially restored the altered expression of PK and PEPCK. TSP treatment also corrected the alterations in the distribution of GLUT4 in the skeletal muscle.

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

Physiology ◽  
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.

Immunolocalization of glucose transporter GLUT4 within human skeletal muscle

Diabetes ◽  
1991 ◽  
Vol 40 (1) ◽  
pp. 150-154 ◽  
Author(s):  
J. E. Friedman ◽  
R. W. Dudek ◽  
D. S. Whitehead ◽  
D. L. Downes ◽  
W. R. Frisell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Glucose Transporter ◽  
Glucose Transporter Glut4

scholarly journals Signalling components involved in contraction-inducible substrate uptake into cardiac myocytes

2004 ◽  
Vol 63 (2) ◽  
pp. 251-258 ◽  
Author(s):  
Joost J. F. P. Luiken ◽  
Susan L. M. Coort ◽  
Debby P. Y. Koonen ◽  
Arend Bonen ◽  
Jan F. C. Glatz
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Glucose Transporter ◽  
Contractile Activity ◽  
Mechanical Activity ◽  
Substrate Uptake ◽  
Extracellular Signal ◽  
Intracellular Compartments ◽  
Glucose Transporter Glut4

Glucose and long-chain fatty acids (LCFA) are two major substrates used by heart and skeletal muscle to support contractile activity. In quiescent cardiac myocytes a substantial portion of the glucose transporter GLUT4 and the putative LCFA transporter fatty acid translocase (FAT)/CD36 are stored in intracellular compartments. Induction of cellular contraction by electrical stimulation results in enhanced uptake of both glucose and LCFA through translocation of GLUT4 and FAT/CD36 respectively to the sarcolemma. The involvement of protein kinase A, AMP-activated protein kinase (AMPK), protein kinase C (PKC) isoforms and the extracellular signal-regulated kinases was evaluated in cardiac myocytes as candidate signalling enzymes involved in recruiting these transporters in response to contraction. The collected evidence excluded the involvement of PKA and implicated an important role for AMPK and for one (or more) PKC isoform(s) in contraction-induced translocation of both GLUT4 and FAT/CD36. The unravelling of further components along this contraction pathway can provide valuable information on the coordinated regulation of the uptake of glucose and of LCFA by an increase in mechanical activity of heart and skeletal muscle.

scholarly journals Phosphatidylinositol 4-kinase, but not phosphatidylinositol 3-kinase, is present in GLUT4-containing vesicles isolated from rat skeletal muscle

1998 ◽  
Vol 335 (2) ◽  
pp. 351-356 ◽  
Author(s):  
S⊘ren KRISTIANSEN ◽  
Toolsie RAMLAL ◽  
Amira KLIP
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transporter ◽  
Kinase Activity ◽  
Surface Membrane ◽  
Fold Increase ◽  
Rat Skeletal Muscle ◽  
Membrane Compartment ◽  
Intracellular Storage ◽  
Glucose Transporter Glut4 ◽  
Adipose Cells

Insulin stimulates the rate of glucose transport into muscle and adipose cells by translocation of glucose transporter (GLUT4)-containing vesicles from an intracellular storage pool to the surface membrane. This event is mediated through the insulin receptor substrates (IRSs), which in turn activate phosphatidylinositol (PI) 3-kinase isoforms. It has been suggested that insulin causes attachment of PI 3-kinases to the intracellular GLUT4-containing vesicles in rat adipose cells. Furthermore, it has also been shown that GLUT4-containing vesicles in adipose cells contain a PI 4-kinase. In the present study we investigate whether GLUT4-containing vesicles isolated from rat skeletal muscle display PI 3-kinase and/or PI 4-kinase activities. Insulin stimulation caused a rapid increase (5–15-fold increase compared with control) in the intracellular cytosolic IRS-1-associated PI-3 kinase activity. This PI 3-kinase activity was also present in a membrane preparation containing the insulin-regulatable pool of GLUT4 transporters. However, when GLUT4-containing vesicles were isolated by immunoprecipitation from basal and insulin-stimulated (3 min) skeletal muscle, the vesicles displayed PI 4-kinase, but not PI 3-kinase, activity. Insulin did not regulate the PI 4-kinase activity in the GLUT4-containing vesicles. In conclusion, GLUT4-containing vesicles from rat skeletal muscle contain a PI 4-kinase, but not a PI 3-kinase. It is suggested that, in skeletal muscle, insulin causes activation of the IRS/PI 3-kinase complex in an intracellular membrane compartment associated closely with the GLUT4-containing vesicles, but not in the GLUT4-containing vesicles themselves.

scholarly journals Regulation of cell surface GLUT4 in skeletal muscle of transgenic mice

1997 ◽  
Vol 321 (1) ◽  
pp. 75-81 ◽  
Author(s):  
Joseph T. BROZINICK ◽  
Scott C. McCOID ◽  
Thomas H. REYNOLDS ◽  
Cindy M. WILSON ◽  
Ralph W. STEVENSON ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Surface ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Subcellular Fractionation ◽  
Muscle Membrane ◽  
Transport Activity ◽  
Hindlimb Muscles ◽  
Subcellular Membrane ◽  
Glucose Transporter Glut4

Marked overexpression of the glucose transporter GLUT4 in skeletal muscle membrane fractions of GLUT4 transgenic (TG) mice is accompanied by disproportionately small increases in basal and insulin-stimulated glucose transport activity. Thus we have assessed cell surface GLUT4 by photolabelling with the membrane-impermeant reagent 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis(d-mannos-4-yloxy)-2-propylamine (ATB-BMPA) and measured the corresponding glucose transport activity using 2-deoxyglucose in isolated extensor digitorum longus (EDL) muscles from non-transgenic (NTG) and GLUT4 TG mice in the absence and presence of 13.3 nM (2000 µ-units/ml) insulin, without or with hypoxia as a model of muscle contraction. TG mice displayed elevated rates of glucose transport activity under basal and insulin-stimulated conditions, and in the presence of insulin plus hypoxia, compared with NTG mice. Photoaffinity labelling of cell surface GLUT4 indicated corresponding elevations in plasma membrane GLUT4 in the basal and insulin-stimulated states, and with insulin plus hypoxia, but no difference in cell surface GLUT4 during hypoxia stimulation. Subcellular fractionation of hindlimb muscles confirmed the previously observed 3-fold overexpression of GLUT4 in the TG compared with the NTG mice. These results suggest that: (1) alterations in glucose transport activity which occur with GLUT4 overexpression in EDL muscles are directly related to cell surface GLUT4 content, regardless of the levels observed in the corresponding subcellular membrane fractions, (2) while overexpression of GLUT4 influences both basal and insulin-stimulated glucose transport activity, the response to hypoxia/contraction-stimulated glucose transport is unchanged, and (3) subcellular fractionation provides little insight into the subcellular trafficking of GLUT4, and whatever relationship is demonstrated in EDL muscles from NTG mice is disrupted on GLUT4 overexpression.

scholarly journals Reduced Expression of Focal Adhesion Kinase Disrupts Insulin Action in Skeletal Muscle Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3333-3343 ◽  
Author(s):  
Danshan Huang ◽  
Michelle Khoe ◽  
Dusko Ilic ◽  
Michael Bryer-Ash
Keyword(s):  
Skeletal Muscle ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Insulin Action ◽  
Glucose Transporter ◽  
Glycogen Synthesis ◽  
Growth Factor Signaling ◽  
L6 Myotubes ◽  
Normal Glucose ◽  
Muscle Insulin Action

Integrins mediate interactions between cells and extracellular matrix proteins that modulate growth factor signaling. Focal adhesion kinase (FAK) is a key multifunctional integrin pathway protein. We recently reported that disruption of FAK impairs insulin-mediated glycogen synthesis in hepatocytes. To test the hypothesis that FAK regulates skeletal muscle insulin action, we reduced FAK expression in L6 myotubes using FAK antisense. In untransfected myotubes, insulin stimulated both FAK tyrosine phosphorylation and kinase activity. Cells treated with antisense FAK showed 78 and 53% reductions in FAK mRNA and FAK protein, respectively, whereas insulin receptor substrate 1/2 and paxillin abundance were unaffected. Insulin-stimulated U-14C-glucose incorporation into glycogen was abolished by FAK antisense, and 2-deoxy-glucose uptake and glucose transporter 4 (GLUT4) translocation were both markedly attenuated. Antisense FAK did not alter GLUT1 or GLUT3 protein abundance. Immunofluorescence staining showed decreased FAK Tyr397 phosphorylation and reduced actin stress fibers. Thus, in skeletal myotubes, FAK regulates the insulin-mediated cytoskeletal rearrangement essential for normal glucose transport and glycogen synthesis. Integrin signaling may play an important regulatory role in muscle insulin action.

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