Developmental reprogramming of rat GLUT-5 requires de novo mRNA and protein synthesis

Fructose transporter (GLUT-5) expression is low in mid-weaning rat small intestine, increases normally after weaning is completed, and can be precociously induced by premature consumption of a high-fructose (HF) diet. In this study, an in vivo perfusion model was used to determine the mechanisms regulating this substrate-induced reprogramming of GLUT-5 development. HF (100 mM) but not high-glucose (HG) perfusion increased GLUT-5 activity and mRNA abundance. In contrast, HF and HG perfusion had no effect on Na+-dependent glucose transporter (SGLT-1) expression but increased c- fos and c- jun expression. Intraperitoneal injection of actinomycin D before intestinal perfusion blocked the HF-induced increase in fructose uptake rate and GLUT-5 mRNA abundance. Actinomycin D also prevented the perfusion-induced increase in c- fos and c- jun mRNA abundance but did not affect glucose uptake rate and SGLT-1 mRNA abundance. Cycloheximide blocked the HF-induced increase in fructose uptake rate but not the increase in GLUT-5 mRNA abundance and had no effect on glucose uptake rate and SGLT-1 mRNA abundance. In neonatal rats, the substrate-induced reprogramming of intestinal fructose transport is likely to involve transcription and translation of the GLUT-5 gene.

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Antihyperglycemic and Antilipidemic Effects of the Ethanol Extract Mixture of Ligularia fischeri and Momordica charantia in Type II Diabetes-Mimicking Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3468040 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15

Author(s):

Hyun Jin Baek ◽

Yong Joon Jeong ◽

Jeong Eun Kwon ◽

Jong Sung Ra ◽

Sung Ryul Lee ◽

...

Keyword(s):

Glucose Uptake ◽

Uptake Rate ◽

Glucose Transporter ◽

Synergistic Effects ◽

Momordica Charantia ◽

C2c12 Cells ◽

Peroxisome Proliferator ◽

Glucose Uptake Rate ◽

Ligularia Fischeri

The extract of the Momordica charantia fruit (MCE) is recognized as an alternative treatment for diabetes. The extract of Ligularia fischeri leaves (LFE) is traditionally used as a folk medicine for treating inflammatory diseases in Korea as well. In this study, we investigated the synergistic effect of MCE combined with LFE on antihyperglycemic and antihyperlipidemic potentials. Based on the α-glucosidase inhibitory effect and promotion of adipocyte differentiation in the 3T3-L1 cell line, the MLM was prepared with MCE:LFE (8:2 weight:weight). MLM showed the synergistic effects in the promotion of the glucose uptake rate, suppression of dipeptidyl peptidase-4 (DPP-4) mRNA expression, upregulation of an insulin receptor substrate and glucose transporter type-4 expression, and an increase in insulin-associated signaling in C2C12 cells. In addition, the efficacy of peroxisome proliferator-activated receptor-γ agonism and glucose uptake rate by MLM supplementation was significantly enhanced in vitro. Then, the antihyperglycemic and antihyperlipidemic effects of MCE, LFE, and MLM at the dose of 50, 100, and 200 mg/kg/day (n = 6 per each group) were determined in streptozotocin (STZ)-insulted mice fed an atherogenic diet (ATH) for 4 weeks. In addition, MLM (50, 100, and 200 mg/kg/day, n = 5 per each group) was supplemented in ATH-fed db/db mice for 10 weeks. Compared with MCE or LFE alone, MLM supplementation led to a more significant reduction of glucose levels in both STZ/ATH and db/db/ATH mice as well as lowered lipid profiles in STZ/ATH mice. In addition, the stimulation of islet of Langerhans regeneration was more pronounced by MLM supplementation in both mice models. In conclusion, antihyperglycemic and antihyperlipidemic effects were strengthened by the combined extracts of L. fischeri and M. charantia (MLM) in diabetes-mimicking mice.

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Fructose-responsive genes in the small intestine of neonatal rats

Physiological Genomics ◽

10.1152/physiolgenomics.00056.2004 ◽

2004 ◽

Vol 18 (2) ◽

pp. 206-217 ◽

Cited By ~ 38

Author(s):

Xue-Lin Cui ◽

Patricia Soteropoulos ◽

Peter Tolias ◽

Ronaldo P. Ferraris

Keyword(s):

Small Intestine ◽

De Novo ◽

Mrna Abundance ◽

Metabolic Intermediate ◽

Gluconeogenic Enzymes ◽

Fructose Metabolism ◽

High Fructose ◽

Fructose 1,6 Bisphosphatase ◽

Dietary Fructose

The intestinal brush border fructose transporter GLUT5 (SLC2A5) typically appears in rats after weaning is completed. However, precocious consumption of dietary fructose or in vivo perfusion for 4 h of the small intestine with high fructose (HF) specifically stimulates de novo synthesis of GLUT5 mRNA and protein before weaning is completed. Intermediary signals linking the substrate, fructose, to GLUT5 transcription are not known but should also respond to fructose perfusion. Hence, we used microarray hybridization and RT-PCR to identify genes whose expression levels change during HF relative to high-glucose (HG) perfusion. Expression of GLUT5 and NaPi2b, the intestinal Na+-dependent phosphate transporter, dramatically increased and decreased, respectively, with HF perfusion for 4 h. Expression of >20 genes, including two key gluconeogenic enzymes, glucose-6-phosphatase (G6P) and fructose-1,6-bisphosphatase, also increased markedly, along with fructose-2,6-bisphosphatase, an enzyme unique to fructose metabolism and regulating fructose-1,6-bisphosphatase activity. GLUT5 and G6P mRNA abundance, which increased dramatically with HF relative to HG, α-methylglucose, and normal Ringer perfusion, may be tightly and specifically linked to changes in intestinal luminal fructose but not glucose concentrations. G6P but not GLUT5 mRNA abundance increased after just 20 min of HF perfusion. This cluster of gluconeogenic enzymes and their common metabolic intermediate fructose-6-phosphate may regulate fructose metabolism and GLUT5 expression in the small intestine.

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Impaired Glucose Transporter Activity in Pressure-Overload Hypertrophy Is an Early Indicator of Progression to Failure

Circulation ◽

10.1161/circ.100.suppl_2.ii-187 ◽

1999 ◽

Vol 100 (suppl_2) ◽

Author(s):

Ingeborg Friehs ◽

Adrian M. Moran ◽

Christof Stamm ◽

Steven D. Colan ◽

Koh Takeuchi ◽

...

Keyword(s):

Glucose Uptake ◽

Uptake Rate ◽

Glucose Transporter ◽

Left Ventricular ◽

Ventricular Dilatation ◽

Resonance Spectroscopy ◽

Glucose Uptake Rate ◽

Transporter Protein ◽

Increase Glucose Uptake ◽

Wet Weight

Background —Severe hypertrophy and heart failure are important risk factors in cardiac surgery. Early adaptive changes in hypertrophy include increased ventricular mass-to-cavity volume ratio (M/V ratio) and increased dependence on glucose for energy metabolism. However, glucose uptake is decreased in the late stages of hypertrophy when ventricular dilatation and failure are present. We hypothesized that impaired glucose uptake would be evident early in the progression of hypertrophy and associated with the onset of ventricular dilatation. Methods and Results —Ten-day-old rabbits underwent banding of the descending aorta. Development of hypertrophy was followed by transthoracic echocardiography to measure left ventricular M/V ratio. Glucose uptake rate, as determined by 31 P-nuclear magnetic resonance spectroscopy measuring 2-deoxyglucose conversion to 2-deoxyglucose-6-phosphate, was measured in isolated perfused hearts obtained from banded rabbits when M/V ratio had increased by 15% from baseline (compensated hypertrophy) and by 30% from baseline (early-decompensated hypertrophy). In age-matched control animals, the rate of glucose uptake was 0.61±0.08 μmol · g of wet weight −1 · 30 min −1 (mean±SEM). With a 15% M/V ratio increase, glucose uptake rate remained at control levels (0.6±0.05 μmol · g of wet weight −1 · 30 min −1 ), compared with hearts with 30% increased M/V ratios, where glucose uptake was significantly lower (0.42±0.05 μmol · g of wet weight −1 · 30 min −1 ; P ≤0.05). Glucose transporter protein expression was the same in all groups. Conclusions —Glucose uptake rate is maintained during compensated hypertrophy. However, coinciding with severe hypertrophy, preceding ventricular dilatation, and glucose transporter protein downregulation, glucose uptake is significantly decreased. Because of the increased dependence of the hypertrophied hearts on glucose use, we speculate that this impairment may be a contributing factor in the progression to failure.

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Time-dependent physiological regulation of ovine placental GLUT-3 glucose transporter protein

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.279.6.r2252 ◽

2000 ◽

Vol 279 (6) ◽

pp. R2252-R2261 ◽

Cited By ~ 24

Author(s):

Utpala G. Das ◽

Jing He ◽

Richard A. Ehrhardt ◽

William W. Hay ◽

Sherin U. Devaskar

Keyword(s):

Glucose Uptake ◽

Uptake Rate ◽

Glucose Transporter ◽

Late Gestation ◽

Time Dependent ◽

Apical Surface ◽

Glucose Uptake Rate ◽

Glut 1 ◽

Chronic Hyperglycemia ◽

Maternal Hyperglycemia

We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17–20 days of chronic hyperglycemia ( P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.

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Enhancement of glucose uptake in stunned myocardium: role of glucose transporter

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1122 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1122-H1130 ◽

Cited By ~ 4

Author(s):

K. Hashimoto ◽

T. Nishimura ◽

M. Ishikawa ◽

K. Koga ◽

T. Mori ◽

...

Keyword(s):

Glucose Uptake ◽

Uptake Rate ◽

Time Course ◽

Glucose Transporter ◽

Stunned Myocardium ◽

Rat Myocardium ◽

Glucose Uptake Rate ◽

Myocardial Glucose Uptake ◽

Phenylisopropyl Adenosine

This study quantifies the myocardial glucose uptake and clarifies the pathway of augmented glucose uptake in myocardium reperfused after a brief period of ischemia (stunned myocardium). The glucose uptake rate was determined from the time course of the sugar phosphate (SP) resonance in rat myocardium (d[SP]/dt) with 31P nuclear magnetic resonance after the substitution of glucose with its analog 2-deoxyglucose. The d[SP]/dt in stunned myocardium [1.03 +/- 0.05 (SE) micromol x g wet wt(-1) x min(-1); n = 8] increased significantly compared with nonischemic control myocardium (0.18 +/- 0.03 micromol x g wet wt(-1) x min(-1); n = 8; P < 0.0001), reaching the maximal stimulatory uptake rate during exposure to insulin (1.05 +/- 0.04 micromol x g wet wt(-1) x min(-1); n = 8). Twenty minutes after reperfusion, the d[SP]/dt was still augmented (0.41 +/- 0.05 micromol x g wet wt(-1) x min(-1); n = 5; P < 0.05 vs. control myocardium). To elucidate further the mechanism of augmented glucose uptake, N6-(L-2-phenylisopropyl)-adenosine (PIA; 100 micromol/l), a potent blocker of the glucose transporter, was administered to stunned hearts and, as a control, to insulin-stimulated hearts. PIA significantly and comparably inhibited the increase in d[SP]/dt in stunned myocardium (0.36 +/- 0.07 micromol x g wet wt(-1) x min(-1); n = 4; P < 0.0001 vs. without PIA) and in insulin-stimulated myocardium (0.38 +/- 0.02 micromol x g wet wt(-1) x min(-1); n = 4; P < 0.0001 vs. without PIA). These results indicate that the augmented glucose uptake in stunned myocardium is maintained by the glucose transporter, the amount of which is almost equal to that which can be maximally recruited by insulin.

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Glucose Transporter 8 (GLUT8) Regulates Enterocyte Fructose Transport and Global Mammalian Fructose Utilization

Endocrinology ◽

10.1210/en.2012-1541 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4181-4191 ◽

Cited By ~ 42

Author(s):

Brian J. DeBosch ◽

Maggie Chi ◽

Kelle H. Moley

Keyword(s):

Glucose Transporter ◽

Serum Insulin ◽

Density Lipoprotein ◽

Wild Type ◽

In Vivo Models ◽

The Metabolic Syndrome ◽

High Fructose

Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [14C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8-deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild-type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome.

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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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Genetic impairment of AMPKα2 signaling does not reduce muscle glucose uptake during treadmill exercise in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90653.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. E924-E934 ◽

Cited By ~ 65

Author(s):

Stine J. Maarbjerg ◽

Sebastian B. Jørgensen ◽

Adam J. Rose ◽

Jacob Jeppesen ◽

Thomas E. Jensen ◽

...

Keyword(s):

Glucose Uptake ◽

Glucose Transporter ◽

Treadmill Exercise ◽

Surface Membrane ◽

Absolute Intensity ◽

Wild Type ◽

Running Speed ◽

Mouse Muscle ◽

Glucose Clearance

Some studies suggest that the 5′-AMP-activated protein kinase (AMPK) is important in regulating muscle glucose uptake in response to intense electrically stimulated contractions. However, it is unknown whether AMPK regulates muscle glucose uptake during in vivo exercise. We studied this in male and female mice overexpressing kinase-dead AMPKα2 (AMPK-KD) in skeletal and heart muscles. Wild-type and AMPK-KD mice were exercised at the same absolute intensity and the same relative intensity (30 and 70% of individual maximal running speed) to correct for reduced exercise capacity of the AMPK-KD mouse. Muscle glucose clearance was measured using 2-deoxy-[3H]glucose as tracer. In wild-type mice, glucose clearance was increased at 30 and 70% of maximal running speed by 40 and 350% in the quadriceps muscle and by 120 and 380% in gastrocnemius muscle, respectively. Glucose clearance was not lower in AMPK-KD muscles compared with wild-type regardless of whether animals were exercised at the same relative or the same absolute intensity. In agreement, surface membrane content of the glucose transporter GLUT4 was increased similarly in AMPK-KD and wild-type muscle in response to running. We also measured signaling of alternative exercise-sensitive pathways that might be compensatorily increased in AMPK-KD muscles. However, increases in phosphorylation of CaMKII, Trisk95, p38 MAPK, and ERK1/2 were not higher in AMPK-KD than in WT muscle. Collectively, these findings suggest that AMPKα2 signaling is not essential in regulating glucose uptake in mouse skeletal muscle during treadmill exercise and that other mechanisms play a central role.

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RalA controls glucose homeostasis by regulating glucose uptake in brown fat

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801050115 ◽

2018 ◽

Vol 115 (30) ◽

pp. 7819-7824 ◽

Cited By ~ 16

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.

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

Circulation Research ◽

10.1161/res.121.suppl_1.158 ◽

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.

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