scholarly journals Glutamate increases glucose uptake in L6 myotubes in a concentration- and time-dependent manner that is mediated by AMPK

2018 ◽  
Vol 43 (12) ◽  
pp. 1307-1313 ◽  
Author(s):  
Tyler Barnes ◽  
Katie M. Di Sebastiano ◽  
Filip Vlavcheski ◽  
Joe Quadrilatero ◽  
Evangelia Litsa Tsiani ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Serum Insulin ◽  
Insulin Response ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
L6 Myotubes ◽  
Compound C ◽  
Carbohydrate Load

Various in vivo studies have investigated the insulin response that is elicited when glutamate is elevated in circulation or in a given tissue; fewer studies have investigated the effects of glutamate on glucose uptake and handling. Glutamate ingestion in humans can attenuate rises in blood glucose following a carbohydrate load in the absence of increases in serum insulin concentrations. However, the underlying mechanisms have yet to be investigated. To elucidate the effects of glutamate on glucose handling in skeletal muscle tissue, differentiated rat L6 myocytes were treated with glutamate, and glucose uptake was assessed with the use of 2-[3H]-deoxy-d-glucose ([3H]-2-DG). Cells treated with 2 mmol/L glutamate experienced the greatest increase in [3H]-2-DG uptake relative to the control condition (177% ± 2% of control, P < 0.001) and the uptake was similar to that of metformin (184% ± 4%, P < 0.001). In line with these findings, differentiated glucose transporter 4 (GLUT4)-overexpressing myotubes treated with 2 mmol/L glutamate displayed significantly increased GLUT4 translocation when compared with the control condition (159% ± 8% of control, P < 0.001) and to an extent similar to that of insulin and metformin (181% ± 7% and 159% ± 12%, respectively). An AMP-activated protein kinase (AMPK) inhibitor (Compound C) abolished the glutamate-stimulated glucose uptake (98% ± 12% of control), and Western blotting revealed significantly elevated AMPK phosphorylation (278% ± 17% of control, P < 0.001) by glutamate. Our findings suggest that when muscle cells are exposed to increased glutamate concentrations, glucose uptake into these cells is augmented through AMPK activation, through mechanisms distinct from those of insulin and leucine.

Increased skeletal muscle glucose uptake by rosemary extract through AMPK activation

2015 ◽  
Vol 40 (4) ◽  
pp. 407-413 ◽  
Author(s):  
Madina Naimi ◽  
Theodoros Tsakiridis ◽  
Theocharis C. Stamatatos ◽  
Dimitris I. Alexandropoulos ◽  
Evangelia Tsiani
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Rosemary Extract ◽  
Dependent Manner ◽  
Ampk Activation ◽  
Compound C ◽  
Increase Glucose Uptake

Stimulation of the energy sensor AMP-activated kinase (AMPK) has been viewed as a targeted approach to increase glucose uptake by skeletal muscle and control blood glucose homeostasis. Rosemary extract (RE) has been reported to activate AMPK in hepatocytes and reduce blood glucose levels in vivo but its effects on skeletal muscle are not known. In the present study, we examined the effects of RE and the mechanism of regulation of glucose uptake in muscle cells. RE stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 5 μg/mL of RE for 4 h (184% ± 5.07% of control, p < 0.001), a response comparable to maximum insulin (207% ± 5.26%, p < 0.001) and metformin (216% ± 8.77%, p < 0.001) stimulation. RE did not affect insulin receptor substrate 1 and Akt phosphorylation but significantly increased AMPK and acetyl-CoA carboxylase phosphorylation. Furthermore, the RE-stimulated glucose uptake was significantly reduced by the AMPK inhibitor compound C, but remained unchanged by the PI3K inhibitor, wortmannin. RE did not affect GLUT4 or GLUT1 glucose transporter translocation in contrast with a significant translocation of both transporters seen with insulin or metformin treatment. Our study is the first to show a direct effect of RE on muscle cell glucose uptake by a mechanism that involves AMPK activation.

Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle

2007 ◽  
Vol 293 (4) ◽  
pp. E1062-E1068 ◽  
Author(s):  
Vitor A. Lira ◽  
Quinlyn A. Soltow ◽  
Jodi H. D. Long ◽  
Jenna L. Betters ◽  
Jeff E. Sellman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Glucose Transporter ◽  
No Donor ◽  
Ampk Signaling ◽  
L6 Myotubes ◽  
Glut4 Expression ◽  
Compound C ◽  
Cgmp Analog

Nitric oxide (NO) and 5′-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4) and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO donor S-nitroso- N-penicillamine (SNAP, 1 and 10 μM) significantly increased GLUT4 mRNA (∼3-fold; P < 0.05) in L6 myotubes, and cotreatment with the AMPK inhibitor compound C ablated this effect. The cGMP analog 8-bromo-cGMP (8-Br-cGMP, 2 mM) increased GLUT4 mRNA by ∼50% ( P < 0.05). GLUT4 protein expression was elevated 40% by 2 days treatment with 8-Br-cGMP, whereas 6 days treatment with 10 μM SNAP increased GLUT4 expression by 65%. Cotreatment of cultures with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one prevented the SNAP-induced increase in GLUT4 protein. SNAP (10 μM) also induced significant phosphorylation of α-AMPK and acetyl-CoA carboxylase and translocation of phosphorylated α-AMPK to the nucleus. Furthermore, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 16 h presented an approximately ninefold increase in GLUT4 mRNA, whereas cotreatment with the non-isoform-specific NOS inhibitor NG-nitro-l-arginine methyl ester, prevented ∼70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12 h after AICAR injection, and this induction was reduced by ∼50% in animals cotreated with the neuronal and inducible nitric oxide synthases selective inhibitor 1-(2-trifluoromethyl-phenyl)-imidazole. We conclude that, in skeletal muscle, NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.

Di(2-ethylhexyl)phthalate exposure impairs insulin receptor and glucose transporter 4 gene expression in L6 myotubes

2013 ◽  
Vol 33 (7) ◽  
pp. 685-700 ◽  
Author(s):  
P Rajesh ◽  
K Balasubramanian
Keyword(s):  
Gene Expression ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Negative Influence ◽  
Receptor Protein ◽  
Dependent Manner ◽  
L6 Myotubes ◽  
Dose Dependent

Di(2-ethyl hexyl)-phthalate (DEHP) is an endocrine disrupter and is the most abundantly used phthalate derivative, which is suspected to be an inevitable environmental exposure contributing to the increasing incidence of type-2 diabetes in humans. Therefore, the present study was designed to address the dose-dependent effects of DEHP on insulin signaling molecules in L6 myotubes. L6 myotubes were exposed to different concentrations (25, 50, and 100 μM) of DEHP for 24 h. At the end of exposure, cells were utilized for assessing various parameters. Insulin receptor and glucose transporter4 (GLUT4) gene expression, insulin receptor protein concentration, glucose uptake and oxidation, and enzymatic and nonenzymatic antioxidants were significantly reduced, but glutamine fructose-6-phosphate amidotransferase, nitric oxide, lipid peroxidation, and reactive oxygen species levels were elevated in a dose-dependent manner in L6 myotubes exposed to DEHP. The present study in turn shows the direct adverse effect of DEHP on the expression of insulin receptor and GLUT4 gene, glucose uptake, and oxidation in L6 myotubes suggesting that DEHP exposure may have a negative influence on insulin signaling.

scholarly journals Dictyostelium Differentiation-Inducing Factor-1 Promotes Glucose Uptake, at Least in Part, via an AMPK-Dependent Pathway in Mouse 3T3-L1 Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2293
Author(s):  
Yuzuru Kubohara ◽  
Yoshimi Homma ◽  
Hiroshi Shibata ◽  
Yoshiteru Oshima ◽  
Haruhisa Kikuchi
Keyword(s):  
Glucose Uptake ◽  
Mammalian Cells ◽  
Glucose Consumption ◽  
Cellular Slime Mold ◽  
Dependent Manner ◽  
Metabolome Analysis ◽  
Compound C ◽  
Dependent Pathway

Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 mM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 mM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

Deoxyandrographolide promotes glucose uptake through glucose transporter-4 translocation to plasma membrane in L6 myotubes and exerts antihyperglycemic effect in vivo

2015 ◽  
Vol 768 ◽  
pp. 207-216 ◽  
Author(s):  
Deepti Arha ◽  
Sukanya Pandeti ◽  
Akansha Mishra ◽  
Swayam Prakash Srivastava ◽  
Arvind Kumar Srivastava ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Transporter 4 ◽  
Antihyperglycemic Effect ◽  
L6 Myotubes

p38γ MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle

2004 ◽  
Vol 286 (2) ◽  
pp. R342-R349 ◽  
Author(s):  
Richard C. Ho ◽  
Oscar Alcazar ◽  
Nobuharu Fujii ◽  
Michael F. Hirshman ◽  
Laurie J. Goodyear
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Adult Skeletal Muscle ◽  
Peripheral Tissues ◽  
L6 Myotubes ◽  
Regulation Of Contraction ◽  
Transporter Expression

Skeletal muscle expresses at least three p38 MAPKs (α, β, γ). However, no studies have examined the potential regulation of glucose uptake by p38γ, the isoform predominantly expressed in skeletal muscle and highly regulated by exercise. L6 myotubes were transfected with empty vector (pCAGGS), activating MKK6 (MKK6CA), or p38γ-specific siRNA. MKK6CA-transfected cells had higher rates of basal 2-deoxy-d-[3H]glucose (2-DG) uptake ( P < 0.05) but lower rates of 2,4-dinitrophenol (DNP)-stimulated glucose uptake, an uncoupler of oxidative phosphorylation that operates through an insulin-independent mechanism ( P < 0.05). These effects were reversed when MKK6CA cells were cotransfected with p38γ-specific siRNA. To determine whether the p38γ isoform is involved in the regulation of contraction-stimulated glucose uptake in adult skeletal muscle, the tibialis anterior muscles of mice were injected with pCAGGS or wild-type p38γ (p38γWT) followed by intramuscular electroporation. Basal and contraction-stimulated 2-DG uptake in vivo was determined 14 days later. Overexpression of p38γWT resulted in higher basal rates of glucose uptake compared with pCAGGS ( P < 0.05). Muscles overexpressing p38γWT showed a trend for lower in situ contraction-mediated glucose uptake ( P = 0.08) and significantly lower total GLUT4 levels ( P < 0.05). These data suggest that p38γ increases basal glucose uptake and decreases DNP- and contraction-stimulated glucose uptake, partially by affecting levels of glucose transporter expression in skeletal muscle. These findings are consistent with the hypothesis that activation of stress kinases such as p38 are negative regulators of stimulated glucose uptake in peripheral tissues.

scholarly journals Quercetin-3-O-glucoside Improves Glucose Tolerance in Rats and Decreases Intestinal Sugar Uptake in Caco-2 Cells

2017 ◽  
Vol 12 (11) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
Denys Torres-Villarreal ◽  
Alberto Camacho ◽  
Fermín I. Milagro ◽  
Rocío Ortiz-Lopez ◽  
Ana Laura de la Garza
Keyword(s):  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
In Vivo Studies ◽  
Sugar Uptake ◽  
Oral Glucose ◽  
Rt Pcr ◽  
Glucose Transporter 1 ◽  
Glucose Transporter 2

Flavonoid-rich foods intake has been associated with lower risk of non-communicable chronic diseases. Quercetin is the most abundant flavonoid in nature (fruits, vegetables, leaves and grains) as well as the most consumed flavonol. This study aims to investigate the potential effects of its conjugated form quercetin-3- O-glucoside (or isoquercetin) on glucose metabolism in rats and Caco-2 cells. To analyse the effect of quercetin-3- O-glucoside on postprandial hyperglycemia, an oral glucose tolerance test (OGTT) was conducted in Wistar rats. Additionally, Caco-2 cells were used to determine the effect of quercetin-3- O-glucoside (30 to 60 μM) on mRNA expression of genes involved in glucose uptake by RT-PCR. Thereby, in vivo studies demonstrated that quercetin-3- O-glucoside decreased blood glucose levels evaluated by OGTT in rats. Furthermore, in the presence of Na+, quercetin-3- O-glucoside inhibited methylglucoside (MG) uptake in enterocytes and both sodium dependent glucose transporter-1 (SGLT1)- and glucose transporter-2 (GLUT2)-mediated glucose uptake were downregulated in Caco-2 cells incubated with quercetin-3- O-glucoside. In summary, our results show that quercetin-3- O-glucoside improves postprandial glycemic control in rats and reduces sugar uptake in Caco-2 cells, possible by decreasing the expression of glucose transporters (SGLT1 and GLUT2) according to the results obtained through RT-PCR.

scholarly journals Antidiabetic Effect of Taxifolin in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Hyperglycemia and Hyperuricemia

2021 ◽  
Vol 43 (3) ◽  
pp. 1293-1306
Author(s):  
Shinji Kondo ◽  
Shin-ichi Adachi ◽  
Fumiaki Yoshizawa ◽  
Kazumi Yagasaki
Keyword(s):  
Protein Kinase ◽  
Glucose Transporter ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
L6 Myotubes ◽  
Compound C ◽  
Type 2 Diabetic

Muscle is the largest tissue in our body and plays an important role in glucose homeostasis and hence diabetes. In the present study, we examined the effects of taxifolin (TXF) on glucose metabolism in cultured L6 muscle cells (myotubes) and in type 2 diabetic (T2D) model KK-Ay/Ta mice. TXF dose-dependently increased glucose uptake (GU) in L6 myotubes under the condition of insulin absence. This increase in GU was partially, but significantly canceled by TXF treatment in combination with either LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), which phosphorylates protein kinase B (Akt) or Compound C, an inhibitor of 5’-adenosine monophosphate-activated protein kinase (AMPK). Furthermore, TXF was demonstrated to activate (=phosphorylate) both Akt and AMPK, and promote glucose transporter 4 (GLUT4) translocation to the plasma membrane from cytosol of L6 myotubes via both PI3K/Akt and AMPK signaling pathways. Based on these in vitro findings, we conducted an in vivo experiment in KK-Ay/Ta mice with hyperglycemia and hyperuricemia. Fasting plasma glucose, insulin, uric acid levels and an index of insulin resistance (HOMA-IR) increased significantly in the T2D model mice compared with normal ones. Such rises in the T2D state were significantly suppressed by oral administration of TXF for four weeks. These results suggest that TXF is a potent antihyperglycemic and antihyperuricemic phytochemical in the T2D state.

scholarly journals AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells

2015 ◽  
Vol 228 (2) ◽  
pp. 105-114 ◽  
Author(s):  
Nami Kim ◽  
Jung Ok Lee ◽  
Hye Jeong Lee ◽  
Yong Woo Lee ◽  
Hyung Ip Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Gene Encoding ◽  
Beneficial Effects ◽  
Calcium Calmodulin Dependent ◽  
L6 Myotubes ◽  
Glut4 Expression ◽  
Compound C ◽  
Dependent Protein

Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-α (PKCα). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicate that isoeugenol exerts beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in skeletal muscle.

scholarly journals Glucolipotoxicity and GLP-1 secretion

2021 ◽  
Vol 9 (1) ◽  
pp. e001905
Author(s):  
Jung-Hee Hong ◽  
Dae-Hee Kim ◽  
Moon-Kyu Lee
Keyword(s):  
Glucose Transporter ◽  
Cell Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Simultaneous Treatment ◽  
L Cells ◽  
Triglyceride Accumulation

IntroductionThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels.Research design and methodsTo investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function.ResultsChronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats.ConclusionThese results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.

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