scholarly journals Ethanolic Extract of Folium Sennae Mediates the Glucose Uptake of L6 Cells by GLUT4 and Ca2+

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2934 ◽  
Author(s):  
Ping Zhao ◽  
Qian Ming ◽  
Junying Qiu ◽  
Di Tian ◽  
Jia Liu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
G Protein ◽  
Glucose Transporter ◽  
Ethanolic Extract ◽  
High Morbidity ◽  
L6 Cells ◽  
Glut4 Expression ◽  
Compound C

In today’s world, diabetes mellitus (DM) is on the rise, especially type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. T2DM has high morbidity, and therapies with natural products have attracted much attention in the recent past. In this paper, we aimed to study the hypoglycemic effect and the mechanism of an ethanolic extract of Folium Sennae (FSE) on L6 cells. The glucose uptake of L6 cells was investigated using a glucose assay kit. We studied glucose transporter 4 (GLUT4) expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), and protein kinase C (PKC) phosphorylation levels using western blot analysis. GLUT4 trafficking and intracellular Ca2+ levels were monitored by laser confocal microscopy in L6 cells stably expressing IRAP-mOrange. GLUT4 fusion with plasma membrane (PM) was observed by myc-GLUT4-mOrange. FSE stimulated glucose uptake; GLUT4 expression and translocation; PM fusion; intracellular Ca2+ elevation; and the phosphorylation of AMPK, Akt, and PKC in L6 cells. GLUT4 translocation was weakened by the AMPK inhibitor compound C, PI3K inhibitor Wortmannin, PKC inhibitor Gö6983, G protein inhibitor PTX/Gallein, and PLC inhibitor U73122. Similarly, in addition to PTX/Gallein and U73122, the IP3R inhibitor 2-APB and a 0 mM Ca2+-EGTA solution partially inhibited the elevation of intracellular Ca2+ levels. BAPTA-AM had a significant inhibitory effect on FSE-mediated GLUT4 activities. In summary, FSE regulates GLUT4 expression and translocation by activating the AMPK, PI3K/Akt, and G protein–PLC–PKC pathways. FSE causes increasing Ca2+ concentration to complete the fusion of GLUT4 vesicles with PM, allowing glucose uptake. Therefore, FSE may be a potential drug for improving T2DM.

scholarly journals Dandelion Chloroform Extract Promotes Glucose Uptake via the AMPK/GLUT4 Pathway in L6 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Ping Zhao ◽  
Qian Ming ◽  
Mingrui Xiong ◽  
Guanjun Song ◽  
Li Tan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Laser Scanning ◽  
Chloroform Extract ◽  
Cell Culture Supernatant ◽  
Glut4 Translocation ◽  
L6 Cells ◽  
Glut4 Expression ◽  
Compound C ◽  
Number Of Patients

The number of patients with type 2 diabetes mellitus (T2DM) is increasing rapidly worldwide. Glucose transporter 4 (GLUT4) is one of the main proteins that transport blood glucose into the cells and is a target in the treatment of T2DM. In this study, we investigated the mechanism of action of dandelion chloroform extract (DCE) on glucose uptake in L6 cells. The glucose consumption of L6 cell culture supernatant was measured by a glucose uptake assay kit, and the dynamic changes of intracellular GLUT4 and calcium (Ca2+) levels were monitored by laser scanning confocal microscopy in L6 cell lines stably expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM) was traced via myc-GLUT4-mOrange. GLUT4 expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), protein kinase C (PKC), and phosphorylation levels were determined by performing western blotting. GLUT4 mRNA expression was detected by real-time PCR. DCE up-regulated GLUT4 expression, promoted GLUT4 translocation and fusion to the membrane eventually leading to glucose uptake, and induced AMPK phosphorylation in L6 cells. The AMPK inhibitory compound C significantly inhibited DCE-induced GLUT4 expression and translocation while no inhibitory effect was observed by the phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin and PKC inhibitor Gö6983. These data suggested that DCE promoted GLUT4 expression and transport to the membrane through the AMPK signaling pathway, thereby stimulating GLUT4 fusion with PM to enhance glucose uptake in L6 cells. DCE-induced GLUT4 translocation was also found to be Ca2+-independent. Together, these findings indicate that DCE could be a new hypoglycemic agent for the treatment of T2DM.

scholarly journals Aloperine Relieves Type 2 Diabetes Mellitus via Enhancing GLUT4 Expression and Translocation

2021 ◽  
Vol 11 ◽  
Author(s):  
Guanjun Song ◽  
Yun Huang ◽  
Mingrui Xiong ◽  
Ziwei Yang ◽  
Qinghua Liu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Uptake ◽  
G Protein ◽  
L6 Cells ◽  
Glut4 Expression ◽  
Intracellular Ca

Aloperine (ALO), a quinolizidine alkaloid isolated from Sophora alopecuroides L. used in the traditional Uygur medicine, induced a significant increase in cellular glucose uptake of L6 cells, suggesting it has the potential to relieve hyperglycemia. Therefore, we investigated the effects of ALO on type 2 diabetes mellitus (T2DM) through in vitro and in vivo studies. The translocation of glucose transporter 4 (GLUT4) and changes in intracellular Ca2+ levels were real-time monitored in L6 cells using a laser scanning confocal microscope and related protein kinase inhibitors were used to explore the mechanism of action of ALO. Furthermore, high fat diet combined with low-dose streptozotocin (STZ) was used to induce T2DM in rats, and ALO was given to the stomach of T2DM rats for 4 weeks. In vitro results showed that ALO-induced enhancement of GLUT4 expression and translocation were mediated by G protein-PLC-PKC and PI3K/Akt pathways and ALO-enhanced intracellular Ca2+ was involved in activating PKC via G protein-PLC-IP3R-Ca2+ pathway, resulting in promoted GLUT4 plasma membrane fusion and subsequent glucose uptake. ALO treatment effectively ameliorated hyperglycemia, glucose intolerance, insulin resistance and dyslipidemia, alleviated hepatic steatosis, protected pancreatic islet function and activated GLUT4 expression in insulin target tissues of T2DM rats. These findings demonstrated that ALO deserves attention as a potential hypoglycemic agent.

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.

Altered renal expression of the insulin-responsive glucose transporter GLUT4 in experimental diabetes mellitus

1994 ◽  
Vol 267 (5) ◽  
pp. F816-F824 ◽  
Author(s):  
R. G. Marcus ◽  
R. England ◽  
K. Nguyen ◽  
M. J. Charron ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Experimental Diabetes ◽  
Diabetic Rats ◽  
Experimental Diabetes Mellitus ◽  
Early Diabetes ◽  
Glut4 Expression ◽  
Microvascular Cells ◽  
Glucose Transporter Glut4

Because the insulin-responsive glucose transporter, GLUT4, is expressed in renal vascular and glomerular cells, we determined the effects of experimental diabetes mellitus on GLUT4 expression and glucose uptake by these tissues. Quantitative reverse-transcription polymerase chain reaction studies of microdissected afferent microvessels and renal glomeruli showed that, after 1 wk of diabetes, GLUT4 mRNA was decreased to 26 and 34% of control values, respectively. GLUT4 immunoblots of renal glomerular and microvessel samples showed that GLUT4 polypeptide was decreased to 51% of control values. These results were confirmed by indirect immunofluorescence, which showed decreased GLUT4 expression in glomerular cells and in vascular smooth muscle cells of the afferent microvasculature of diabetic animals. Uptake of the glucose analogue, 2-deoxyglucose, was also depressed in microvessels of diabetic rats to 57% of control values, supporting the conclusion that fewer total glucose transporters were available for glucose uptake into diabetic renal glomerular and microvascular cells. Thus both GLUT4 expression and glucose uptake by glomerular and microvascular cells are decreased in diabetic animals. These results have led us to suggest a mechanism by which decreased renal GLUT4 expression could contribute to glomerular hyperfiltration and hypertension seen in early diabetes.

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.

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 Reduction of Insulin-Stimulated Glucose Uptake in L6 Myotubes by the Protein Kinase Inhibitor SB203580 Is Independent of p38MAPK Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3773-3781 ◽  
Author(s):  
C. N. Antonescu ◽  
C. Huang ◽  
W. Niu ◽  
Z. Liu ◽  
P. A. Eyers ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Small Interfering Rnas ◽  
Insulin Stimulation ◽  
L6 Myotubes ◽  
Low Levels ◽  
Glucose Transporter Glut4

Abstract Insulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38MAPK, and inhibitors of p38MAPKα and p38MAPKβ (e.g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38α and/or p38β. Here we further explore the possible participation of p38MAPK through a combination of molecular strategies. SB203580 reduced insulin stimulation of glucose uptake in L6 myotubes overexpressing an SB203580-resistant p38α (drug-resistant p38α) but barely affected phosphorylation of the p38 substrate MAPK-activated protein kinase-2. Expression of dominant-negative p38α or p38β reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific small interfering RNAs reduced expression of p38α or p38β by 60–70% without diminishing insulin-stimulated glucose uptake. SB203580 reduced photoaffinity labeling of GLUT4 by bio-LC-ATB-BMPA only in the insulin-stimulated state. Unless low levels of p38MAPK suffice to regulate glucose uptake, these results suggest that the inhibition of insulin-stimulated glucose transport by SB203580 is likely not mediated by p38MAPK. Instead, changes experienced by insulin-stimulated GLUT4 make it susceptible to inhibition by SB203580.

scholarly journals 5-Aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal glucose transport: a possible role for AMPK

2005 ◽  
Vol 385 (2) ◽  
pp. 485-491 ◽  
Author(s):  
John WALKER ◽  
Humberto B. JIJON ◽  
Hugo DIAZ ◽  
Payam SALEHI ◽  
Thomas CHURCHILL ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Western Blotting ◽  
Glucose Transporter ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Energy Status ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein

AMPK (AMP-activated protein kinase) is a key sensor of energy status within the cell. Activated by an increase in the AMP/ATP ratio, AMPK acts to limit cellular energy depletion by down-regulating selective ATP-dependent processes. The purpose of the present study was to determine the role of AMPK in regulating intestinal glucose transport. [3H]3-O-methyl glucose fluxes were measured in murine jejunum in the presence and absence of the AMPK activators AICAR (5-aminoimidazole-4-carboxamide riboside) and metformin and the p38 inhibitor, SB203580. To differentiate between a sodium-coupled (SGLT1) and diffusive (GLUT2) route of entry, fluxes were measured in the presence of the SGLT1 and GLUT2 inhibitors phloridzin and phloretin. Glucose transporter mRNA levels were measured by reverse transcriptase–PCR, and localization by Western blotting. Surface-expressed GLUT2 was assessed by luminal biotinylation. Activation of p38 mitogen-activated protein kinase was analysed by Western blotting. We found that treatment of jejunal tissue with AICAR resulted in enhanced net glucose uptake and was associated with phosphorylation of p38 mitogen-activated protein kinase. Inhibition of p38 abrogated the stimulation of AICAR-stimulated glucose uptake. Phloretin abolished the AICAR-mediated increase in glucose flux, whereas phloridzin had no effect, suggesting the involvement of GLUT2. In addition, AICAR decreased total protein levels of SGLT1, concurrently increasing levels of GLUT2 in the brush-border membrane. The anti-diabetic drug metformin, a known activator of AMPK, also induced the localization of GLUT2 to the luminal surface. We conclude that the activation of AMPK results in an up-regulation of non-energy requiring glucose uptake by GLUT2 and a concurrent down-regulation of sodium-dependent glucose transport.

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

2010 ◽  
Vol 298 (2) ◽  
pp. C377-C385 ◽  
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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