Ready, set, internalize: mechanisms and regulation of GLUT4 endocytosis

2008 ◽  
Vol 29 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Costin N. Antonescu ◽  
Michelangelo Foti ◽  
Nathalie Sauvonnet ◽  
Amira Klip
Keyword(s):  
Insulin Resistance ◽  
Muscle Contraction ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Fat Cells ◽  
Intracellular Membrane ◽  
Membrane Compartments ◽  
Glucose Transporter Glut4

The facilitative glucose transporter GLUT4, a recycling membrane protein, is required for dietary glucose uptake into muscle and fat cells. GLUT4 is also responsible for the increased glucose uptake by myofibres during muscle contraction. Defects in GLUT4 membrane traffic contribute to loss of insulin-stimulated glucose uptake in insulin resistance and Type 2 diabetes. Numerous studies have analysed the intracellular membrane compartments occupied by GLUT4 and the mechanisms by which insulin regulates GLUT4 exocytosis. However, until recently, GLUT4 internalization was less well understood. In the present paper, we review: (i) evidence supporting the co-existence of clathrin-dependent and independent GLUT4 internalization in adipocytes and muscle cells; (ii) the contrasting regulation of GLUT4 internalization by insulin in these cells; and (iii) evidence suggesting regulation of GLUT4 endocytosis in muscle cells by signals associated with muscle contraction.

Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

2013 ◽  
Vol 304 (1) ◽  
pp. E1-E13 ◽  
Author(s):  
Katharina Timper ◽  
Jean Grisouard ◽  
Nadine S. Sauter ◽  
Tanja Herzog-Radimerski ◽  
Kaethi Dembinski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Hormone Sensitive Lipase ◽  
Human Adipocytes ◽  
Chemotactic Protein ◽  
Fatty Acid Release ◽  
Glucose Transporter Glut4

Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

scholarly journals Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1612
Author(s):  
Sun-Young Yoon ◽  
Jae Sik Yu ◽  
Ji Young Hwang ◽  
Hae Min So ◽  
Seung Oh Seo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Muscle Cells ◽  
Protein Tyrosine ◽  
C2c12 Muscle Cells

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 μM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

scholarly journals Attenuation of Free Fatty Acid (FFA)-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol is Linked to Activation of AMPK and Inhibition of mTOR and p70 S6K

2020 ◽  
Vol 21 (14) ◽  
pp. 4900
Author(s):  
Danja J. Den Hartogh ◽  
Filip Vlavcheski ◽  
Adria Giacca ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Specific Proteins ◽  
P70 S6k

Insulin resistance, a main characteristic of type 2 diabetes mellitus (T2DM), is linked to obesity and excessive levels of plasma free fatty acids (FFA). Studies indicated that significantly elevated levels of FFAs lead to skeletal muscle insulin resistance, by dysregulating the steps in the insulin signaling cascade. The polyphenol resveratrol (RSV) was shown to have antidiabetic properties but the exact mechanism(s) involved are not clearly understood. In the present study, we examined the effect of RSV on FFA-induced insulin resistance in skeletal muscle cells in vitro and investigated the mechanisms involved. Parental and GLUT4myc-overexpressing L6 rat skeletal myotubes were used. [3H]2-deoxyglucose (2DG) uptake was measured, and total and phosphorylated levels of specific proteins were examined by immunoblotting. Exposure of L6 cells to FFA palmitate decreased the insulin-stimulated glucose uptake, indicating insulin resistance. Palmitate increased ser307 (131% ± 1.84% of control, p < 0.001) and ser636/639 (148% ± 10.1% of control, p < 0.01) phosphorylation of IRS-1, and increased the phosphorylation levels of mTOR (174% ± 15.4% of control, p < 0.01) and p70 S6K (162% ± 20.2% of control, p < 0.05). Treatment with RSV completely abolished these palmitate-induced responses. In addition, RSV increased the activation of AMPK and restored the insulin-mediated increase in (a) plasma membrane GLUT4 glucose transporter levels and (b) glucose uptake. These data suggest that RSV has the potential to counteract the FFA-induced muscle insulin resistance.

scholarly journals Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

2018 ◽  
Vol 46 (5) ◽  
pp. 1985-1998 ◽  
Author(s):  
Tomoyuki Nishizaki
Keyword(s):  
Cell Surface ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Surface Localization ◽  
Cell Surface Localization ◽  
Glucose Transporter Glut4

Background/Aims: Phosphatidylethanolamine, a component of the plasma membrane, regulates diverse cellular processes. The present study investigated the role of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in the trafficking of the glucose transporter GLUT4 and the glucose homeostasis. Methods: Monitoring of GLUT4 trafficking, GLUT4 internalization assay, and glucose uptake assay were carried out using differentiated 3T3-L1-GLUT4myc adipocytes. Akt1/2 and PKC isozymes were knocked-down by transfecting each siRNA. Cell-free PKC assay and in situ PKCα assay with a FRET probe were carried out. Oral glucose tolerance test (OGTT) was performed using BKS.Cg-+Lepdb/+Lebdb/Jcl mice, an animal model of type 2 diabetes mellitus (DM). Results: DOPE increased cell surface localization of the glucose transporter GLUT4 in differentiated 3T3-L1-GLUT4myc adipocytes, regardless of Akt activation. Likewise, PKCα deficiency increased cell surface localization of GLUT4, that occludes the effect of DOPE. DOPE clearly suppressed phorbol 12-myristate 13-acetate-induced PKCα activation in the cell-free and in situ PKC assay. DOPE and PKCα deficiency cancelled endocytic internalization of GLUT4 localized on the plasma membrane after insulin stimulation. DOPE significantly enhanced glucose uptake into cells. A similar effect was obtained by knocking-down PKCα, that occludes the effect of DOPE. In OGTT, oral administration with DOPE effectively restricted an increase in the blood glucose levels after glucose loading in type 2 DM model mice. Conclusion: The results of the present study show that DOPE retains cell surface GLUT4 by suppressing PKCα-driven endocytic internalization of GLUT4, to enhance glucose uptake into cells and restrict an increase in the blood glucose levels after glucose loading in type 2 DM.

scholarly journals A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes

2014 ◽  
Vol 25 (19) ◽  
pp. 3059-3069 ◽  
Author(s):  
Sheelarani Karunanithi ◽  
Tingting Xiong ◽  
Maeran Uhm ◽  
Dara Leto ◽  
Jingxia Sun ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
G Protein ◽  
Glucose Transporter ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Storage Vesicles ◽  
Membrane Compartments ◽  
Bona Fide ◽  
Glucose Transporter Glut4 ◽  
Protein Kinase Akt

Insulin-stimulated glucose uptake in fat and muscle is mediated by the major facilitative glucose transporter Glut4. Insulin controls the trafficking of Glut4 to the plasma membrane via regulation of a series of small G proteins, including RalA and Rab10. We demonstrate here that Rab10 is a bona fide target of the GTPase-activating protein AS160, which is inhibited after phosphorylation by the protein kinase Akt. Once activated, Rab10 can increase the GTP binding of RalA by recruiting the Ral guanyl nucleotide exchange factor, Rlf/Rgl2. Rab10 and RalA reside in the same pool of Glut4-storage vesicles in untreated cells, and, together with Rlf, they ensure maximal glucose transport. Overexpression of membrane-tethered Rlf compensates for the loss of Rab10 in Glut4 translocation, suggesting that Rab10 recruits Rlf to membrane compartments for RalA activation and that RalA is downstream of Rab10. Together these studies identify a new G protein cascade in the regulation of insulin-stimulated Glut4 trafficking and glucose uptake.

Efficacy and cardiovascular safety of Thiazolidinediones

2020 ◽  
Vol 15 ◽  
Author(s):  
Raveendran Arkiath Veettil ◽  
Cornelius James Fernandez ◽  
Koshy Jacob
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Glucose Transporter ◽  
Cell Function ◽  
Cardiovascular Safety ◽  
Cardiovascular Outcome Trials ◽  
Glucose Transporter 2 ◽  
Insulin Sensitizers

: Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though, thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

scholarly journals Gundelia tournefortii: Fractionation, Chemical Composition and GLUT4 Translocation Enhancement in Muscle Cell Line

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3785
Author(s):  
Sleman Kadan ◽  
Sarit Melamed ◽  
Shoshana Benvalid ◽  
Zipora Tietel ◽  
Yoel Sasson ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Rapid Development ◽  
Muscle Cells ◽  
Flash Chromatography ◽  
Glucose Disposal ◽  
Gas Chromatography Mass Spectrometry ◽  
Glut4 Translocation ◽  
Toxic Concentrations ◽  
L6 Muscle Cells

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 μg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography–mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.

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

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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