Glucose Transporter Isoform Research Articles

Natural compounds regulate glycolysis in hypoxic tumor microenvironment.

In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.

839: Placental glucose transporter 8 (GLUT8) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction

Fetal growth requires the transport of glucose across the placenta from mother-to-fetus, whose own glucose production is minimal. The expression of GLUT8 has been recently demonstrated in human placental syncytiotrophoblast and fetal endothelial cells, suggesting involvement of this glucose transporter isoform in transplacental transfer of glucose. Yet the effect of intrauterine growth restriction (IUGR) on placental GLUT8 expression is unknown. This study seeks to compare placental GLUT8 expression in IUGR to that of normal pregnancies.

The expression of the miR-25/93/106b family of micro-RNAs in the adipose tissue of women with polycystic ovary syndrome.

In adipose tissue (AT) micro-RNA-93 (miR-93) is significantly overexpressed in polycystic ovary syndrome (PCOS) women and non-PCOS women with insulin resistance (IR). Overexpressed miR-93 directly inhibits glucose transporter isoform 4, impairing both glucose metabolism and insulin sensitivity. The mechanisms behind increased miR-93 expression are unclear. Our objective was to determine whether miR-93 expression is concordant with its host gene, MCM7, which contains the miR-25/93/106b gene cluster. AT was excised from 16 women with PCOS (eight with and eight without IR) and 15 non-PCOS (nine with and six without IR). Expression of MCM7 and miR-25/93/106b was measured in AT and 3T3-L1 cells. MCM7 expression was lower in both non-PCOS/IR and PCOS women and tended to be lowest in women with PCOS and IR. Overall, the expression of MCM7 in human AT was negatively associated with miR-93 expression and with increased subject IR. Additionally, miR-25 and miR-106b expression is uncoupled from the MCM7 host gene and are positively correlated with IR, although no PCOS-specific difference was observed. MCM7 expression appears to be negatively correlated with increasing fasting glucose. In 3T3-L1 adipocytes, increasing glucose had no effect on miR-93 or miR-25, although it reduced MCM7 and increased miR-106b expression in a dose-dependent fashion. In turn, in 3T3-L1 adipocytes, increasing insulin had no effect on either MCM7 or miR-25/93/106b expression. Our data suggest that the expression of MCM7 and miR-93/25 is PCOS and IR related, whereas that of miR-106b is related to IR only. In 3T3-L1 adipocytes, neither hyperglycemia nor hyperinsulinemia altered the expression of miR-93 or miR-25, although increasing glucose levels down-regulated MCM7 and paradoxically increased that of miR-106b expression. The expression of the miR-25/93/106b family may be regulated through mechanisms distinct from its host gene, MCM7. Finally, our studies suggest potential epigenetic mechanisms for both IR and PCOS.

Abstract 15813: Loss-of-Function Mutation in Toll-Like Receptor 4 Partially Protects Against Peripheral and Cardiac Insulin Resistance During a Long-Term High-Fat Diet

Diabetes mellitus is an epidemic disease characterized by alterations in glucose transport, which is tightly regulated by a family of specialized proteins called the glucose transporters (GLUTs). Although diabetic cardiomyopathy is a common complication in diabetic patients, its pathogenesis is still not well understood. Toll-like receptor (TLR) 4, which plays a central role in pathogen recognition by the innate immune system, may also play a critical role in linking inflammation and metabolic disease. We hypothesized that TLR4 activation triggers cardiac insulin resistance. We used mice with a loss-of function mutation in TLR4 (C3H/HeJ) and age-matched wild-type (WT, C57BL/6N) mice (n=8/group) to investigate how feeding a high-fat diet (HFD, 60% kcal from fat) for 16 weeks affected whole-body and cardiac glucose metabolism. After 16 weeks, WT mice fed a HFD were obese and developed hyperglycemia and insulin resistance compared to WT mice on a control diet (10% kcal from fat). The C3H/HeJ mice were partially protected against HFD-induced obesity and insulin resistance. In the heart, WT mice fed a HFD had a 30% decrease (P<0.05) in GLUT4 protein content as measured by Western Blot of cardiac crude membrane protein extracts. In contrast, the loss-of-function point mutation in TLR4 partially rescued cardiac GLUT4 content in the face of a HFD. Interestingly, there was a 40% increase (P<0.05) in the novel GLUT isoform, GLUT8, in the heart when mice of either genotype were fed a HFD. Additionally, GLUT4 protein content was negatively (P<0.05) correlated with GLUT8 content in the myocardium, suggesting that GLUT8 may act as a compensatory mechanism in the face of HFD-induced GLUT4 downregulation. Phosphorylated Akt, a key protein of the insulin signaling pathway, was positively (P<0.05) correlated with GLUT4 content, while the basal/inactive form was negatively correlated. In conclusion, these data suggest that activation of TLR4 activation during diabetes and obesity alters glucose transport by an Akt mechanism, and as such is a pathogenic factor during peripheral and cardiac insulin resistance. Overall, TLR4 appears to be a key modulator in the cross-talk between inflammatory and metabolic pathways, as well as a potential therapeutic target for diabetes.

Abstract 15940: Calcium and Insulin Regulate the Novel Glucose Transporter 8 (GLUT8) in the Healthy and Diabetic Myocardium

Diabetes, an epidemic disease, is associated with the development of diabetic cardiomyopathy. Glucose uptake from the bloodstream into the cell is the rate-limiting step in whole body glucose utilization and is regulated by a family of membrane proteins called the glucose transporters (GLUT). The translocation of GLUT4, the main isoform, to the cell surface is insulin and contraction/calcium dependent in striated muscle. Contraction is regulated by the sarcoplasmic reticulum calcium ATPase (SERCA) pump. We recently demonstrated that diabetes impairs cardiac GLUT4 trafficking due to alterations of insulin signaling pathway and SERCA pump activity. However, the role of other GLUTs in the heart is still not elucidated. Although GLUT8 is highly expressed in the heart and could play a key role in cardiac glucose transport, its function and regulation are unknown. We hypothesized that, as for GLUT4, insulin and calcium will regulate GLUT8 translocation to the myocardial cell surface, which will be impaired during diabetes. Active cell surface GLUT (4 & 8) content was quantified by a biotinylated photolabeled assay in both intact perfused myocardium and isolated ventricular myocytes. To our knowledge, we are the first to apply this technique to GLUT8. Total GLUT (4 & 8) protein expression was measured by Western blot. Diabetes was induced by streptozotocin injection in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart and compared to their respective healthy littermates (n=16/group). In healthy myocytes, GLUT8 was primarily located intracellularly under basal condition, as for GLUT4. Insulin, calcium and isoproterenol stimulation (a beta-adrenergic agonist) significantly increased the translocation of both GLUT-4 and -8 to the cell surface. In addition, total GLUT-4 and -8 protein content was increased by 30 and 40% (P<0.05), respectively, in TG healthy mice overexpressing the SERCA pump compared to WT mice. As for GLUT4, active cell surface GLUT8 was decreased by 80% (P<0.05) in the diabetic ventricle but was restored by SERCA overexpression. Overall, our data suggest that, as for GLUT4, GLUT8 is a novel insulin-sensitive GLUT isoform in the heart, and its translocation is regulated by both insulin and calcium dependent pathways.

GLUT2, glucose sensing and glucose homeostasis.

The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

The impact of prolonged hyperinsulinaemia on glucose transport in equine skeletal muscle and digital lamellae.

An increased incidence of metabolic disease in horses has led to heightened recognition of the pathological consequences of insulin resistance. Laminitis, failure of the weightbearing digital lamellae, is an important consequence. Altered trafficking of specialised glucose transporters (GLUTs), responsible for glucose uptake, is central to the dysregulation of glucose metabolism and may play a role in the pathophysiology of laminitis. We hypothesised that prolonged hyperinsulinaemia alters the regulation of glucose transport in insulin-sensitive tissue and digital lamellae. Our objectives were to compare the relative protein expression of major GLUT isoforms in striated muscle and digital lamellae in healthy horses and during marked and moderate hyperinsulinaemia. Randomised, controlled study. Prolonged hyperinsulinaemia and lamellar damage were induced by a prolonged euglycaemic-hyperinsulinaemic clamp or a prolonged glucose infusion, and results were compared with those of electrolyte-treated control animals. Protein expression of GLUTs was examined with immunoblotting. Lamellar tissue contained more GLUT1 protein than skeletal muscle (P = 0.002) and less GLUT4 than the heart (P = 0.037). During marked hyperinsulinaemia and acute laminitis (induced by the prolonged euglycaemic-hyperinsulinaemic clamp), GLUT1 protein expression was decreased in skeletal muscle (P = 0.029) but unchanged in the lamellae, while novel GLUTs (8 and 12) were increased in the lamellae (P = 0.03) but not in skeletal muscle. However, moderate hyperinsulinaemia and subclinical laminitis (induced by the prolonged glucose infusion) did not cause differential GLUT protein expression in the lamellae compared with control horses. The results suggest that lamellar tissue functions independently of insulin and that insulin resistance may not be an essential component of the aetiology of laminitis. Marked differences in GLUT expression exist between insulin-sensitive and insulin-independent tissues during metabolic dysfunction in horses. The different expression profiles of novel GLUTs during acute and subclinical laminitis may be important to disease pathophysiology and require further investigation.

Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression

Early life nutritional intervention causes adult-onset insulin resistance and obesity in rats. Thyroid hormone receptor (TR), in turn, transcriptionally enhances skeletal muscle Glut4 expression. We tested the hypothesis that reduced circulating thyroid-stimulating hormone and T4 concentrations encountered in postnatal (PN4–PN24) high-carbohydrate (HC) milk formula-fed versus the mother-fed controls (MF) would epigenetically interfere with TR induction of adult (100days) male rat skeletal muscle Glut4 expression, thereby providing a molecular mechanism mediating insulin resistance. We observed increased DNA methylation of the CpG island with enhanced recruitment of Dnmt3a, Dnmt3b and MeCP2 in the glut4 promoter region along with reduced acetylation of histone (H)2A.Z and H4 particularly at the H4.lysine (K)16 residue, which was predominantly mediated by histone deacetylase 4 (HDAC4). This was followed by enhanced recruitment of heterochromatin protein 1β to the glut4 promoter with increased Suv39H1 methylase concentrations. These changes reduced TR binding of the T3 response element of the glut4 gene (TREs; −473 to −450bp) detected qualitatively in vivo (electromobility shift assay) and quantified ex vivo (chromatin immunoprecipitation). In addition, the recruitment of steroid receptor coactivator and CREB-binding protein to the glut4 promoter–protein complex was reduced. Co-immunoprecipitation experiments confirmed the interaction between TR and CBP to be reduced and HDAC4 to be enhanced in HC versus MF groups. These molecular changes were associated with diminished skeletal muscle Glut4 mRNA and protein concentrations. We conclude that early postnatal exposure to HC diet epigenetically reduced TR induction of adult male skeletal muscle Glut4 expression, uncovering novel molecular mechanisms contributing to adult insulin resistance and obesity.

Rab5 activity regulates GLUT4 sorting into insulin-responsive and non-insulin-responsive endosomal compartments: a potential mechanism for development of insulin resistance.

Glucose transporter isoform 4 (GLUT4) is the insulin-responsive glucose transporter mediating glucose uptake in adipose and skeletal muscle. Reduced GLUT4 translocation from intracellular storage compartments to the plasma membrane is a cause of peripheral insulin resistance. Using a chronic hyperinsulinemia (CHI)-induced cell model of insulin resistance and Rab5 mutant overexpression, we determined these manipulations altered endosomal sorting of GLUT4, thus contributing to the development of insulin resistance. We found that CHI induced insulin resistance in 3T3-L1 adipocytes by retaining GLUT4 in a Rab5-activity-dependent compartment that is unable to equilibrate with the cell surface in response to insulin. Furthermore, CHI-mediated retention of GLUT4 in this non-insulin-responsive compartment impaired filling of the transferrin receptor (TfR)-positive and TfR-negative insulin-responsive storage compartments. Our data suggest that hyperinsulinemia may inhibit GLUT4 by chronically maintaining GLUT4 in the Rab5 activity-dependent endosomal pathway and impairing formation of the TfR-negative and TfR-positive insulin-responsive GLUT4 pools. This model suggests that an early event in the development of insulin-resistant glucose transport in adipose tissue is to alter the intracellular localization of GLUT4 to a compartment that does not efficiently equilibrate with the cell surface when insulin levels are elevated for prolonged periods of time.

Intraosseous Venous Malformations of the Zygoma

Primary intraosseous venous malformations affecting the zygoma are rare vascular lesions, with only 35 cases reported in the surgical literature. Despite the establishment of the binary classification system, which serves to distinguish vascular tumors from malformations, inappropriate use of the term "hemangioma" to describe a variety of distinct vascular anomalies remains widespread. The authors present 3 cases of zygomatic intraosseous venous malformations and summarize the clinical, radiographic, and immunohistochemical features of these lesions. In each case, an insidious clinical course, combined with the pathognomonic finding of radiating trabeculae on computed tomography, suggests the diagnosis of intraosseous venous malformation. Negative glucose transporter isoform 1 immunoreactivity and histopathological analysis were used to reinforce this diagnosis in 1 patient. Management was individualized in each case, based on symptom complex and aesthetic concern. Given that the therapeutic approach to vascular anomalies is dependent on accurate diagnosis, resolution of semantic matters will optimize the management of these lesions.

Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1)

Type 1 diabetic (T1D) adolescent children on insulin therapy suffer episodes of both hyper- and hypoglycemic episodes. Glucose transporter isoform GLUT1 expressed in blood-brain barrier (BBB) and red blood cells (RBC) compensates for perturbed circulating glucose toward protecting the supply to brain and RBCs. We hypothesized that RBC-GLUT1 concentration, as a surrogate for BBB-GLUT1, is altered in T1D children. To test this hypothesis, we measured RBC-GLUT1 by enzyme-linked immunosorbent assay (ELISA) in T1D children (n = 72; mean age 15.3 ± 0.2 yr) and control children (CON; n = 11; mean age 15.6 ± 0.9 yr) after 12 h of euglycemia and during a hyperinsulinemic-hypoglycemic clamp with a nadir blood glucose of ~3.3 mmol/L for 90 min (clamp I) or ~3 mmol/L for 45 min (clamp II). Reduced baseline RBC-GLUT1 was observed in T1D (2.4 ± 0.17 ng/ng membrane protein); vs. CON (4.2 ± 0.61 ng/ng protein) (p < 0.0001). Additionally, baseline RBC-GLUT1 in T1D negatively correlated with hemoglobin A1c (HbA1c) (R = -0.23, p < 0.05) but not in CON (R = 0.06, p < 0.9). Acute decline in serum glucose to 3.3 mmol/L (90 min) or 3 mmol/L (45 min) did not change baseline RBC-GLUT1 in T1D or CON children. We conclude that reduced RBC-GLUT1 encountered in T1D, with no ability to compensate by increasing during acute hypoglycemia over the durations examined, may demonstrate a vulnerability of impaired RBC glucose transport (serving as a surrogate for BBB), especially in those with the worst control. We speculate that this may contribute to the perturbed cognition seen in T1D adolescents.

Glucose transporter isoform 1 (GLUT1) expression determines tumorigenicity of melanoma cells and their potential to form hepatic metastasis

The liver is the site of metastasis from virtually any primary malignant tumor and high portal glucose levels may be one of the factors supporting tumor growth in the liver. The facilitative glucose transporter isoform 1 (GLUT1) is the key rate-limiting factor in glucose transport into cancer cells, and we have previously shown that GLUT1 is a tumor-promotor in hepatocellular carcinoma, while its expression is at the detection limit in normal hepatocytes.

Mechanisms in exercise-induced increase in glucose disposal in skeletal muscle.

This chapter reviews current knowledge of the various signaling pathways that cause the glucose transporter isoform 4 (GLUT4)-containing vesicles to translocate from intracellular compartments of skeletal muscle cells to the plasma membrane in response to exercise. Specifically, the signaling cascades that arise from increases in AMP (adenosine monophosphate), nitric oxide (NO) and calcium (Ca2+) are described. Evidence is provided that these signaling pathways converge with the insulin signaling cascade at: (a) aPKC (atypical protein kinase C), which signals via GTPases to remodel microtubules along which GLUT4-containing vesicles translocate, and (b) AS160 (a 160-kDa Akt substrate that has Rab-GTPase activity) to activate microtubule motor kinesin proteins that power vesicle translocation. Experimental evidence showing that joint activation of AS160 and aPKC pathways are necessary for GLUT4 mobilization to the cell surface is given along with evidence of overlap between Ca2+, NO and AMP-dependent protein kinase-signaling pathways. The chapter also describes the molecular mechanisms by which exercise increases GLUT4 expression to boost glucose disposal capacity of skeletal muscle.

Chronic stress modulates regional cerebral glucose transporter expression in an age-specific and sexually-dimorphic manner

Facilitative glucose transporters (GLUT) mediate glucose uptake across the blood–brain-barrier into neurons and glia. Deficits in specific cerebral GLUT isoforms are linked to developmental and neurological dysfunction, but less is known about the range of variation in cerebral GLUT expression in normal conditions and the effects of environmental influences on cerebral GLUT expression. Knowing that puberty is a time of increased cerebral plasticity, metabolic demand, and shifts in hormonal balance for males and females, we first assessed gene expression of five GLUT subtypes in four brain regions in male and female adolescent and adult Wistar rats. The data indicated that sex differences in GLUT expression were most profound in the hypothalamus, and the transition from adolescence to adulthood had the most profound effect on GLUT expression in the hippocampus. Next, given the substantial energetic demands during adolescence and prior demonstrations of the adverse effects of adolescent stress, we determined the extent to which chronic stress altered GLUT expression in males and females in both adolescence and adulthood. Chronic stress significantly altered cerebral GLUT expression in males and females throughout both developmental stages but in a sexually dimorphic and brain region-specific manner. Collectively, our data demonstrate that cerebral GLUTs are expressed differentially based on brain region, sex, age, and stress exposure. These results suggest that developmental and environmental factors influence GLUT expression in multiple brain regions. Given the importance of appropriate metabolic balance within the brain, further assessment of the functional implications of life stage and environmentally-induced changes in GLUTs are warranted.

Insight Into the Pathogenesis of Fetal Growth Restriction in Placental Malaria: Decreased Placental Glucose Transporter Isoform 1 Expression

Placental malaria, especially when complicated with intervillositis, can cause fetal growth restriction. Transplacental glucose transport by glucose transporter isoform 1 (GLUT-1) on the syncytiotrophoblast microvillous and basal plasma membranes regulates fetal growth. We found that GLUT-1 expression in the microvillous plasma membrane of Plasmodium falciparum-negative placenta biopsy specimens was comparable to that in P. falciparum-positive placenta biopsy specimens with or without intervillositis, whereas GLUT-1 expression in the basal plasma membrane was lowest in P. falciparum-positive placenta biopsy specimens with intervillositis, compared with the other 2 specimen types (P ≤ .0016). GLUT-1 expression in the basal plasma membrane also correlated negatively with monocyte infiltrate density (r = -0.43; P = .003) and positively with birth weight (r = 0.28; P = .06). These findings suggest that intervillositis, more than placental malaria per se, might cause fetal growth restriction, through impaired transplacental glucose transport.

Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression

Diminished transplacental glucose transport plays an important role in prenatal calorie restriction (CR) induced reduction in fetal growth. Fetal growth restriction (FGR) has an impact in shaping the adult phenotype with transgenerational implications. To understand the mechanisms underlying prenatal CR-induced transplacental glucose transport, we examined the epigenetic regulation of placental glucose transporter (Glut1 and Glut3) expression. We restricted calories by 50% in C57BL6 pregnant mice from gestational days 10 to 19 (CR; n=8) vs. controls (CON; n=8) and observed a 50% diminution in placental Glut3 expression (P<.05) with no effect on Glut1 expression by reverse transcription and quantitative real-time polymerase chain reaction (PCR). CR enhanced DNA methylation of a CpG island situated ~1000 bp upstream from the transcriptional start site of the glut3 gene, with no such effect on the glut1 gene as assessed by methylation-sensitive PCR and bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assays demonstrated enhanced MeCP2 binding to the CpG island of the glut3 gene in response to CR vs. CON (P<.05). Sequential ChIP demonstrated that enhanced MeCP2 binding of the glut3-mCpG island enhanced histone deacetylase 2 recruitment (P<.05) but interfered with Sp1 binding (P<.001), although it did not affect Sp3 or Creb/pCreb interaction. We conclude that late-gestation CR enhanced DNA methylation of the placental glut3 gene. This epigenetic change augmented specific nuclear protein–DNA complex formation that was associated with prenatal CR-induced reduction of placental glut3 expression and thereby transplacental glucose transport. This molecular complex provides novel targets for developing therapeutic interventions aimed at reversing FGR.

Epigallocatechin gallate improves insulin signaling by decreasing toll‐like receptor 4 (TLR4) activity in adipose tissues of high‐fat diet rats

In this study, we investigated the beneficial effects and the underlying mechanism of epigallocatechin gallate (EGCG) in adipose tissues of rats fed with a high-fat diet (HFD). Fasting plasma insulin, epididymal fat coefficient and free fatty acids, homeostasis model assessment-insulin resistance index, and the average glucose infusion rate were determined. EGCG significantly decreased free fatty acids, fasting insulin, homeostasis model assessment-insulin resistance index, and epididymal fat coefficient, and increased glucose infusion rate in HFD group. The levels of toll-like receptor 4, TNF receptor associated factor 6, inhibitor-kappa-B kinase β, p-nuclear factor κB, tumor necrosis factor α, and IL-6 in the EGCG group were all significantly lower than the HFD control group. EGCG also decreased the level of phosphorylated insulin receptor substrate 1 and increased phosphoinositide-3-kinase and glucose transporter isoform 4 in the HFD group. Decreased macrophage infiltration was in EGCG group versus HFD group, and the protein level of CD68 in EGCG group was also significantly lower than that of HFD group. EGCG attenuated inflammation by decreasing the content of macrophages, interfered the toll-like receptor 4 mediated inflammatory response pathway, thus, improving insulin signaling in adipose tissues.

Increased Gene Expression of Glucose Transporters in the Mouse Brain after Treatment with Fluoxetine and Pergolide

Glucose transporters play key roles in the homeostatic control of brain functions. In the present study, we examined the effect of fluoxetine, a selective serotonin reuptake inhibitor, and pergolide, a dopamine D receptor agonist, on the gene expression levels of glucose transporters in the mouse brain. mRNAs for 8 sodium-independent glucose transporters (GLUTs), other than GLUT4 and GLUT9, and sodium-dependent glucose transporter 1 (SGLT1) were confirmed to be expressed in brain tissue. Fluoxetine and pergolide significantly increased the expression levels of mRNAs for GLUT1 and GLUT10 in the brain. Furthermore, the expression of GLUT6 in tissue was increased by administering pergolide to mice. On the other hand, fluoxetine and pergolide had no effect on the expression levels of mRNAs for the other GLUTs and SGLT1. Therefore, we concluded that the gene expression of several GLUT isoforms in the mouse brain was affected by the treatment with fluoxetine and pergolide.

Glucose transporter isoform 1 (GLUT1) expression in melanoma enhances formation and growth of hepatic metastases

Glucose transporter isoform 1 (GLUT1) expression in melanoma enhances formation and growth of hepatic metastases

Sorting of GLUT4 into its insulin-sensitive store requires the Sec1/Munc18 protein mVps45.

Insulin stimulates glucose transport in fat and muscle cells by regulating delivery of the facilitative glucose transporter, glucose transporter isoform 4 (GLUT4), to the plasma membrane. In the absence of insulin, GLUT4 is sequestered away from the general recycling endosomal pathway into specialized vesicles, referred to as GLUT4-storage vesicles. Understanding the sorting of GLUT4 into this store is a major challenge. Here we examine the role of the Sec1/Munc18 protein mVps45 in GLUT4 trafficking. We show that mVps45 is up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes and is expressed at stoichiometric levels with its cognate target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor, syntaxin 16. Depletion of mVps45 in 3T3-L1 adipocytes results in decreased GLUT4 levels and impaired insulin-stimulated glucose transport. Using sub-cellular fractionation and an in vitro assay for GLUT4-storage vesicle formation, we show that mVps45 is required to correctly traffic GLUT4 into this compartment. Collectively our data reveal a crucial role for mVps45 in the delivery of GLUT4 into its specialized, insulin-regulated compartment.