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Background Whereas selective sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently showed cardiovascular protective effects in large outcome trials independent of the presence of type 2 diabetes mellitus (T2DM), the cardiovascular effects of dual SGLT1/2 inhibitors remain to be elucidated. Despite its clinical relevance, data are scarce regarding left ventricular (LV) SGLT1 expression in distinct heart failure (HF) pathologies. We aimed to characterize LV SGLT1 expression in human patients with end-stage HF, in context of the other two major glucose transporters: GLUT1 and GLUT4. Methods Control LV samples (Control, n = 9) were harvested from patients with preserved LV systolic function who went through mitral valve replacement. LV samples from HF patients undergoing heart transplantation (n = 71) were obtained according to the following etiological subgroups: hypertrophic cardiomyopathy (HCM, n = 7); idiopathic dilated cardiomyopathy (DCM, n = 12); ischemic heart disease without T2DM (IHD, n = 14), IHD with T2DM (IHD + T2DM, n = 11); and HF patients with cardiac resynchronization therapy (DCM:CRT, n = 9, IHD:CRT, n = 9 and IHD-T2DM:CRT, n = 9). We measured LV SGLT1, GLUT1 and GLUT4 gene expressions with qRT-PCR. The protein expression of SGLT1, and activating phosphorylation of AMP-activated protein kinase (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2) were quantified by western blotting. Immunohistochemical staining of SGLT1 was performed. Results Compared with controls, LV SGLT1 mRNA and protein expressions were significantly and comparably upregulated in HF patients with DCM, IHD and IHD + T2DM (all P < 0.05), but not in HCM. LV SGLT1 mRNA and protein expressions positively correlated with LVEDD and negatively correlated with EF (all P < 0.01). Whereas AMPKα phosphorylation was positively associated with SGLT1 protein expression, ERK1/2 phosphorylation showed a negative correlation (both P < 0.01). Immunohistochemical staining revealed that SGLT1 expression was predominantly confined to cardiomyocytes, and not fibrotic tissue. Overall, CRT was associated with reduction of LV SGLT1 expression, especially in patients with DCM. Conclusions Myocardial LV SGLT1 is upregulated in patients with HF (except in those with HCM), correlates significantly with parameters of cardiac remodeling (LVEDD) and systolic function (EF), and is downregulated in DCM patients with CRT. The possible role of SGLT1 in LV remodeling needs to be elucidated.

Maternal glucose levels and body mass index (BMI) are determinants of fetal overgrowth, but their relation to fetal glucose consumption is not well characterized in human pregnancy. To quantify uteroplacental glucose uptake and the allocation of glucose between the placenta and fetus and to identify factors that affect fetal glucose consumption. Human in vivo study in term pregnancies. Oslo University Hospital, Norway. One hundred seventy-nine healthy women with elective cesarean section. Uterine and umbilical blood flow was determined using Doppler ultrasonography. Glucose and insulin were measured in the maternal radial artery and uterine vein and the umbilical artery and vein. In a subcohort (n = 33), GLUT1 expression was determined in isolated syncytiotrophoblast basal and microvillous plasma membranes. Uteroplacental glucose uptake and placental and fetal glucose consumption quantified by the Fick principle. Median (Q1, Q3) uteroplacental glucose uptake was 117.1 (59.1, 224.9) μmol⋅min-1, and fetal and placental glucose consumptions were 28.9 (15.4, 41.8) µmol⋅min-1⋅kg fetus-1 and 51.4 (-65.8, 185.4) µmol⋅min-1⋅kg placenta-1, respectively. Fetal glucose consumption correlated with birth weight (ρ: 0.34; P < 0.001) and maternal-fetal glucose gradient (ρ: 0.60; P < 0.001), but not with maternal BMI or uteroplacental glucose uptake. Uteroplacental glucose uptake was correlated to placental glucose consumption (ρ: 0.77; P < 0.001). Fetal and placental glucose consumptions were inversely correlated (ρ: -0.47; P < 0.001), but neither was correlated with placental GLUT1 expression. These findings suggest that fetal glucose consumption is balanced against the placental needs for glucose and that placental glucose consumption is a key modulator of maternal-fetal glucose transfer in women.

AimsBreast cancer (BC) during pregnancy (PrBC) and the postpartum period (PPBC) often exhibits more aggressive tumour characteristics and is associated with a poorer prognosis compared with age-matched nonpregnant patients with BC. The underlying mechanisms for this increased aggressiveness remain unresolved. Intratumoral hypoxia, a known adverse prognostic marker in nonpregnant BC, has not yet been studied in PrBC/PPBC. This is particularly intriguing due to the potential exposure to angiogenesis-stimulating factors during pregnancy, which may influence tumour behaviour.MethodsTumour tissues from 148 patients with PrBC and 45 patients with PPBC were used to create a tissue microarray (TMA), and clinical and outcome data were obtained. The TMAs were stained for hypoxia-associated protein markers: glucose transporter-1, carbonic anhydrase IX and hypoxia-inducible factor-1α.ResultsOf all 193 tumours, 152 (79%) expressed at least one of these proteins indicative of intratumoral hypoxia. The presence of intratumoral hypoxia was associated with a higher histological grade (83% grade III vs 63%) and frequent hormone receptor negativity (68% vs 39%). In a multivariable analysis, the presence of intratumoral hypoxia indicated a significantly worse prognosis (HR 2.532, 95% CI 1.1 to 5.7) for patients with PrBC and PPBC.ConclusionThis unique study, the first in patients with PrBC and PPBC, showed that, despite their likely exposure to angiogenesis-stimulating factors, intratumoral hypoxia is frequent and affects 79% of patients. Importantly, patients with tumours overexpressing hypoxia markers have significantly worse survival. This suggests that hypoxia may be an important mechanism in carcinogenesis and clinical behaviour of PrBC and PPBC.

CD8 cytotoxic T lymphocytes (CTLs) rely on rapid reorganization of the branched F-actin network to drive the polarized secretion of lytic granules, initiating target cell death during the adaptive immune response. Branched F-actin is generated by the nucleation factor actin-related protein 2/3 (Arp2/3) complex. Patients with mutations in the actin-related protein complex 1B (ARPC1B) subunit of Arp2/3 show combined immunodeficiency, with symptoms of immune dysregulation, including recurrent viral infections and reduced CD8+ T cell count. Here, we show that loss of ARPC1B led to loss of CTL cytotoxicity, with the defect arising at 2 different levels. First, ARPC1B is required for lamellipodia formation, cell migration, and actin reorganization across the immune synapse. Second, we found that ARPC1B is indispensable for the maintenance of TCR, CD8, and GLUT1 membrane proteins at the plasma membrane of CTLs, as recycling via the retromer and WASH complexes was impaired in the absence of ARPC1B. Loss of TCR, CD8, and GLUT1 gave rise to defects in T cell signaling and proliferation upon antigen stimulation of ARPC1B-deficient CTLs, leading to a progressive loss of CD8+ T cells. This triggered an activation-induced immunodeficiency of CTL activity in ARPC1B-deficient patients, which could explain the susceptibility to severe and prolonged viral infections.

To elucidate the molecular mechanisms underlying the insufficient sensitivity in the detection of hepatocellular carcinoma (HCC) by [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the characteristics of glucose metabolism-related protein expression in HCC were examined in liver metastasis from colorectal cancer (Meta). Thirty-four patients (14 Meta and 20 HCC) who underwent FDG-PET and hepatectomy were studied. The relationships between the maximum standardized uptake value (SUV) in tumors and the mRNA expression of glucose metabolism-related proteins [hexokinase (HK), glucose transporter 1 (GLUT1), and glucose-6-phosphatase (G6Pase)] and proliferating cell nuclear antigen (PCNA) were examined in snap-frozen specimens with quantitative PCR. Tumor detection rates were lower in HCC (15/20) compared to Meta (13/14) patients. HK and GLUT1 expression was lower and G6Pase expression was higher in HCC compared to Meta. In particular, GLUT1 overexpression was 92-fold in Meta and 11-fold in HCC compared to the surrounding liver. The SUV correlated with GLUT1 and PCNA expression in HCC, but not Meta patients. Of note, four cases of poorly differentiated (P/D) HCC compared to moderately differentiated (M/D) HCC produced completely different results for FDG uptake (SUV, 14.4 vs. 4.0) and mRNA expression (G6Pase expression, 0.007 vs. 1.5). Variations in the expression of glucose metabolism-related enzymes between HCC and Meta patients are attributed to origin or degree of differentiation. Low FDG uptake in M/D HCC reflected low GLUT1 and high G6Pase expression, while high FDG accumulation in P/D HCC could reflect increased GLUT1 and decreased G6Pase expression. These results may explain why M/D HCC is not detected as sensitively by FDG-PET.

Background The aim of this study was to investigate the relationship between multiple metabolism parameters derived from FDG and tumor TNM stages as well as tumor metastasis-associated protein of GLUT-1 and MACC1 in colorectal carcinoma (CRC). Methods Thirty-eight patients (24 males and 14 females) with primary CRC confirmed by elective surgery pathological, who also accepted 18 F-FDG PET/CT scans during 2017 to 2019 were included in this study. The tumor classification of T, N and M is explained by the 7th American Joint Committee on Cancer (AJCC). 18 F-FDG parameters of SUVmax, SUVmean, TLG and MTV were measured by drawing a region of interest on the primary lesions. The expression of GLUT-1 and MACC1 was quantified by immunohistochemical, and the correlation between metabolism parameters and tumor biomarkers were analyzed. Results According to our analysis, the 18 F-FDG parameters of SUVmean was significantly correlated with tumor M status ( P  = 0.000) of primary CRC. The primary tumor lesion with higher SUVmax, TLG and MTV values prone to a high-T status ( P  = 0.002, 0.002 and 0.001, respectively). The high expression of GLUT-1/MACC1 weas more frequently involved with T3–4 stage and was poorly differentiated in CRC patients. Multivariate analysis found that the expression of GLUT-1 protein was correlated with SUVmax and MTV ( R 2  = 0.42, P  = 0.013 and 0.004, respectively), moreover, the expression of MACC1 protein was correlated with TLG ( R 2  = 0.372, P  = 0.000). Conclusion Glucose metabolism parameters derived from FDG provides a noninvasive assessment of M status and T status in CRC patients. The expression of GLUT-1 and MACC1 was associated with 18 F-FDG uptake in CRC patients.

In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3β and nuclear translocation of β-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.

CD4 and CD8 T lymphocyte activation requires the generation of sufficient energy to support new biosynthetic demands. Following T cell receptor (TCR) engagement, these requirements are met by an increased glycolysis, due, at least in part, to induction of the Glut1 glucose transporter. As Glut1 is upregulated on tumor cells in response to hypoxia, we assessed whether surface Glut1 levels regulate the antigen responsiveness of human T lymphocytes in both hypoxic and atmospheric oxygen conditions. Notably, Glut1 upregulation in response to TCR stimulation was significantly higher in T lymphocytes activated under hypoxic as compared to atmospheric oxygen conditions. Furthermore, TCR-stimulated human T lymphocytes sorted on the basis of Glut1-Lo and Glut1-Hi profiles maintained distinct characteristics, irrespective of the oxygen tension. While T cells activated in hypoxia divided less than those activated in atmospheric oxygen, Glut1-Hi lymphocytes exhibited increased effector phenotype acquisition, augmented proliferation and an inverted CD4/CD8 ratio in both oxygen conditions. Moreover, Glut1-Hi T lymphocytes exhibited a significantly enhanced ability to produce IFN-γ and this secretion potential was completely dependent on continued glycolysis. Thus, Glut1 surface levels identify human T lymphocytes with distinct effector functions in both hypoxic and atmospheric oxygen tensions.

This work aims to clarify the effect of dietary supplementation with Bisphenol A (BPA), a chemical widely present in beverage and food containers, on placental glucose transfer and pregnancy outcome. The study was performed on female Sprague Dawley rats fed with a diet containing BPA (2.5, 25 or 250 μg/Kg/day) for a period of a month (virgin state) plus 20 days during pregnancy. Western blot analysis and immunohistochemistry were performed in placental tissues for glucose type 1 transporter (GLUT1). Furthermore, human trophoblast, HTR8-SV/neo cells, were used to evaluate the effect of BPA on glucose transport and uptake. Studies in rats showed that food supplementation with BPA, produces a higher fetal weight (FW) to placenta weight (PW) ratio at the lowest BPA concentration. Such low concentrations also reduced maternal weight gain in late pregnancy and up-regulated placental expression of GLUT1. Treatment of HTR8-SV/neo with the non-toxic dose of 1 nM BPA confirmed up-regulation of GLUT1 expression and revealed higher activity of the transporter with an increase in glucose uptake and GLUT1 membrane translocation. Overall, these results indicate that prenatal exposure to BPA affects pregnancy and fetal growth producing changes in the placental nutrients-glucose transfer.

Background and Objectives: Glucose Transporter-1 (GLUT1) is the key target gene for hypoxia-inducible factor (HIF), which helps cells uptake glucose during cell division, malignant transformation, and nutrient depletion. Cancer hypoxia is a well-known condition caused by an oxygen imbalance in the cancer microenvironment. During chronic hypoxia, certain cancer cells can survive and adapt. These cellular alterations can make cancer more aggressive, causing invasion and metastasis. The study investigated the presence of GLUT1 in oral epithelial dysplasia (OED) and various histopathological grades of oral squamous cell carcinoma (OSCC) to assess the significance of GLUT1 as a prognostic indicator. Material and Methods: A total of 40 samples of tissue blocks, including 5 cases of normal oral mucosa, 5 cases of epithelial dysplasia, and 30 cases of OSCC with 10 cases each of well-differentiated, moderately differentiated, and poorly differentiated OSCCs, these cases were diagnosed using the Hematoxylin and Eosin (H&E) staining technique. GLUT1 expression was assessed using immunohistochemical staining, which involved evaluating the location of the stain and the percentage of staining. Results: The mean area percent was highest in poorly differentiated cases (47.37) and lowest in well-differentiated cases (13.42). In poorly differentiated cases, diffuse expression was observed in almost all malignant cells, exhibiting membrane, cytoplasmic and nuclear staining. A significant difference (p < 0.001) between all groups in regard to immunostaining was detected. Conclusions: GLUT1 expression increased from oral epithelial dysplasia to oral squamous cell carcinoma histological grades. GLUT1 in actively dividing cells may reflect the tumor’s aggressiveness and treatment response. Hypoxia increases this marker’s expression, indicating division and proliferation.