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Cancer cells deploy several glucose transport protein (GLUT) channels on the cell membranes to increase glucose uptake. Cancer cells die within 24 h in the absence of glucose. Thus, preventing the deployment of GLUT channels can deprive them of glucose, resulting in apoptosis within 24 h. Herein, we developed the

Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both

Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation, and hepatocyte injury with or without fibrosis. It has emerged as the second leading indication for liver transplantation with a rising death rate in the non-transplantable population. While there are many drugs in evaluation, currently no approved therapies are on the market for this condition. Given this importance, the Food and Drug Administration has provided formal guidance regarding drug development for stopping or reversing NASH or NASH associated fibrosis. The complex pathogenesis of NASH and its bidirectional relationship with metabolic syndrome has highlighted multiple drugs of interest that address metabolic, inflammatory, and fibrotic factors. A few promising liver specific targets include farnesoid X receptor agonists and peroxisome proliferator-activated receptor agonists. Previously studied drug classes such as glucagon-like peptide-1 analogs or sodium/glucose transport protein 2 inhibitors have also demonstrated ability to improve hepatic steatosis. Here we discuss current rationale, scientific work, and preliminary data in combining multiple drugs for the purposes of a multimodal attack on the pathogenesis of NASH. We highlight multiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve a response rate higher than previously assessed monotherapies for this condition. Ultimately, one of these combination strategies may rise above in its safety and efficacy to become a part of a standardized approach to NASH.

The increased glucose uptake observed in cancer cells is mediated by glucose transporters (GLUTs), a class of transmembrane proteins that facilitate the transport of glucose and other substrates across the plasma membrane. Despite the important role of glucose in the pathophysiology of oral squamous cell carcinoma (OSCC), there is very limited data regarding the expression of GLUTs in normal or malignant cells from the oral mucosa. We analysed the messenger RNA (mRNA) expression of all 14 GLUTs in two OSCC (H357/H400) and one non-malignant oral keratinocyte (OKF6) cell line using a quantitative polymerase chain reaction. GLUT expression was evaluated at baseline and after treatment with two specific GLUT inhibitors, namely, BAY876 (GLUT1) and WZB117 (GLUT1, GLUT3 and GLUT4). Here, we show that GLUT1, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12 and GLUT13 transcripts were measurably expressed in all cell lines while GLUT2, GLUT7, GLUT9, GLUT11 and GLUT14 were not expressed. GLUT10 was only found in H357. In the presence of BAY876 and WZB117, OSCC cells exhibited significant alterations in the transcriptional profile of GLUTs. In particular, we observed distinct proliferation-dependent changes of mRNAs to GLUT1, GLUT3, GLUT4, GLUT5 and GLUT6 in response to selective GLUT inhibitors. In summary, we documented for the first time the expression of GLUT5, GLUT6 and GLUT12 in normal and malignant oral keratinocytes. Whilst regulation of GLUT transcripts was cell line and inhibitor specific, GLUT3 was consistently upregulated in actively proliferating OSCC cell lines, but not in OKF6, regardless of the inhibitor used, suggesting that modulation of this transporter may act as one of the primary compensation mechanisms for OSCC cells upon inhibition of glucose uptake.

The discovery and synthesis of insulin has been vital in the study and treatment of diabetes mellitus. From the studies carried by Dr. Nicolae C. Paulescu in 1921 and descriptions of the pancrein, before those published by Banting and Macleod, the Nobel Prize winners in 1923, more metabolic and non-metabolic actions have been discovered and that are fundamental for life, growth and development of different organs and systems. Diverse studies in animal models have shown the participation in the development of the central nervous system, regeneration, neuronal apoptosis, and synaptic transmission, as well as the effects of its dysregulation in the pathophysiology of diseases such as dementia. Different researchers have demonstrated the synthesis of insulin at the brain, the mechanisms through which the blood-brain barrier crosses and how it regulates non-metabolic systems linked with the nueromodulation. This document to integrate these findings in the cerebral insulin circuit and the translation in clinical practice.El descubrimiento y la síntesis de la insulina ha sido vitales en el estudio y el tratamiento de la diabetes mellitus. Desde los estudios realizados por el Dr. Nicolae C. Paulescu en 1921 y sus descripciones de la pancreína, antes de los publicados por Banting y Macleod, galardonados con el Premio Nobel en 1923, se han descubierto cada vez más acciones metabólicas y no metabólicas fundamentales para la vida, el crecimiento y el desarrollo de diferentes órganos y sistemas. En la actualidad, el estudio de esta hormona se nutre con más evidencia científica de su utilidad en blancos terapéuticos no metabólicos. Diversos estudios en modelos animales han demostrado su participación en el desarrollo del sistema nervioso central, la regeneración, la apoptosis neuronal y la transmisión sináptica, así como los efectos de su disregulación en la fisiopatología de enfermedades como la demencia. En la actualidad, diferentes investigadores han demostrado la síntesis de insulina en el cerebro, los mecanismos por los cuales atraviesa la barrera hematoencefálica y cómo regula sistemas no metabólicos ligados con la nueromodulación. Este documento trata de integrar estos hallazgos en un sistema insulinérgico cerebral y su posible traducción en la práctica clínica.

To examine the association between common comorbidities, eGFR and loci involved in the hyperuricaemia-gout transition. This study was conducted in people with gout from the UK Biobank. Logistic regression was used to examine the association between self-reported physician-diagnosed hypertension, diabetes, hypercholesterolemia and ischaemic heart disease (IHD) with the following variants: rs1260326(GCKR), rs16890979(SLC2A9), rs2231142(ABCG2), rs1229984(ADH1B) and rs2078267(SLC22A11) and adjusted for age, sex and 10-principal components. Linear regression was used to examine the association with eGFR. 7,049 participants with gout were included. After adjusting for multiple testing, there was a statistically significant positive association between urate lowering allele at SLC2A9 and hypertension, and negative association between urate raising allele at ABCG2 and hypertension (OR 1.17 and OR 0.86, respectively). Number of urate lowering risk alleles associated with hypertension [OR (95%CI) 1.13 (1.06–1.21)]. High eGFR associated with urate raising allele at rs2231142 (β = 1.38). The SNP in ADH1B that protects from alcohol excess showed a negative association with IHD (OR 0.53). Unlike in general population studies urate lowering genetic variants associate with hypertension in gout patients with dose–response. This may be due to high prevalence of other risk factors of hypertension such as obesity, poor diet etc. and needs validation in independent datasets.

Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I ( n=20), CIN II/III ( n=16), or ICC ( n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.

Cerebral ischemia is a leading cause of death in the globe, with a large societal cost. Deprivation of blood flow, together with consequent glucose and oxygen shortage, activates a variety of pathways that result in permanent brain damage. As a result, ischemia raises energy demand, which is linked to significant alterations in brain energy metabolism. Even at the low glucose levels reported in plasma during ischemia, glucose transport activity may adjust to assure the supply of glucose to maintain normal cellular function. Glucose transporters in the brain are divided into two groups: sodium-independent glucose transporters (GLUTs) and sodium-dependent glucose cotransporters (SGLTs).This review assess the GLUT structure, expression, regulation, pathobiology of GLUT in cerebral ischemia and regulators of GLUT and it also provides the synopsis of the literature exploring the relationship between GLUT and the various downstream signalling pathways for e.g., AMP-activated protein kinase (AMPK), CREB (cAMP response element-binding protein), Hypoxia-inducible factor 1 (HIF)-1, Phosphatidylinositol 3-kinase (PI3-K), Mitogen-activated protein kinase (MAPK) and adenylate-uridylate-rich elements (AREs). Therefore, the aim of the present review was to elaborate the therapeutic implications of GLUT in the cerebral ischemia.

Despite advances in resolving the structures of multi-pass membrane proteins, little is known about the native folding pathways of these complex structures. Using single-molecule magnetic tweezers, we here report a folding pathway of purified human glucose transporter 3 (GLUT3) reconstituted within synthetic lipid bilayers. The N-terminal major facilitator superfamily (MFS) fold strictly forms first, serving as a structural template for its C-terminal counterpart. We found polar residues comprising the conduit for glucose molecules present major folding challenges. The endoplasmic reticulum membrane protein complex facilitates insertion of these hydrophilic transmembrane helices, thrusting GLUT3's microstate sampling toward folded structures. Final assembly between the N- and C-terminal MFS folds depends on specific lipids that ease desolvation of the lipid shells surrounding the domain interfaces. Sequence analysis suggests that this asymmetric folding propensity across the N- and C-terminal MFS folds prevails for metazoan sugar porters, revealing evolutionary conflicts between foldability and functionality faced by many multi-pass membrane proteins.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). METHODS: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. RESULTS: We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. CONCLUSIONS: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.

With the rapid rise in prevalence, diabetes mellitus is one of the leading causes of mortality worldwide. Impaired cellular glucose transport is a major contributor to diabetes progression and, thus, an important target for treatment. Functional foods are a rich source of antidiabetic agents. These compounds target multiple physiological contributors to diabetes with lower risk for side effects. This perspective highlights recent advances in food-derived compounds that regulate the gene expression or activity of glucose transport proteins (SGLT1, SGLT2, GLUT1, GLUT2, and GLUT4) and provides insights for future research on targeting the transporters as a promising antidiabetic mechanism of nutraceutical compounds.

To investigate the performance of H22954, a novel long non-coding RNA (lncRNA), in inhibiting glucose uptake in leukemia cells.H22954, a novel lncRNA, inhibited glucose uptake in leukemia cells. Using bioinformatics and microarray analyses, GLUT10 was identified as a possible target molecule of H22954. H22954 targeted the 3'untranslated region of GLUT10. In the luciferase assay, the luciferase activity of pGL3-GLUT10 was inhibited by H22954. Consistently, H22954 expression levels were inversely correlated with GLUT10 expression in cell lines and acute myeloid leukemia (AML) samples. Conversely, the degradation rate ofThe lncRNA H22954 regulated GLUT10 expression to inhibit glucose uptake in leukemia cells. Our findings provide potentially valuable data for designing new targeted strategies based on H22954.

How does progesterone improve fetal outcome and change the expression of placental glucose transporters (GLUT) in dexamethasone-induced intrauterine growth restriction (IUGR)?A total of 64 rats were divided randomly into four different treatment groups based on daily i.p. injections of either saline or dexamethasone in the presence or absence of progesterone. Injections started on the 15th day of gestation (15dg) and lasted until the day of sacrifice at 19dg or 21dg. Maternal plasma progesterone concentrations were measured by enzyme-linked immunosorbent assay. The gene and protein expression of placental GLUT1 and GLUT3 were evaluated in the placental labyrinth and basal zones by real-time polymerase chain reaction and Western blotting, respectively. The localization of GLUT1 and GLUT3 was evaluated by immunohistochemistry.Dexamethasone induced significant decreases in maternal serum progesterone concentrations (P = 0.029) and placental (P 0.001) and fetal body (P = 0.009) weights. Dexamethasone also reduced the expression of GLUT1 in the labyrinth zone (P = 0.028) and GLUT3 in both the labyrinth (P = 0.002) and basal zones (P = 0.026). Coadministration of dexamethasone and progesterone prevented the reduction in fetal body weight, placental weight and placental GLUT expression compared with that seen in dexamethasone-treated groups.These results suggest that progesterone prevents the significant reduction in fetal and placental weights in dexamethasone-induced IUGR, possibly through improving the expression of placental GLUT.

Neuropathic pain, such as that seen in diabetes mellitus, results in part from central sensitisation in the dorsal horn. However, the mechanisms responsible for such sensitisation remain unclear. There is evidence that disturbances in the integrity of the spinal vascular network can be causative factors in the development of neuropathic pain. Here we show that reduced blood flow and vascularity of the dorsal horn leads to the onset of neuropathic pain. Using rodent models (type 1 diabetes and an inducible endothelial-specific vascular endothelial growth factor receptor 2 knockout mouse) that result in degeneration of the endothelium in the dorsal horn, we show that spinal cord vasculopathy results in nociceptive behavioural hypersensitivity. This also results in increased hypoxia in dorsal horn neurons, depicted by increased expression of hypoxia markers such as hypoxia inducible factor 1α, glucose transporter 3, and carbonic anhydrase 7. Furthermore, inducing hypoxia through intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn neurons as well as mechanical and thermal hypersensitivity. This shows that hypoxic signalling induced by reduced vascularity results in increased hypersensitivity and pain. Inhibition of carbonic anhydrase activity, through intraperitoneal injection of acetazolamide, inhibited hypoxia-induced pain behaviours. This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain.

Background and Aims. Elevated serum uric acid (SUA) is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD); however, whether this association is causal is undetermined. Methods. Each participant from the Dongfeng-Tongji cohort study based on 27,009 retirees was interviewed face-to-face following a clinical examination. Covariance, logistic regression analysis, and instrumental variables were used to assess associations between SUA and (severity of) NAFLD and the causal link. Results. Among 8,429 subjects free of NAFLD at baseline, 2,007 participants developed NAFLD after 5 years of follow-up. The multivariable-adjusted odds ratio (OR) for NAFLD for individuals in the fourth quartile of SUA level versus those in the first was 1.71 (95% CI: 1.45-2.01, P for trend P = 0.25 ) from what was expected (1.03, 95% CI: 1.03-1.03). Conclusions. SUA was positively associated with NAFLD incidence especially in female and normal-weight individuals and the suspected progression risk of newly developed NAFLD. However, the Mendelian randomization analyses lend no causal evidence, suggesting high SUA as a marker and not a cause of NAFLD.

Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by ∼ 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the β-adrenergic receptor (βAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases. NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.

Elevated serum uric acid (UA) level has been shown to be influenced by multiple genetic variants, but it remains uncertain how UA-associated variants differ in their influence on hyperuricemia risk in people taking antihypertensive drugs. We examined a total of 43 UA-related variants at 29 genes in 1840 patients with hypertension from a community-based longitudinal cohort during a median 2.25-year follow-up (including 1031 participants with normal UA, 440 prevalent hyperuricemia at baseline, and 369 new-onset hyperuricemia). Compared with the wild-type genotypes, patients carrying the SLC2A9 rs3775948G allele or the rs13129697G allele had decreased risk of hyperuricemia, while patients carrying the SLC2A9 rs11722228T allele had increased risk of hyperuricemia, after adjustment for cardiovascular risk factors and correction for multiple comparisons; moreover, these associations were modified by the use of diuretics, β-blockers, or angiotensin converting enzyme inhibitors. The rs10821905A allele of A1CF gene was associated with increased risk of hyperuricemia, and this risk was enhanced by diuretics use. The studied variants were not observed to confer risk for incident cardiovascular events during the follow-up. In conclusion, the genes SLC2A9 and A1CF may serve as potential genetic markers for hyperuricemia risk in relation to antihypertensive drugs therapy in Chinese hypertensive patients.

This study aims to investigate the anti-hyperuricemia effect and mechanism of anserine in hyperuricemic rats. Hyperuricemic rats were induced with a combination of 750 mg per kg bw d potassium oxazinate (PO) and 200 mg per kg bw d hypoxanthine for a week, and the rats were separately orally administered anserine (20, 40, 80 mg kg

Objective This study is aimed to describe the clinical and genetic characteristics of a Chinese woman diagnosed with renal hypouricemia type 2 (RHUC2). We also summarize the advances in research on RHUC2 by reviewing related literature. Methods We measured clinical parameters of a 57-year-old female and performed whole-exome sequencing to screen for mutations. Human embryonic kidney 293 cells were transiently transfected with plasmids containing wild-type or mutants. Relative mRNA quantification was determined by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results This patient was diagnosed with diabetes and coronary heart disease. In addition, a decrease in 24-hour urinary chloride was observed. Two novel heterozygous variants of SLC2A9 (NM_020041.2): c.682-2_682-1insC and c.267C > G (p.Y89X) were identified. The mini-gene splicing assay revealed that c.682-2_682-1insC variant resulted in a frameshift mutation p. E228PfsX23. There was a statistically significant difference in mRNA expression level between the two mutants and the wild-type. Conclusions These findings strongly suggest that the two novel mutations are the causative agents of RHUC2. In particular, our findings provide further insights into the function of SLC2A9 and mechanisms of the complications.

Glucose is vital to embryogenesis, as are glucose transporters. Glucose transporter 4 (Glut4) is one of the glucose transporters, which is involved in rapid uptake of glucose by various cells and promotes glucose homeostasis. Although energy metabolism in insect reproduction is well known, the molecular mechanism of Glut4 in insect reproduction is poorly understood. We suspect that Glut4 is involved in maintaining glucose concentrations in the ovaries and affecting vitellogenesis, which is critical for subsequent oocyte maturation and insect fertility. Harmonia axyridis (Pallas) is a model organism for genetic research and a natural enemy of insect pests. We studied the influence of the Glut4 gene on the reproduction and development of H. axyridis using RNA interference technology. Reverse transcription quantitative polymerase chain reaction analysis revealed that HaGlut4 was most highly expressed in adults. Knockdown of the HaGlut4 gene reduced the transcript levels of HaGlut4, and the weight and number of eggs produced significantly decreased. In addition, the transcript levels of vitellogenin receptor and vitellogenin in the fat bodies and the ovaries of H. axyridis decreased after the interference of Glut4, and decreased the triglyceride, fatty acid, total amino acid and adenosine triphosphate content of H. axyridis. This resulted in severe blockage of ovary development and reduction of yolk formation; there was no development of ovarioles in the developing oocytes. These changes indicate that a lack of HaGlut4 can impair ovarian development and oocyte maturation and result in decreased fecundity.

This study aimed to evaluate whether FGF19 can alleviate insulin resistance and change the expression of placental IRS1/GLUTs.Mice transgenic for Fgf15 (the murine homologue of human FGF19) were constructed, and human recombinant FGF19 was administered to pregnant high-fat diet mice. Then, glycolipid metabolism parameters and the weight of foetus and placenta were observed. The expression levels of key molecules of the insulin signalling pathway and glucose transporters in placentae were detected by qRT-PCR and western blotting. Primary trophoblasts and JAR cells were cultured in high-glucose medium, and FGF19 was added to observe its regulatory effects on IRS1/GLUTs.Overexpressing FGF15 or exogenously administering FGF19 reduced the levels of fasting blood glucose, HOMA-IR, triglycerides, and free fatty acids in pregnant high-fat diet mice compared to control mice (P 0.05). FGF15/FGF19 did not significantly affect placental weight, foetal weight or litter size (P 0.05). In addition, FGF15/FGF19 upregulated the expression of p-IRS1 and GLUT4 in the placentae of high-fat diet mice and upregulated GLUT1 levels in the placentae of normal diet-fed mice (P 0.05), while it did not significantly alter total IRS1 and GLUT3 levels (P 0.05). Consistent with the results of the animal experiments, FGF19 increased the expression of p-IRS1 and GLUT4 in trophoblast cells cultured in high-glucose medium (P 0.05).Overexpressing FGF15 or administering FGF19 to pregnant high-fat diet mice can improve glycolipid metabolism and alleviate systemic and local insulin resistance. The possible underlying mechanism may involve upregulation of placental expression of p-IRS1 and GLUT4.

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5’ adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

BackgroundGout is a highly hereditary disease, but not all those carrying well-known risk variants have developing gout attack even in hyperuricemia status. We performed a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis to illustrate the new genetic architectures of gout and asymptomatic hyperuricemia (AH).MethodsGWAS was performed to identify variants associated with gout/AH compared with normouricemia. The participants were males, enrolled from the Taiwan Biobank and China Medical University, and divided into discovery (n=39,594) and replication (n=891) cohorts for GWAS. For PRS analysis, the discovery cohort was grouped as base (n=21,814) and target (n=17,780) cohorts, and the score was estimated by grouping the polymorphisms into protective or not for the phenotypes in the base cohort.ResultsThe genesABCG2andSLC2A9were found as the major genetic factors governing gouty and AH, and even in those carrying the rs2231142 (ABCG2) wild-genotype. Surprisingly, variants on chromosome 1, such as rs7546668 (DNAJC16), rs10927807 (AGMAT), rs9286836 (NUDT17), rs4971100 (TRIM46), rs4072037 (MUC1), and rs2974935 (MTX1), showed significant associations with gout in both discovery and replication cohorts (allp-values < 1e−8). Concerning the PRS, the rates of gout and AH increased with increased quartile PRS in those SNPs having risk effects on the phenotypes; on the contrary, gout/AH rates decreased with increased quartile PRS in those protective SNPs.ConclusionsWe found new variants on chromosome 1 significantly relating to gout, and PRS predicts the risk of developing gout/AH more robustly based on the SNPs’ effect types on the trait.

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18 F-deoxyglucose positron emission tomography ( 18 F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18 F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18 F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Here we report synthetic monosaccharide channels built with shape-persistent organic cages, porphyrin boxes (PBs), that allow facile transmembrane transport of glucose and fructose through their windows. PBs show a much higher transport rate for glucose and fructose over disaccharides such as sucrose, as evidenced by intravesicular enzyme assays and molecular dynamics simulations. The transport rate can be modulated by changing the length of the alkyl chains decorating the cage windows. Insertion of a linear pillar ligand into the cavity of PBs blocks the monosaccharide transport. In vitro cell experiment shows that PBs transport glucose across the living-cell membrane and enhance cell viability when the natural glucose transporter GLUT1 is blocked. Time-dependent live-cell imaging and MTT assays confirm the cyto-compatibility of PBs. The monosaccharide-selective transport ability of PBs is reminiscent of natural glucose transporters (GLUTs), which are crucial for numerous biological functions.

The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg body weight). Diabetic rats were treated with nerolidol (25 mg/kg BW) for 28 days. Results showed that nerolidol treatment significantly reduced ( p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved ( p < 0.05) the body weight and insulin level. Nerolidol also considerably improved ( p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered ( p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing ( p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering ( p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring ( p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.

Oat β-glucan (OBG) and L-arabinose (LA) have exhibited positive effects on diabetes and its complications. However, it is unclear whether OBG and LA have a synergistic effect. We investigated the effect of variable compositions (OBG : LA = 1 : 1, 1 : 2, 1 : 4,1 : 6, 1 : 8, 1 : 10, 2 : 1, 4 : 1, 6 : 1, 8 : 1, 10 : 1) on glucose uptake in IR-HepG2 cells induced by dexamethasone (DEX) to find out the optimal composition showing synergistic effects. Furthermore, this study evaluated the anti-diabetic activity of the optimal composition in db/db mice.

In recent years, a broad spectrum of molecular image biomarkers for assessment of adrenal functional imaging have penetrated the clinical arena. Those include positron emission tomography and single photon emission computed tomography radiotracers, which either target glucose transporter, CYP11B enzymes, C-X-C motif chemokine receptor 4, norepinephrine transporter or somatostatin receptors. We will provide an overview of key radiopharmaceuticals and determine their most relevant clinical applications, thereby providing a roadmap for the right image biomarker at the right time for the right patient.Numerous radiotracers for assessment of adrenal incidentalomas ([ 18 F]FDG; [ 123 I]IMTO/IMAZA), ACC ([ 123 I]IMTO/IMAZA; [ 18 F]FDG; [ 68 Ga]PentixaFor), pheochromocytomas and paragangliomas ([ 123 I]mIBG; [ 18 F]flubrobenguane; [ 18 F]AF78; [ 68 Ga]DOTATOC/-TATE), or primary aldosteronism ([ 11 C]MTO, [ 68 Ga]PentixaFor) are currently available and have been extensively investigated in recent years. In addition, the field is currently evolving from adrenal functional imaging to a patient-centered adrenal theranostics approach, as some of those radiotracers can also be labeled with ß-emitters for therapeutic purposes.The herein reviewed functional image biomarkers may not only allow to increase diagnostic accuracy for adrenal gland diseases but may also enable for achieving substantial antitumor effects in patients with adrenocortical carcinoma, pheochromocytoma or paraganglioma.

Sugar uptake is of great significance in industrially relevant microorganisms. Clostridium thermocellum has extensive potential in lignocellulose biorefineries as an environmentally prominent, thermophilic, cellulolytic bacterium. The bacterium employs five putative ATP-binding cassette transporters which purportedly take up cellulose hydrolysates. Here, we first applied combined genetic manipulations and biophysical titration experiments to decipher the key glucose and cellodextrin transporters.

Brain-derived neurotrophic factor (BDNF) is expressed in both hypothalamic neurons and microglia, and plays a critical role in the regulation of metabolism. Although hypothalamic expression of BDNF is regulated by metabolic signals such as nutrients and hormones, it remains unknown whether these signals differentially regulate BDNF expression in different cell types. The present study aimed to determine whether glucose and fructose regulate BDNF expression in microglia via the specific glucose transporter. To determine the effect of glucose and fructose on Bdnf mRNA and protein expression, murine microglial cell line SIM-A9 cells were exposed to the maintenance concentration of glucose (17.5 mmol/l), high glucose (25 mmol/l), or fructose (7.5 mmol/l) for 40 min to 24 h. To determine whether the blockade of glucose transporter 5 (GLUT5) negates the effect of glucose on Bdnf mRNA expression, cells were exposed to 25 mmol/l glucose in the presence or absence of the GLUT5 inhibitor for 4 h. Levels of Bdnf mRNA and protein were measured by real-time PCR and ELISA, respectively. High glucose caused a significant increase in both pan-Bdnf and long-form Bdnf (L-Bdnf) mRNA as well as protein levels when compared with the maintenance of concentration of glucose in a time-dependent manner. Fructose treatment also increased L-Bdnf mRNA expression. Pharmacological blockade of GLUT5 did not affect glucose-induced Bdnf mRNA expression. These findings suggest that glucose and fructose directly stimulate Bdnf mRNA expression in microglia and these responses may mediate the metabolic actions of glucose and fructose.

Aim: The relationship between hyperuricemia and polymorphisms of transporter genes in coronary artery disease (CAD) patients in China remains unclear. Materials & methods: A total of 258 hyperuricemia patients with CAD and 242 control patients with CAD were recruited in this case–control study. Twenty-four SNPs in genes of ABCG2, PDZK1, URAT1, OAT4, GLUT9, ABCC4, NPT1 and NPT4 were genotyped using direct sequencing in all subjects. Results: The mutation of ABCG2 rs2231142 locus increases the risk of hyperuricemia, and there is a gene dose effect in the influence of mutant heterozygotes and homozygotes. rs3825017 in URAT1 and rs62293298 in GLUT9 were also confirmed to be associated with hyperuricemia. Conclusion: Age, weight, creatinine clearance rate, diuretics and SNPs on ABCG2, URAT1 and GLUT9 were all risk factors of hyperuricemia.

Differentiated mammary epithelial cells are responsible for milk synthesis during lactation, supporting early postnatal life in mammals. These cells are found in the terminal alveoli of a secretory epithelium, which is surrounded by myoepithelial cells and a stroma rich in fatty tissue. The aim of this study was to explore the cell-specific expression of the glucose transporter GLUT8 in mammary gland and evaluate its functionality for glucose transport, in order to confirm its role in lactose synthesis. Our histological results revealed that GLUT8 is expressed in adipocytes and the epithelial and myoepithelial cells in mammary gland, with a predominant intracellular granular pattern. Colocalization studies of endogenous and green fluorescent protein fused GLUT8 revealed their expressions in lysosome and Golgi, respectively, with Pearson's coefficient correlations of 0.82 ± 0.05 and 0.68 ± 0.16. Functional studies of dileucine to dialanine mutant of GLUT8 showed a fructose-sensitive 2-deoxy glucose uptake at a rate of 83.3 pmoles/(min∗106 cells), 7 folds over empty vector, with a 60 ± 4 and 72 ± 6% decline in 2-deoxy glucose in the presence of 20 and 50 mM fructose, respectively. We concluded that functional GLUT8 is expressed in mammary gland, localizing in mammary epithelial and myoepithelial cells, and adipocytes. In lactation, GLUT8 is expressed mainly in luminal epithelial cells, at the compartments of the endomembrane system. It is necessary to explore the physiological/pathological functions of GLUT8 in mammary gland, including its role in lactation.

Excess circulating lipids increase total intramyocellular (IMC) lipid content and ectopic fat storage, resulting in lipotoxicity and insulin resistance in skeletal muscle. Consumption of a diet high in fat and refined sugars—a Western diet (WD)—has been shown to activate mineralocorticoid receptors (MRs) and promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study, we investigated the mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic skeletal muscle lipid accumulation and related insulin resistance. Six-week-old C57BL/6J mice were fed either a mouse chow diet or a WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD-induced in vivo glucose intolerance and insulin resistance, and improved soleus insulin metabolic signaling. Improved insulin sensitivity was accompanied by increased glucose transporter 4 (Glut4) expression in conjunction with decreased soleus free fatty acid and IMC lipid content, as well as CD36 expression. Additionally, spironolactone prevented WD-induced soleus mitochondria dysfunction. Furthermore, MR signaling also mediated WD/aldosterone-induced reductions in soleus microRNA (miR)-99a, which was identified to negatively target CD36 and prevented palmitic acid–induced increases in CD36 expression, lipid droplet formation, mitochondria dysfunction, and insulin resistance in C2C12 cells. These data indicate that inhibition of MR activation with spironolactone prevented diet-induced abnormal expression of miR-99a, which had the capacity to reduce CD36, leading to reduced IMC lipid content and improved soleus mitochondria function and insulin sensitivity.

Maintenance of intestinal metabolic function is important for optimal growth performance in post-weaning pigs. This study aimed to evaluate the effect of pyrroloquinoline quinone (PQQ) on maintaining intestinal glycolipid metabolism in weaned pigs. Seventy-two Duroc × Landrace × Yorkshire crossbred pigs were divided into two groups: pigs fed a basal diet (CTRL group) and pigs fed a basal diet supplemented with 3.0 mg kg

Insulin stimulates translocation of glucose transporter 4 (GLUT4) from the perinuclear location to the plasma membrane. In the unstimulated state, intracellular vesicles containing GLUT4 are sequestered into specialized storage vesicles that have come to be known as the insulin-responsive compartment (IRC). The IRC is a functional compartment in the perinuclear region that is a target of the insulin signaling cascade, although its precise nature is unclear. Here, we report a novel molecular mechanism facilitating formation of the IRC.We determined synaptosomal-associated protein of 29 kDa (SNAP29) by mass spectrometry to be an EH domain-containing protein 1 (EHD1)-binding protein. Then, its expression was confirmed by western blotting. Subcellular localization of SNAP29 was determined by immunofluorescent microscopy. Interactions between SNAP29 and syntaxins were determined by immunoprecipitation. We measured glucose uptake and GLUT4 translocation in 3T3-L1 adipocyte expressing SNAP29 or silencing SNAP29.We found SNAP29 to be localized in the perinuclear region and to show partial co-localization with GLUT4 under basal conditions. We also found that SNAP29 binds to syntaxin6, a Qc-SNARE, in adipocytes. In SNAP29-expressing cells, vesicles containing GLUT4 were observed to aggregate around the perinuclear region. In contrast, when SNAP29 was silenced, perinuclear GLUT4 vesicles were dispersed throughout the cytosol. Insulin-stimulated glucose uptake was inhibited in both SNAP29-expressing and SNAP29-silenced cells.These data suggest that SNAP29 sequesters and anchors GLUT4-containing vesicles in the perinuclear region, and might have a role in the biogenesis of the perinuclear IRC.

Neuroendocrine tumors (NETs) are heterogeneous group of tumors arising from enterochromaffin cells. Neuroendocrine tumors are most commonly found in bowel and pancreatic tissue. Because of paucity of enterochromaffin cells in biliary tract, NETs of bile duct are very rare. Most of the neoplasms in the extrahepatic bile duct are adenocarcinomas; only 0.2% to 0.3% of NETs arise from the bile duct. Cases reported in the literature of biliary carcinoid are diagnosed postoperatively on histopathologic evaluation. We hereby demonstrate a rare presentation of CBD NET identified preoperatively on somatostatin receptor but not on glucose transporter imaging, confirmed by histopathology and immunohistochemistry to be grade 2 NET (Ki-67, 20%).

Hyperhimatins A-P (1-16), sixteen new bicyclic polyprenylated acylphloroglucinols (BPAPs), were isolated and identified from Hypericum himalaicum. The planner structures of hyperhimatins A-P were confirmed via extensive NMR and careful HRESIMS data analysis. The absolute configurations of the new compounds were mainly determined by electronic circular dichroism (ECD) calculation, NMR calculation, and the circular dichroism data of the in situ formed [Rhsub2/sub(OCOCFsub3/sub)sub4/sub] complexes. All compounds were assessed for the glucose transporter 4 (GLUT-4) translocation and expression enhancing effects in L6 myotubes. Compounds 1-16 could promote the GLUT-4 expression by the range of 1.95-6.04 folds, and accelerate the GLUT-4 fusion with the plasma membrane ranged from 53.56% to 76.97% at a consistence of 30 μg/mL, among compound 10 displayed the strongest GLUT-4 translocation effect.

Avenanthramides are phenolic compounds unique to oats and may contribute to health-promoting properties associated with oat consumption. This study used Xenopus laevis oocytes expressing the glucose transporters, glucose transporter 2 (GLUT2) or sodium-glucose transport protein 1 (SGLT1) and human Caco-2 cells models to investigate the effect of oat avenanthramides on human intestinal glucose transporters. The presence of avenanthramide reduced the glucose uptake in a dose-dependent manner in Caco-2 cells. Glucose uptake in oocytes expressing either GLUT2 or SGLT1 was nullified by oat avenanthramide. There was no significant difference between the inhibition potencies of avenanthramides C and B. Thus, our results suggest that avenanthramides may contribute to the antidiabetic properties of oats. PRACTICAL APPLICATIONS: The present research focus on the antidiabetic properties of avenanthramides, which are unique phenolic compounds found in oats. Inhibiting the activities of the glucose transport proteins expressed in the small intestine is a known strategy to improve the control of postprandial glucose level. We therefore examined the inhibitory effects of avenanthramides on two glucose transporters, glucose transporter 2 and sodium-glucose transport protein 1, predominantly found in the small intestine using the human small intestinal cell model Caco-2 cell line and by heterologously expressing these two transporters in the Xenopus laevis oocytes. Based on our results, we have confirmed for the first time that the glucose uptake is indeed inhibited by the presence of avenanthramides, suggesting the possibility of incorporating avenanthramides in foods to enhance postprandial glucose response, and ultimately improve the management of diabetes. Therefore, future research could consider utilizing this evidence in the development of diabetic-friendly functional foods or nutraceuticals containing avenanthramides.

The Gram-positive bacterium

Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these EVs may be a pathogenic biomarker of UASD. Methods: Urinary EVs bearing UA transporters (SLC2A9, SLC17A3, SLC22A12, SLC5A8, ABCG2, and ZNF365) were quantified in urine from UA stone formers (UASFs), calcium stone formers (CSFs), and age-/sex-matched non-stone formers (NSFs) using a standardized and published method of digital flow cytometry. Results: Urinary pH was lower (p < 0.05) and serum and urinary UA were greater (p < 0.05) in UASFs compared with NSFs. Urinary EVs carrying SLC17A3 and SLC5A8 were lower (p < 0.05) in UASFs compared with NSFs. Urinary EVs bearing SLC2A9, SLC22A12, SLC5A8, ABCG2, and ZNF365 were lower (p < 0.05) in CSFs than UASFs, while excretion of SLC17A3-bearing EVs did not differ between groups. Conclusion: EVs bearing specific UA transporters might contribute to the pathogenesis of UASD and represent non-invasive pathogenic biomarkers for calcium and UA stone risk.

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues’ glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.

Diabetes mellitus is the leading disorder and affects more than millions of people worldwide. Nowadays, the usage of herbal drugs is said to control adiposity and hyperglycemia. The current research investigated the anti-adiposity and antidiabetic activity of S. saman leaf extract and bioactive compounds. Therefore, the results lower the sugar absorption into the blood and reveal the extract's antidiabetic properties. STZ-induced diabetic rats, Samanea saman methanolic extract show improvement in the parameters like fasting blood glucose levels, body weight, other biochemical parameters supported by the histopathological analysis, and an increase in serum levels in the experimental groups. The antioxidant plays a vital role by increasing SOD and catalase activity levels and decreasing lipid peroxidation levels. The methanolic extract protects the tissue from oxidation stress, which is responsible for the glycemic properties. According to the findings, diabetic-treated rats had overnight blood glucose levels lower and near standard biochemical markers. Histopathology of the liver, pancreas, kidneys, and adipose tissues supported the pharmacological observations. Further, we screened and documented S. saman extract used for in vitro and in vivo methods. In terms of effectiveness, the crude extracts exhibit 0.8-fold GLUT4 down-regulation. Consequently, this result contributes to clinical trials and develops antidiabetic therapy as a substitute for synthetic pharmaceuticals.

Repaglinide (RPG) is an oral insulin secretagogue used in the treatment of diabetes. In this study, a new RPG analog was synthesized. Its antidiabetic and neuroprotective effects on dorsal root ganglions (DRG) in streptozotocin (STZ)-induced diabetic rats were examined compared to RPG. To assess the effects of 2-methoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethoxy)benzoic acid (OXR), the impact of OXR on oxidative stress biomarkers, motor function, and the expression of the glutamate dehydrogenase 1 (GLUD1), SLC2A2/glucose transporter 2 (GLUT2), and glucokinase (GCK) genes in STZ-induced diabetic rats were assessed. DRGs were examined histologically using hemotoxylin and eosin staining. Molecular docking was used to investigate the interactions between OXR and the binding site of RPG, the ATP-sensitive potassium (KATP) channel. Following 5 weeks of treatment, OXR significantly increased the level of total antioxidant power, decreased reactive oxygen species, and lipid peroxidation in the DRGs of diabetic rats. OXR restored STZ-induced pathophysiological damages in DRG tissues. Administration of OXR improved motor function of rats with diabetic neuropathy. Administration of 0.5 mg/kg OXR reduced blood glucose while promoting insulin, mainly through upregulation of messenger RNA expression of GLUD1, GLUT2, and GCK in the pancreas. Molecular docking revealed a favorable binding mode of OXR to the KATP channel. In conclusion, OXR has neuroprotective effects in diabetic rats by lowering oxidative stress, lowering blood glucose, and stimulating insulin secretion. We report that 0.5 mg/kg OXR administration was the most effective concentration of the compound in this study. OXR may be a promising target for further research on neuroprotective antidiabetic molecules.

Gain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as a reporter of the GLUT4 vesicle trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 μM ionomycin, indicating that in addition to impairing exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease.

Although impaired insulin signaling at a post-receptor level was a well-established key driver of insulin resistance, the role of surface abnormal insulin receptor (INSR) location in insulin resistance pathogenesis tended to be ignored and its molecular mechanisms remained obscure. Herein, this study aimed to investigate hepatic apolipoprotein E (APOE) impaired cellular insulin action via reducing cell surface INSR, especially in caveolae.Downregulation of APOE enhanced the caveolae translocation of INSR and glucose transporter 2 (GLUT2), and improved hepatic cells' sensitivity to insulin. Consistently, mice with selective suppression of liver tissue APOE showed lower fasting insulin and fasting glucose levels, better homeostatic model assessment (HOMA) index (HOMA-IS, HOMA-IR, HOMA-β) and quantitative insulin sensitivity check index (QUICKI). Furthermore, the co-localization of INSR and CAV1 in the liver of these mice were more substantial than controls.APOE might adversely set the basal gain of INSR signaling implied that APOE could be a new endogenous INSR regulator.

Insulin stimulates glucose transport in muscle and adipocytes. This is achieved by regulated delivery of intracellular glucose transporter (GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, resulting in increased cell surface GLUT4 levels. Recent work identified a potential further regulatory step, in which insulin increases the dispersal of GLUT4 in the plasma membrane away from the sites of vesicle fusion. EFR3 is a scaffold protein that facilitates localization of phosphatidylinositol 4-kinase type IIIα to the cell surface. Here we show that knockdown of EFR3 or phosphatidylinositol 4-kinase type IIIα impairs insulin-stimulated glucose transport in adipocytes. Using direct stochastic reconstruction microscopy, we also show that EFR3 knockdown impairs insulin stimulated GLUT4 dispersal in the plasma membrane. We propose that EFR3 plays a previously unidentified role in controlling insulin-stimulated glucose transport by facilitating dispersal of GLUT4 within the plasma membrane.

BACKGROUND Amphibians possess three kinds of dermal chromatophore: melanophores, iridophores, and xanthophores. Knockout Xenopus tropicalis that lack the pigmentation of melanophores and iridophores have been reported. The identification of the causal genes for xanthophore pigmentation or differentiation could lead to the creation of a see-through frog without three chromatophores. The genes causing xanthophore differentiation mutants are slc2a11b and slc2a15b in Japanese medaka (Oryzias latipes). RESULTS To obtain a heritable line of X tropicalis mutants without yellow pigment, we generated slc2a7 and slc2a15a knockout animals because they have the greatest similarity to the O latipes slc2a11b and slc2a15b genes. The slc2a7 knockout frog had a bluish skin and there were no visible yellow pigments in stereo microscope and skin section observations. Furthermore, no pterinosomes, which are characteristic of xanthophores, were observed via transmission electron microscopy in the skin of knockout animals. CONCLUSIONS We report the successful generation of a heritable no-yellow-pigment X tropicalis mutant after knock out of the slc2a7 gene. This finding will enable the creation of a see-through frog with no chromatophores.

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.