Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

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Opie, L H

2014-08-01

Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors during Ramadan Fasting: Evidence, Perceptions and Guidelines

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Salem A. Beshyah

2016-06-01

Full Text Available Sodium-glucose co-transporter 2 (SGLT2 inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients.  One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients’ education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis.

Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2 inhibitor for the treatment of type 2 diabetes

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Joshua J Neumiller

2014-06-01

Full Text Available Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2 inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™.

Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy.

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Clements, Jennifer N; Whitley, Heather P; D'Souza, Jennifer J; Gross, Benjamin; Hess, Rick; Reece, Sara; Gentry, Chad; Shealy, Kayce

2015-01-01

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication's efficacy, safety, and cost, along with the patient's preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents - dapagliflozin and empagliflozin - were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.

Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors.

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Rahelić, Dario; Javor, Eugen; Lucijanić, Tomo; Skelin, Marko

2017-02-01

Elevated hemoglobin A 1c (HbA 1c ) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors. Key messages Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs. The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM.

[Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD].

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Insalaco, Monica; Zanoli, Luca; Rastelli, Stefania; Lentini, Paolo; Rapisarda, Francesco; Fatuzzo, Pasquale; Castellino, Pietro; Granata, Antonio

2015-01-01

Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD.

Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.

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Scheen, André J

2015-01-01

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin

Sodium glucose transporter 2 (SGLT2 inhibition and ketogenesis

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Sanjay Kalra

2015-01-01

Full Text Available Sodium glucose transporter 2 (SGLT2 inhibitors are a recently developed class of drug that have been approved for use in type 2 diabetes. Their unique extra-pancreatic glucuretic mode of action has encouraged their usage in type 1 diabetes as well. At the same time, reports of pseudo ketoacidosis and ketoacidosis related to their use have been published. No clear mechanism for this phenomenon has been demonstrated so far. This communication delves into the biochemical effects of SGLT2 inhibition, discusses the utility of these drugs and proposes steps to maximize safe usage of the molecules.

Sodium-Glucose linked transporter 2 (SGLT2) inhibitors--fighting diabetes from a new perspective.

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Angelopoulos, Theodoros P; Doupis, John

2014-06-01

Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.

Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

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Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

2016-01-01

Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.

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Packer, Milton

2018-06-01

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin. © 2018 John Wiley & Sons Ltd.

Construction of bioartificial renal tubule assist device in vitro and its function of transporting sodium and glucose.

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Dong, Xinggang; Chen, Jianghua; He, Qiang; Yang, Yi; Zhang, Wei

2009-08-01

To explore a new way of constructing bioartificial renal tubule assist device (RAD) in vitro and its function of transporting sodium (Na(+)) and glucose and to evaluate the application of atomic force microscope in the RAD construction, rat renal tubular epithelial cell line NRK-52E was cultured in vitro, seeded onto the outer surfaces of hollow fibers in a bioreactor, and then cultured for two weeks to construct RAD. Bioreactor hollow fibers without NRK-52E cells were used as control. The morphologies of attached cells were observed with scanning electron microscope, and the junctions of cells and polysulfone membrane were observed with atomic force microscope. Transportation of Na(+) and glucose was measured. Oubaine and phlorizin were used to inhibit the transporting property. The results showed that NRK-52E cells and polysulfone membrane were closely linked, as observed under atomic force microscope. After exposure to oubaine and phlorizin, transporting rates of Na(+) and glucose were decreased significantly in the RAD group as compared with that in the control group (Pconstructed successfully in vitro, and it is able to selectively transport Na(+) and glucose.

A 96-well automated method to study inhibitors of human sodium-dependent D-glucose transport.

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Castaneda, Francisco; Kinne, Rolf K-H

2005-12-01

The sodium-dependent D-glucose transporter (SGLT) family is involved in glucose uptake via intestinal absorption (SGLT1) or renal reabsorption (SGLT1 and SGLT2). Current methods for the screening of inhibitors of SGLT transporters are complex, expensive and very labor intensive, and have not been applied to human SGLT transporters. The purpose of the present study was to develop an alternative 96-well automated method to study the activity of human SGLT1 and SGLT2. Chinese hamster ovary (CHO) Flp-In cells were stably transfected with pcDNA5-SGLT1 or pcDNA5-SGLT2 plasmid and maintained in hygromycin-selection Ham's F12 culture medium until hygromycin-resistant clones were developed. SGLT1 and SGLT2 gene expression was evaluated by relative real-time reverse transcription-polymerase chain reaction (RT-PCR) quantification, Western blotting, and immunocytochemical analysis. The clones with higher expression of SGLT1 and SGLT2 were used for transport studies using [14C]-methyl-alpha-D-glucopyranoside ([14C]AMG). The advantage of using the 96-well format is the low amount of radioactive compounds and inhibitory substances required, and its ability to establish reproducibility because repetition into the assay. This method represents an initial approach in the development of transport-based high-throughput screening in the search for inhibitors of glucose transport. The proposed method can easily be performed to yield quantitative data regarding key aspects of glucose membrane transport and kinetic studies of potential inhibitors of human SGLT1 and SGLT2.

Glucose transport in brain - effect of inflammation.

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Jurcovicova, J

2014-01-01

Glucose is transported across the cell membrane by specific saturable transport system, which includes two types of glucose transporters: 1) sodium dependent glucose transporters (SGLTs) which transport glucose against its concentration gradient and 2) sodium independent glucose transporters (GLUTs), which transport glucose by facilitative diffusion in its concentration gradient. In the brain, both types of transporters are present with different function, affinity, capacity, and tissue distribution. GLUT1 occurs in brain in two isoforms. The more glycosylated GLUT1 is produced in brain microvasculature and ensures glucose transport across the blood brain barrier (BBB). The less glycosylated form is localized in astrocytic end-feet and cell bodies and is not present in axons, neuronal synapses or microglia. Glucose transported to astrocytes by GLUT1 is metabolized to lactate serving to neurons as energy source. Proinflammatory cytokine interleukin (IL)-1β upregulates GLUT1 in endothelial cells and astrocytes, whereas it induces neuronal death in neuronal cell culture. GLUT2 is present in hypothalamic neurons and serves as a glucose sensor in regulation of food intake. In neurons of the hippocampus, GLUT2 is supposed to regulate synaptic activity and neurotransmitter release. GLUT3 is the most abundant glucose transporter in the brain having five times higher transport capacity than GLUT1. It is present in neuropil, mostly in axons and dendrites. Its density and distribution correlate well with the local cerebral glucose demands. GLUT5 is predominantly fructose transporter. In brain, GLUT5 is the only hexose transporter in microglia, whose regulation is not yet clear. It is not present in neurons. GLUT4 and GLUT8 are insulin-regulated glucose transporters in neuronal cell bodies in the cortex and cerebellum, but mainly in the hippocampus and amygdala, where they maintain hippocampus-dependent cognitive functions. Insulin translocates GLUT4 from cytosol to plasma

The expression and regulation of glucose transporters in tumor cells

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Pengfei Zhao

2016-12-01

Full Text Available Glucose transporter proteins are involved in many physiological and biochemical processes. In particular, the high expressions of sodium-glucose cotransporter and glucose transporter proteins in tumor cells show that these two transporters play a key role in tumor cell metabolism. Studying the crystal structure and conformation of human glucose transporter proteins has enabled the development of drugs based on specific binding sites, opening up a new path towards more effective cancer treatments. This mini review serves to summarize our existing understanding of the metabolic pathways of tumor cells, focusing on the roles of glucose transporter proteins.

The Sodium Glucose Cotransporter SGLT1 Is an Extremely Efficient Facilitator of Passive Water Transport.

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Erokhova, Liudmila; Horner, Andreas; Ollinger, Nicole; Siligan, Christine; Pohl, Peter

2016-04-29

The small intestine is void of aquaporins adept at facilitating vectorial water transport, and yet it reabsorbs ∼8 liters of fluid daily. Implications of the sodium glucose cotransporter SGLT1 in either pumping water or passively channeling water contrast with its reported water transporting capacity, which lags behind that of aquaporin-1 by 3 orders of magnitude. Here we overexpressed SGLT1 in MDCK cell monolayers and reconstituted the purified transporter into proteoliposomes. We observed the rate of osmotic proteoliposome deflation by light scattering. Fluorescence correlation spectroscopy served to assess (i) SGLT1 abundance in both vesicles and plasma membranes and (ii) flow-mediated dilution of an aqueous dye adjacent to the cell monolayer. Calculation of the unitary water channel permeability, pf, yielded similar values for cell and proteoliposome experiments. Neither the absence of glucose or Na(+), nor the lack of membrane voltage in vesicles, nor the directionality of water flow grossly altered pf Such weak dependence on protein conformation indicates that a water-impermeable occluded state (glucose and Na(+) in their binding pockets) lasts for only a minor fraction of the transport cycle or, alternatively, that occlusion of the substrate does not render the transporter water-impermeable as was suggested by computational studies of the bacterial homologue vSGLT. Although the similarity between the pf values of SGLT1 and aquaporin-1 makes a transcellular pathway plausible, it renders water pumping physiologically negligible because the passive flux would be orders of magnitude larger. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Effects of taurine on plasma glucose concentration and active glucose transport in the small intestine.

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Tsuchiya, Yo; Kawamata, Koichi

2017-11-01

Taurine lowers blood glucose levels and improves hyperglycemia. However, its effects on glucose transport in the small intestine have not been investigated. Here, we elucidated the effect of taurine on glucose absorption in the small intestine. In the oral glucose tolerance test, addition of 10 mmol/L taurine suppressed the increase in hepatic portal glucose concentrations. To investigate whether the suppressive effect of taurine occurs via down-regulation of active glucose transport in the small intestine, we performed an assay using the everted sac of the rat jejunum. Addition of taurine to the mucosal side of the jejunum suppressed active glucose transport via sodium-glucose cotransporter 1 (SGLT1). After elimination of chloride ions from the mucosal solution, taurine did not show suppressive effects on active glucose transport. These results suggest that taurine suppressed the increase in hepatic portal glucose concentrations via suppression of SGLT1 activity in the rat jejunum, depending on chloride ions. © 2017 Japanese Society of Animal Science.

Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery.

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Patching, Simon G

2017-03-01

Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors.

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Blaschek, Wolfgang

2017-08-01

Glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glucose absorption, gluconeogenesis, biosynthesis and mobilization of glycogen, glucose consumption in all tissues and glomerular filtration, and reabsorption of glucose in the kidneys. Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the family of facilitative glucose transporters (GLUTs) or to the family of sodium glucose cotransporters (SGLTs). The intestinal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the kidney SGLT2 and SGLT1 are responsible for reabsorption of filtered glucose from the primary urine, and GLUT2 and GLUT1 enable the transport of glucose from epithelial cells back into the blood stream.The flavonoid phlorizin was isolated from the bark of apple trees and shown to cause glucosuria. Phlorizin is an inhibitor of SGLT1 and SGLT2. With phlorizin as lead compound, specific inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of type 2 diabetes. Inhibition of SGLT2 eliminates excess glucose via the urine. In recent times, the dual SGLT1/SGLT2 inhibitory activity of phlorizin has served as a model for the development and testing of new drugs exhibiting both activities.Besides phlorizin, also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes. Georg Thieme Verlag KG Stuttgart · New York.

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

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Gluud, Lise L.; Bennett, Cathy; Grøndahl, Magnus F.; Christensen, Mikkel B.; Knop, Filip K.; Vilsbøll, Tina

2016-01-01

Objective Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. Design Systematic review and meta-analysis. Data Sources and Study Selection We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. Results Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to ‘low quality’ due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). Conclusion

Metabolic evidence that serosal sodium does not recycle through the active transepithelial transport pathway of toad bladder.

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Canessa, M; Labarca, P; Leaf, A

1976-12-25

The possibility that sodium from the serosal bathing medium "back diffuses" into the active sodium transport pool within the mucosal epithelial cell of the isolated toad bladder was examined by determining the effect on the metabolism of the tissue of removing sodium from the serosal medium. It was expected that if recycling of serosal sodium did occur through the active transepithelial transport pathway of the isolated toad bladder, removal of sodium from the serosal medium would reduce the rate of CO2 production by the tissue and enhance of stoichiometric ratio of sodium ions transported across the bladder per molecula of sodium transport dependent CO2 produced simultaneously by the bladder (JNa/JCO2). The data revealed no significant change in this ratio (17.19 with serosal sodium and 16.13 after replacing serosal sodium with choline). Further, when transepithelial sodium transport was inhibited (a) by adding amiloride to the mucosal medium, or (b) by removing sodium from the mucosal medium, subsequent removal of sodium from the serosal medium, or (c) addition of ouabain failed to depress the basal rate of CO2 production by the bladder [(a)rate of basal, nontransport related, CO2 production (JbCO2) equals 1.54 +/- 0.52 with serosal sodium and 1.54 +/- 0.37 without serosal sodium; (b) Jb CO2 equals 2.18 +/- 0.21 with serosal sodium and 2.09 +/- 0.21 without serosal sodium; (c) 1.14 +/- 0.26 without ouabain and 1.13 +/- 0.25 with ouabain; unite of JbCO2 are nmoles mg d.w.-1 min-1]. The results support the hypothesis that little, if any, recycling of serosal sodium occurs in the total bladder.

Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

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Santos Cavaiola T

2018-04-01

Full Text Available Tricia Santos Cavaiola, Jeremy Pettus Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA Abstract: As the first cardiovascular (CV outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM, the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME® trial, which investigated the sodium glucose cotransporter 2 (SGLT2 inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL, which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. Keywords: canagliflozin, cardiovascular outcomes, dapagliflozin, empagliflozin, mechanisms, sodium glucose cotransporter 2 inhibitors

An Integrated Glucose Sensor with an All-Solid-State Sodium Ion-Selective Electrode for a Minimally Invasive Glucose Monitoring System

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Junko Kojima

2015-06-01

Full Text Available We developed a minimally invasive glucose monitoring system that uses a microneedle to permeate the skin surface and a small hydrogel to accumulate interstitial fluid glucose. The measurement of glucose and sodium ion levels in the hydrogel is required for estimating glucose levels in blood; therefore, we developed a small, enzyme-fixed glucose sensor with a high-selectivity, all-solid-state, sodium ion-selective electrode (ISE integrated into its design. The glucose sensor immobilized glucose oxidase showed a good correlation between the glucose levels in the hydrogels and the reference glucose levels (r > 0.99, and exhibited a good precision (coefficient of variation = 2.9%, 0.6 mg/dL. In the design of the sodium ISEs, we used the insertion material Na0.33MnO2 as the inner contact layer and DD16C5 exhibiting high Na+/K+ selectivity as the ionophore. The developed sodium ISE exhibited high selectivity (\\( \\log \\,k^{pot}_{Na,K} = -2.8\\ and good potential stability. The sodium ISE could measure 0.4 mM (10−3.4 M sodium ion levels in the hydrogels containing 268 mM (10−0.57 M KCl. The small integrated sensor (ϕ < 10 mm detected glucose and sodium ions in hydrogels simultaneously within 1 min, and it exhibited sufficient performance for use as a minimally invasive glucose monitoring system.

A cell-based fluorescent glucose transporter assay for SGLT2 inhibitor discovery

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Yi Huan

2013-04-01

Full Text Available The sodium/glucose cotransporter 2 (SGLT2 is responsible for the majority of glucose reabsorption in the kidney, and currently, SGLT2 inhibitors are considered as promising hypoglycemic agents for the treatment of type 2 diabetes mellitus. By constructing CHO cell lines that stably express the human SGLT2 transmembrane protein, along with a fluorescent glucose transporter assay that uses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-ylamino]2-deoxyglucose (2-NBDG as a glucose analog, we have developed a nonradioactive, cell-based assay for the discovery and characterization of SGLT2 inhibitors.

Intracellular ascorbic acid inhibits transport of glucose by neurons, but not by astrocytes.

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Castro, Maite A; Pozo, Miguel; Cortés, Christian; García, María de Los Angeles; Concha, Ilona I; Nualart, Francisco

2007-08-01

It has been demonstrated that glutamatergic activity induces ascorbic acid (AA) depletion in astrocytes. Additionally, different data indicate that AA may inhibit glucose accumulation in primary cultures of rat hippocampal neurons. Thus, our hypothesis postulates that AA released from the astrocytes during glutamatergic synaptic activity may inhibit glucose uptake by neurons. We observed that cultured neurons express the sodium-vitamin C cotransporter 2 and the facilitative glucose transporters (GLUT) 1 and 3, however, in hippocampal brain slices GLUT3 was the main transporter detected. Functional activity of GLUTs was confirmed by means of kinetic analysis using 2-deoxy-d-glucose. Therefore, we showed that AA, once accumulated inside the cell, inhibits glucose transport in both cortical and hippocampal neurons in culture. Additionally, we showed that astrocytes are not affected by AA. Using hippocampal slices, we observed that upon blockade of monocarboxylate utilization by alpha-cyano-4-hydroxycinnamate and after glucose deprivation, glucose could rescue neuronal response to electrical stimulation only if AA uptake is prevented. Finally, using a transwell system of separated neuronal and astrocytic cultures, we observed that glutamate can reduce glucose transport in neurons only in presence of AA-loaded astrocytes, suggesting the essential role of astrocyte-released AA in this effect.

Elucidation of the glucose transport pathway in glucose transporter 4 via steered molecular dynamics simulations.

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Aswathy Sheena

Full Text Available BACKGROUND: GLUT4 is a predominant insulin regulated glucose transporter expressed in major glucose disposal tissues such as adipocytes and muscles. Under the unstimulated state, GLUT4 resides within intracellular vesicles. Various stimuli such as insulin translocate this protein to the plasma membrane for glucose transport. In the absence of a crystal structure for GLUT4, very little is known about the mechanism of glucose transport by this protein. Earlier we proposed a homology model for GLUT4 and performed a conventional molecular dynamics study revealing the conformational rearrangements during glucose and ATP binding. However, this study could not explain the transport of glucose through the permeation tunnel. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the molecular mechanism of glucose transport and its energetic, a steered molecular dynamics study (SMD was used. Glucose was pulled from the extracellular end of GLUT4 to the cytoplasm along the pathway using constant velocity pulling method. We identified several key residues within the tunnel that interact directly with either the backbone ring or the hydroxyl groups of glucose. A rotation of glucose molecule was seen near the sugar binding site facilitating the sugar recognition process at the QLS binding site. CONCLUSIONS/SIGNIFICANCE: This study proposes a possible glucose transport pathway and aids the identification of several residues that make direct interactions with glucose during glucose transport. Mutational studies are required to further validate the observation made in this study.

Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

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Cavaiola, Tricia Santos; Pettus, Jeremy

2018-01-01

As the first cardiovascular (CV) outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM), the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, which investigated the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. PMID:29695924

Comparative cation dependency of sugar transport by crustacean hepatopancreas and intestine

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Ada Duka

2014-06-01

Full Text Available Glucose is transported in crustacean hepatopancreas and intestine by Na+-dependent co-transport, while Na+-dependent D-fructose influx has only been described for the hepatopancreas. It is still unclear if the two sugars are independently transported by two distinct cation-dependent co-transporter carrier systems. In this study, lobster (Homarus americanus hepatopancreas brush border membrane vesicles (BBMV were used to characterize, in detail, the cation-dependency of both D-[3H]-glucose and D-[3H]-fructose influxes, while in vitro perfused intestines were employed to determine the nature of cation-dependent sugar transport across this organ. Over the sodium concentration range of 0–100 mM, both [3H]-glucose and [3H]-fructose influxes (0.1 mM; 1 min uptakes by hepatopancreatic BBMV were hyperbolic functions of [Na+]. [3H]-glucose and [3H]-fructose influxes by hepatopancreatic BBMV over a potassium concentration range of 15–100 mM were hyperbolic functions of [K+]. Both sugars displayed significant (p<0.01 Na+/K+-dependent and cation-independent uptake processes. Transepithelial 25 µM [3H]-glucose and [3H]-fructose fluxes across lobster intestine over luminal sodium and potassium concentration ranges of 0–50 mM and 5–100 mM, respectively, were hyperbolic functions of luminal [Na+] and [K+]. As with hepatopancreatic sugar transport, transepithelial intestinal sugar transport exhibited both significant (p<0.01 Na+/K+-dependent and cation-independent processes. Results suggest that both D-glucose and D-fructose are transported by a single SGLT-type carrier in each organ with sodium being the “preferred”, high affinity, cation for both sugars in the hepatopancreas, and potassium being the “preferred”, high affinity, cation for both sugars in the intestine.

Inhibition of Glucose Transport by Tomatoside A, a Tomato Seed Steroidal Saponin, through the Suppression of GLUT2 Expression in Caco-2 Cells.

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Li, Baorui; Terazono, Yusuke; Hirasaki, Naoto; Tatemichi, Yuki; Kinoshita, Emiko; Obata, Akio; Matsui, Toshiro

2018-02-14

We investigated whether tomatoside A (5α-furostane-3β,22,26-triol-3-[O-β-d-glucopyranosyl (1→2)-β-d-glucopyranosyl (1→4)-β-d-galactopyranoside] 26-O-β-d-glucopyranoside), a tomato seed saponin, may play a role in the regulation of intestinal glucose transport in human intestinal Caco-2 cells. Tomatoside A could not penetrate through Caco-2 cell monolayers, as observed in the transport experiments using liquid chromatography-mass spectrometry. The treatment of cells with 10 μM tomatoside A for 3 h resulted in a 46.0% reduction in glucose transport as compared to untreated cells. Western blotting analyses revealed that tomatoside A significantly (p transporter 2 (GLUT2) in Caco-2 cells, while no change in the expression of sodium-dependent glucose transporter 1 was observed. In glucose transport experiments, the reduced glucose transport by tomatoside A was ameliorated by a protein kinase C (PKC) inhibitor and a multidrug resistance-associated protein 2 (MRP2) inhibitor. The tomatoside A-induced reduction in glucose transport was restored in cells treated with apical sodium-dependent bile acid transporter (ASBT) siRNA or an ASBT antagonist. These findings demonstrated for the first time that the nontransportable tomato seed steroidal saponin, tomatoside A, suppressed GLUT2 expression via PKC signaling pathway during the ASBT-influx/MRP2-efflux process in Caco-2 cells.

Activation of glycolysis and inhibition of glucose transport into leaves by fluoride

Energy Technology Data Exchange (ETDEWEB)

Lustinec, J; Pokorna, V; Ruzicka, J

1962-01-01

During stimulation of wheat leaf respiration by fluoride at 100 to 200 ppM fluorine in dry tissue the ratio of radioactivities of /sup 14/CO/sub 2/ released from glucose-6-/sup 14/C and that released from glucose-1-/sup 14/C (C/sub 6//C/sub 1/) increases due especially to an increased output of 6-/sup 14/CO/sub 2/ which suggests an activation of glycolysis. The absolute values of radioactivity of /sup 14/CO/sub 2/, however, are decreased by the action of fluoride due to its inhibition of the transport of glucose into leaves. 15 references, 2 figures, 2 tables.

Rates of myocardial infarction and stroke in patients initiated on SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice

DEFF Research Database (Denmark)

Kosiborod, Mikhail; Birkeland, Kåre I; Cavender, Matthew A

2018-01-01

The multinational, observational CVD-REAL study recently showed that initiation of sodium-glucose co-transporter-2 inhibitors (SGLT-2i) was associated with significantly lower rates of death and heart failure vs. other glucose-lowering drugs (oGLDs). This sub-analysis of CVD-REAL sought to determ...

Effect of gamma radiation on glucose and sodium chloride solutions for injection

International Nuclear Information System (INIS)

Lakoza, G.N.; Grigor'eva, O.L.; Mart'yanova, B.M.; Vorob'eva, E.N.; Kuznetsova, R.M.

1976-01-01

Irradiation of 40% glucose solution with 0.5-4.0 Mrads di not affect the detoxicating properties of glucose or its ability to raise blood sugar levels. Such doses had no effect on the toxicological properties of 40% glucose solution and on 0.9% sodium chloride solution. The biological and physicochemical properties of 40% solution and 0.9% sodium chloride solutions irradiated with sterilizing doses showed no significant alterations during storage for one and three years, respectively. It is concluded that the solutions studied may be sterilized by radiation. (auth.)

Effect of beverage glucose and sodium content on fluid delivery

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Cole Johnny

2009-02-01

Full Text Available Abstract Background Rapid fluid delivery from ingested beverages is the goal of oral rehydration solutions (ORS and sports drinks. Objective The aim of the present study was to investigate the effects of increasing carbohydrate and sodium content upon fluid delivery using a deuterium oxide (D2O tracer. Design Twenty healthy male subjects were divided into two groups of 10, the first group was a carbohydrate group (CHO and the second a sodium group (Na. The CHO group ingested four different drinks with a stepped increase of 3% glucose from 0% to 9% while sodium concentration was 20 mmol/L. The Na group ingested four drinks with a stepped increase of 20 mmol/L from 0 mmol/L to 60 mmol/l while glucose concentration was 6%. All beverages contained 3 g of D2O. Subjects remained seated for two hours after ingestion of the experimental beverage, with blood taken every 5 min in the first hour and every 10 min in the second hour. Results Including 3% glucose in the beverage led to a significantly greater AUC 60 min (19640 ± 1252 δ‰ vs. VSMOW.60 min than all trials. No carbohydrate (18381 ± 1198 δ‰ vs. VSMOW.60 min had a greater AUC 60 min than a 6% (16088 ± 1359 δ‰ vs. VSMOW.60 min and 9% beverage (13134 ± 1115 δ‰ vs. VSMOW.60 min; the 6% beverage had a significantly greater AUC 60 min than the 9% beverage. There was no difference in fluid delivery between the different sodium beverages. Conclusion In conclusion the present study showed that when carbohydrate concentration in an ingested beverage was increased above 6% fluid delivery was compromised. However, increasing the amount of sodium (0–60 mmol/L in a 6% glucose beverage did not lead to increases in fluid delivery.

Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle

DEFF Research Database (Denmark)

Ploug, T; Stallknecht, B M; Pedersen, O

1990-01-01

exhaustive single exercise session the day before experiment both maximum insulin- and contraction-stimulated transport rates were increased in all muscle types in trained rats. Accordingly, the increased glucose transport capacity in trained muscle was not due to a residual effect of the last training...... session. Half-times for reversal of contraction-induced glucose transport were similar in trained and untrained muscles. The concentrations of mRNA for GLUT-1 (the erythrocyte-brain-Hep G2 glucose transporter) and GLUT-4 (the adipocyte-muscle glucose transporter) were increased approximately twofold......The effect of 10 wk endurance swim training on 3-O-methylglucose (3-MG) uptake (at 40 mM 3-MG) in skeletal muscle was studied in the perfused rat hindquarter. Training resulted in an increase of approximately 33% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers...

Renal glucose handling in diabetes and sodium glucose cotransporter 2 inhibition

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Resham Raj Poudel

2013-01-01

Full Text Available The kidneys play a major role in glucose homeostasis through its utilization, gluconeogenesis, and reabsorption via sodium glucose cotransporters (SGLTs. The defective renal glucose handling from upregulation of SGLTs, mainly the SGLT2, plays a fundamental role in the pathogenesis of type 2 diabetes mellitus. Genetic mutations in a SGLT2 isoform that results in benign renal glycosuria, as well as clinical studies with SGLT2 inhibitors in type 2 diabetes support the potential of this approach. These studies indicate that inducing glycosuria by suppressing SGLT2 can reduce plasma glucose and A1c levels, as well as decrease weight, resulting in improved β-cell function and enhanced insulin sensitivity in liver and muscle. Because the mechanism of SGLT2 inhibition is independent of insulin secretion and sensitivity, these agents can be combined with other antidiabetic agents, including exogenous insulin. This class represents a novel therapeutic approach with potential for the treatment of both type 2 and type 1 diabetes.

Positioning of sodium-glucose cotransporter-2 inhibitors in national and international guidelines.

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Morillas, Carlos

2016-11-01

Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) selectively and reversibly inhibit sodium-glucose cotransporter-2 (SGLT2), promoting renal glucose excretion and reducing plasma glycaemia. By increasing renal glucose excretion, these drugs favour a negative energy balance, leading to weight loss. Their glucoselowering effect is independent of insulin. Although these drugs have only recently been developed, they have been included in all the main national and international guidelines since 2014. The present review summarises the most important recommendations on the use of SGLT2 in patients with DM2 contained in the most recently published guidelines and consensus statements. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice.

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Suzuki, Masayuki; Honda, Kiyofumi; Fukazawa, Masanori; Ozawa, Kazuharu; Hagita, Hitoshi; Kawai, Takahiro; Takeda, Minako; Yata, Tatsuo; Kawai, Mio; Fukuzawa, Taku; Kobayashi, Takamitsu; Sato, Tsutomu; Kawabe, Yoshiki; Ikeda, Sachiya

2012-06-01

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.

The regulation of glucose transport in the heart of control and diabetic rats: With special emphasis on the glucose transporter

International Nuclear Information System (INIS)

Pleta, M. de Leoz.

1989-01-01

Glucose transport regulation with insulin and high perfusion pressure in the perfused rat hearts from control and diabetic rat hearts was investigated. [ 3 H]-cytochalasin B binding assay was used to study the distribution of glucose transporters within the subcellular membranes fractionated by linear sucrose density gradient centrifugation. In the present study, insulin increased glucose uptake in the perfused heart of control and diabetic animals. This coincided with an increase of glucose transporters on the plasma membrane. The increase in glucose transporters on the plasma membrane could not be accounted for by a decrease of glucose transporters from the microsomal membranes. High perfusion pressure did not change the number of glucose transporters on the plasma membrane compared to basal in the control and diabetic animals, though it increased glucose uptake above that observed for insulin in the control. Instead, high perfusion pressure altered the distribution of glucose transporters within the subcellular membranes in reverse to that with insulin, increasing an intermediate membrane pool believed to reside between the plasma membrane and microsomal membranes as well as the intracellular membrane pool

Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle

International Nuclear Information System (INIS)

Ploug, T.; Stallknecht, B.M.; Pedersen, O.; Kahn, B.B.; Ohkuwa, T.; Vinten, J.; Galbo, H.

1990-01-01

The effect of 10 wk endurance swim training on 3-O-methylglucose (3-MG) uptake (at 40 mM 3-MG) in skeletal muscle was studied in the perfused rat hindquarter. Training resulted in an increase of approximately 33% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers and an increase of approximately 33% for contraction-stimulated transport in slow-twitch red fibers compared with nonexercised sedentary muscle. A fully additive effect of insulin and contractions was observed both in trained and untrained muscle. Compared with transport in control rats subjected to an almost exhaustive single exercise session the day before experiment both maximum insulin- and contraction-stimulated transport rates were increased in all muscle types in trained rats. Accordingly, the increased glucose transport capacity in trained muscle was not due to a residual effect of the last training session. Half-times for reversal of contraction-induced glucose transport were similar in trained and untrained muscles. The concentrations of mRNA for GLUT-1 (the erythrocyte-brain-Hep G2 glucose transporter) and GLUT-4 (the adipocyte-muscle glucose transporter) were increased approximately twofold by training in fast-twitch red muscle fibers. In parallel to this, Western blot demonstrated a approximately 47% increase in GLUT-1 protein and a approximately 31% increase in GLUT-4 protein. This indicates that the increases in maximum velocity for 3-MG transport in trained muscle is due to an increased number of glucose transporters

Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain.

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Jiang, Chunyang; Zhang, Shun; Liu, Hongliang; Guan, Zhizhong; Zeng, Qiang; Zhang, Cheng; Lei, Rongrong; Xia, Tao; Wang, Zhenglun; Yang, Lu; Chen, Yihu; Wu, Xue; Zhang, Xiaofei; Cui, Yushan; Yu, Linyu; Wang, Aiguo

2014-03-01

Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.

Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures.

Science.gov (United States)

Gao, Chen; Zhou, Liya; Zhu, Wenxia; Wang, Hongyun; Wang, Ruijuan; He, Yunfei; Li, Zhiyun

2015-05-06

Hypoxic and low-glucose stressors contribute to neuronal death in many brain diseases. Astrocytes are anatomically well-positioned to shield neurons from hypoxic injury. During hypoxia/ischemia, lactate released from astrocytes is taken up by neurons and stored for energy. This process is mediated by monocarboxylate transporters (MCTs) in the central nervous system. In the present study, we investigated the ability of astrocytes to protect neurons from oxygen- and glucose-deprivation (OGD) injury via an MCT-dependent mechanism in vitro. Primary cultures of neurons, astrocytes, and astrocytes-neurons derived from rat hippocampus were subjected to OGD, MCT inhibition with small interfering (si)RNA. Cell survival and expression of MCT4, MCT2, glial fibrillary acidic protein, and neuronal nuclear antigen were evaluated. OGD significantly increased cell death in neuronal cultures and up-regulated MCT4 expression in astrocyte cultures, but no increased cell death was observed in neuron-astrocyte co-cultures or astrocyte cultures. However, neuronal cell death in co-cultures was increased by exposure to MCT4- or MCT2-specific siRNA, and this effect was attenuated by the addition of lactate into the extracellular medium of neuronal cultures prior to OGD. These findings demonstrate that resistance to OGD injury in astrocyte-neuron co-cultures occurs via an MCT-dependent mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Relevance of sodium/glucose cotransporter-1 (SGLT1) to diabetes mellitus and obesity in dogs.

Science.gov (United States)

Batchelor, D J; German, A J; Shirazi-Beechey, S P

2013-04-01

Glucose transport across the enterocyte brush border membrane by sodium/glucose cotransporter-1 (SGLT1, coded by Slc5a1) is the rate-limiting step for intestinal glucose transport. The relevance of SGLT1 expression in predisposition to diabetes mellitus and to obesity was investigated in dogs. Cultured Caco-2/TC7 cells were shown to express SGLT1 in vitro. A 2-kbp fragment of the Slc5a1 5' flanking region was cloned from canine genomic DNA, ligated into reporter gene plasmids, and shown to drive reporter gene expression in these cells above control (P obesity (Labrador retriever and cocker spaniel). The Slc5a1 5' flanking region was amplified from 10 healthy individuals of each of these breeds by high-fidelity PCR with the use of breed-labeled primers and sequenced by pyrosequencing. The sequence of the Slc5a1 5' flanking region in all individuals of all breeds tested was identical. On this evidence, variations in Slc5a1 promoter sequence between dogs do not influence the pathogenesis of diabetes mellitus or obesity in these breeds. Copyright © 2013 Elsevier Inc. All rights reserved.

Expression of Na+/glucose co-transporter 1 (SGLT1) is enhanced by supplementation of the diet of weaning piglets with artificial sweeteners.

Science.gov (United States)

Moran, Andrew W; Al-Rammahi, Miran A; Arora, Daleep K; Batchelor, Daniel J; Coulter, Erin A; Daly, Kristian; Ionescu, Catherine; Bravo, David; Shirazi-Beechey, Soraya P

2010-09-01

In an intensive livestock production, a shorter suckling period allows more piglets to be born. However, this practice leads to a number of disorders including nutrient malabsorption, resulting in diarrhoea, malnutrition and dehydration. A number of strategies have been proposed to overcome weaning problems. Artificial sweeteners, routinely included in piglets' diet, were thought to enhance feed palatability. However, it is shown in rodent models that when included in the diet, they enhance the expression of Na+/glucose co-transporter (SGLT1) and the capacity of the gut to absorb glucose. Here, we show that supplementation of piglets' feed with a combination of artificial sweeteners saccharin and neohesperidin dihydrochalcone enhances the expression of SGLT1 and intestinal glucose transport function. Artificial sweeteners are known to act on the intestinal sweet taste receptor T1R2/T1R3 and its partner G-protein, gustducin, to activate pathways leading to SGLT1 up-regulation. Here, we demonstrate that T1R2, T1R3 and gustducin are expressed together in the enteroendocrine cells of piglet intestine. Furthermore, gut hormones secreted by the endocrine cells in response to dietary carbohydrates, glucagon-like peptides (GLP)-1, GLP-2 and glucose-dependent insulinotrophic peptide (GIP), are co-expressed with type 1 G-protein-coupled receptors (T1R) and gustducin, indicating that L- and K-enteroendocrine cells express these taste elements. In a fewer endocrine cells, T1R are also co-expressed with serotonin. Lactisole, an inhibitor of human T1R3, had no inhibitory effect on sweetener-induced SGLT1 up-regulation in piglet intestine. A better understanding of the mechanism(s) involved in sweetener up-regulation of SGLT1 will allow the identification of nutritional targets with implications for the prevention of weaning-related malabsorption.

Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

DEFF Research Database (Denmark)

Richter, Erik; Hansen, B F; Hansen, S A

1988-01-01

in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

Detection Test for Leakage of CO2 into Sodium Loop

International Nuclear Information System (INIS)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong

2015-01-01

This report is about the facility for the detection test for leakage of CO 2 into sodium loop. The facility for the detection test for leakage of CO 2 into sodium loop was introduced. The test will be carried out. Our experimental results are going to be expected to be used for approach methods to detect CO 2 leaking into sodium in heat exchangers. A sodium-and-carbon dioxide (Na-CO 2 ) heat exchanger is one of the key components for the supercritical CO 2 Brayton cycle power conversion system of sodium-cooled fast reactors (SFRs). A printed circuit heat exchanger (PCHE) is considered for the Na-CO 2 heat exchanger, which is known to have potential for reducing the volume occupied by the exchangers compared to traditional shell-and-tube heat exchangers. Among various issues about the Na- CO 2 exchanger, detection of CO 2 leaking into sodium in the heat exchanger is most important thing for its safe operation. It is known that reaction products from sodium and CO 2 such as sodium carbonate (Na 2 CO 3 ) and amorphous carbon are hardly soluble in sodium, which cause plug sodium channels. Detection technique for Na 2 CO 3 in sodium loop has not been developed yet. Therefore, detection of CO 2 and CO from reaction of sodium and CO 2 are proper to detect CO 2 leakage into sodium loop

Effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis

Directory of Open Access Journals (Sweden)

Lubin Xu

2017-06-01

Full Text Available Aim To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes. Methods We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR and/or urine albumin/creatinine ratio (ACR changes. Data were synthesized using the random-effects model. Results Forty-seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD, −0.33 ml/min per 1.73 m2, 95% CI [−0.90 to 0.23] or in patients with chronic kidney disease (CKD (WMD −0.78 ml/min per 1.73 m2, 95% CI [−2.52 to 0.97]. SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD −0.98 ml/min per 1.73 m2, 95% CI [−1.42 to −0.54], and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]. Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD −7.24 mg/g, 95% CI [−15.54 to 1.06], but was significant in patients with CKD (WMD −107.35 mg/g, 95% CI [−192.53 to −22.18]. Conclusions SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD.

Sodium-carbonate co-substituted hydroxyapatite ceramics

Directory of Open Access Journals (Sweden)

Zoltan Z. Zyman

2013-12-01

Full Text Available Powders of sodium-carbonate co-substituted hydroxyapatite, having sodium content in the range of 0.25–1.5 wt.% with a 0.25 wt.% step, were prepared by a precipitation-solid state reaction route. Compacts of the powders were sintered in a CO2 flow (4 mL/min at 1100 °C for 2 h. The sintered ceramics contained sodium and carbonate ions in the ranges of 0–1.5 wt.% and 1.3–6 wt.%, respectively, which are typical impurity concentrations in biological apatite. A relationship between sodium and carbonate contents and the type of carbonate substitution was found. The total carbonate content progressively increased with the sodium content. The obtained ceramics showed an AB-type carbonate substitution. However, the substitution became more B-type as the sodium content increased. As a result, the carbonation was almost B-type (94 % for the highest sodium content (1.5 wt.%.

Transperitoneal transport of sodium during hypertonic peritoneal dialysis

DEFF Research Database (Denmark)

Graff, J; Fugleberg, S; Brahm, J

1996-01-01

The mechanisms of transperitoneal sodium transport during hypertonic peritoneal dialysis were evaluated by kinetic modelling. A total of six nested mathematical models were designed to elucidate the presence or absence of diffusive, non-lymphatic convective and lymphatic convective solute transport....... Experimental results were obtained from 26 non-diabetic patients undergoing peritoneal dialysis. The model validation procedure demonstrated that only diffusive and non-lymphatic convective transport mechanisms were identifiable in the transperitoneal transport of sodium. Non-lymphatic convective sodium...

Gibbs Free-Energy Gradient along the Path of Glucose Transport through Human Glucose Transporter 3.

Science.gov (United States)

Liang, Huiyun; Bourdon, Allen K; Chen, Liao Y; Phelix, Clyde F; Perry, George

2018-06-11

Fourteen glucose transporters (GLUTs) play essential roles in human physiology by facilitating glucose diffusion across the cell membrane. Due to its central role in the energy metabolism of the central nervous system, GLUT3 has been thoroughly investigated. However, the Gibbs free-energy gradient (what drives the facilitated diffusion of glucose) has not been mapped out along the transport path. Some fundamental questions remain. Here we present a molecular dynamics study of GLUT3 embedded in a lipid bilayer to quantify the free-energy profile along the entire transport path of attracting a β-d-glucose from the interstitium to the inside of GLUT3 and, from there, releasing it to the cytoplasm by Arrhenius thermal activation. From the free-energy profile, we elucidate the unique Michaelis-Menten characteristics of GLUT3, low K M and high V MAX , specifically suitable for neurons' high and constant demand of energy from their low-glucose environments. We compute GLUT3's binding free energy for β-d-glucose to be -4.6 kcal/mol in agreement with the experimental value of -4.4 kcal/mol ( K M = 1.4 mM). We also compute the hydration energy of β-d-glucose, -18.0 kcal/mol vs the experimental data, -17.8 kcal/mol. In this, we establish a dynamics-based connection from GLUT3's crystal structure to its cellular thermodynamics with quantitative accuracy. We predict equal Arrhenius barriers for glucose uptake and efflux through GLUT3 to be tested in future experiments.

Detection Test for Leakage of CO{sub 2} into Sodium Loop

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-10-15

This report is about the facility for the detection test for leakage of CO{sub 2} into sodium loop. The facility for the detection test for leakage of CO{sub 2} into sodium loop was introduced. The test will be carried out. Our experimental results are going to be expected to be used for approach methods to detect CO{sub 2} leaking into sodium in heat exchangers. A sodium-and-carbon dioxide (Na-CO{sub 2}) heat exchanger is one of the key components for the supercritical CO{sub 2} Brayton cycle power conversion system of sodium-cooled fast reactors (SFRs). A printed circuit heat exchanger (PCHE) is considered for the Na-CO{sub 2} heat exchanger, which is known to have potential for reducing the volume occupied by the exchangers compared to traditional shell-and-tube heat exchangers. Among various issues about the Na- CO{sub 2} exchanger, detection of CO{sub 2} leaking into sodium in the heat exchanger is most important thing for its safe operation. It is known that reaction products from sodium and CO{sub 2} such as sodium carbonate (Na{sub 2}CO{sub 3}) and amorphous carbon are hardly soluble in sodium, which cause plug sodium channels. Detection technique for Na{sub 2}CO{sub 3} in sodium loop has not been developed yet. Therefore, detection of CO{sub 2} and CO from reaction of sodium and CO{sub 2} are proper to detect CO{sub 2} leakage into sodium loop.

Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

Science.gov (United States)

Heald, Adrian H; Fryer, Anthony A; Anderson, Simon G; Livingston, Mark; Lunt, Mark; Davies, Mark; Moreno, Gabriela Y C; Gadsby, Roger; Young, Robert J; Stedman, Mike

2018-03-08

To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found

Preliminary conceptual design of the secondary sodium circuit-eliminated JSFR (Japan Sodium Fast Reactor) adopting a supercritical CO2 turbine system (1). Sodium/CO2 heat exchanger

International Nuclear Information System (INIS)

Kisohara, Naoyuki; Sakamoto, Yoshihiko; Kotake, Shoji

2014-09-01

Research and development of the supercritical CO 2 (S-CO 2 ) cycle turbine system is underway in various countries for further improvement of the safety and economy of sodium-cooled fast reactors. The Component Design and Balance-Of-Plant (CD and BOP) of the Generation IV International Nuclear Forum (Gen-IV) has addressed this study, and their analytical and experimental results have been discussed between the relevant countries. JAEA, who is a member of the CD and BOP, has performed a design study of an S-CO 2 gas turbine system applied to the Japan Sodium-cooled Fast Reactor (JSFR). In this study, the S-CO 2 cycle turbine system was directly connected to the primary sodium system of the JSFR to eliminate the secondary sodium circuit, aiming for further economical improvement. This is because there is no risk of sodium-water reaction in the S-CO 2 cycle turbine system of SFRs. The Na/CO 2 heat exchanger is one of the key components for the secondary sodium system eliminated SFR, and this report describes its structure and the safety in case of CO 2 leak. A Printed Circuit Heat Exchanger (PCHE), which has a greater heat transfer performance, is employed to the heat exchanger. Another advantage of the PCHE is to limit the area affected by a leak of CO 2 because of its partitioned flow path structure. A SiC/SiC ceramic composite material is used for the PCHE to prevent crack growth and to reduce thermal stress. The Na/CO 2 heat exchanger has been designed in such a way that a number of small heat transfer modules are combined in the vessel in consideration of manufacture and repair. The primary sodium pump is installed in the center of the heat exchanger vessel. CO 2 leak events in the heat exchanger have been also evaluated, and it revealed that no significant effect has arisen on the core or the primary sodium boundary. (author)

Graphene wrapped porous Co_3O_4/NiCo_2O_4 double-shelled nanocages with enhanced electrocatalytic performance for glucose sensor

International Nuclear Information System (INIS)

Xue, Bei; Li, Kezhi; Feng, Lei; Lu, Jinhua; Zhang, Leilei

2017-01-01

Highlights: • Graphene wrapped Co_3O_4/NiCo_2O_4 DSNCs has been prepared for detection of glucose. • Sensing performance was improved by synergy between electrocatalytic activity and efficient electron transport. • The sensor has excellent sensing performance with high sensitivity and low detection limit. • The developed method was successfully applied to detect glucose in human serum. - Abstract: Graphene (G) wrapped porous Co_3O_4/NiCo_2O_4 double-shelled nanocages (Co_3O_4/NiCo_2O_4 DSNCs@G) were prepared by the formation of Co_3O_4/NiCo_2O_4 DSNCs using zeolite imidazole frameworks-67 as template with the subsequent calcination and package of G by hydrothermal method. The abundant accessible active sites provided by the porous structure of Co_3O_4/NiCo_2O_4 DSNCs and efficient electron transport pathways for electrocatalytic reaction offered by the high conductive G worked very well together in a ferocious synergy, which endowed Co_3O_4/NiCo_2O_4 DSNCs@G with excellent electrocatalytic behaviors for determining glucose. A comparison between Co_3O_4/NiCo_2O_4 DSNCs without G packing and Co_3O_4/NiCo_2O_4 DSNCs@G showed that former had linear response window concentrations of 0.01-3.52 mM (correlation coefficient = 0.999), detection limit of 0.744 μM (S/N = 3) and sensitivity of 0.196 mA mM"−"1 cm"−"2, whereas the latter exhibited linear response window concentrations of 0.01-3.52 mM (correlation coefficient = 0.999), detection limit of 0.384 μM (S/N = 3) and sensitivity of 0.304 mA mM"−"1 cm"−"2. The combination of Co_3O_4/NiCo_2O_4 DSNCs and G was a meaningful strategy to fabricate high-performance non-enzyme glucose sensors with low detection limit, good selectivity and high sensitivity.

Screening for Inhibitors of Essential Leishmania Glucose Transporters

Science.gov (United States)

2013-07-01

Leishmania Glucose Transporters PRINCIPAL INVESTIGATOR: Scott M. Landfear, Ph.D. CONTRACTING ORGANIZATION: Oregon Health & Science...COVERED 1 July 2009- 30 June 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Screening for Inhibitors of Essential Leishmania Glucose Transporters 5b...The objective of this project was to identify compounds that selectively inhibit the essential Leishmania glucose transporters and could hence serve

Adipocyte glucose transport regulation by eicosanoid precursors and inhibitors

International Nuclear Information System (INIS)

Lee, H.C.C.

1987-01-01

Glucose uptake and free fatty acid release by adipocytes are increased by catecholamines. The mechanism of the stimulatory action of catecholamines on glucose uptake may be via eicosanoid production from release fatty acids. Rats were fed iso-nutrient diets with high or low safflower oil. After one month, 5 rats per diet group were fed diets with aspirin or without aspirin for 2 days. Isolated adipocytes from epididymal fat pads were incubated at 37 0 C, gassed with 95% O 2 -5% CO 2 in KRB buffer with 3% bovine serum albumin and with or without eicosanoid modifiers; a stimulator (10 -5 M norepinephrine, N), or inhibitors (167 μl of antiserum to prostaglandin E (AntiE) per 1600 μl or 23mM Asp), or combinations of these. At 2-, 5-, and 10-min incubation, samples of incubation mixtures were taken to measure 2-deoxy glucose transport using 3 H-2-deoxy glucose, 14 C-inulin, and liquid scintillation counter

[Contribution of the kidney to glucose homeostasis].

Science.gov (United States)

Segura, Julián; Ruilope, Luis Miguel

2013-09-01

The kidney is involved in glucose homeostasis through three major mechanisms: renal gluconeogenesis, renal glucose consumption, and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most important physiological functions of the kidney, allowing full recovery of filtered glucose, elimination of glucose from the urine, and prevention of calorie loss. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where glucose transporter-2 (GLUT2) and sodium-glucose transporter-2 (SGLT2) are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters. In patients with hyperglycemia, the kidney continues to reabsorb glucose, thus maintaining hyperglycemia. Most of the renal glucose reabsorption is mediated by SGLT2. Several experimental and clinical studies suggest that pharmacological blockade of this transporter might be beneficial in the management of hyperglycemia in patients with type 2 diabetes. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment

DEFF Research Database (Denmark)

Jensen, Janni M; Mose, Frank H; Kulik, Anna-Ewa O

2015-01-01

AIM: To quantify changes in urinary excretion of aquaporin2 water channels (u-AQP2), the sodium-potassium-chloride co-transporter (u-NKCC2) and the epithelial sodium channels (u-ENaC) during treatment with bendroflumethiazide (BFTZ), amiloride and placebo. METHODS: In a randomized, double....... General linear model with repeated measures or related samples Friedman's two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group. RESULTS: At baseline there were no differences in u...... by the constant infusion clearance technique with (51)Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC (u-ENaCγ), and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U...

Activity-Dependent Regulation of Surface Glucose Transporter-3

OpenAIRE

Ferreira, Jainne M.; Burnett, Arthur L.; Rameau, Gerald A.

2011-01-01

Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation o...

Effect of feeding soybean meal and differently processed peas on intestinal morphology and functional glucose transport in the small intestine of broilers.

Science.gov (United States)

Röhe, I; Boroojeni, F Goodarzi; Zentek, J

2017-09-01

Peas are locally grown legumes being rich in protein and starch. However, the broad usage of peas as a feed component in poultry nutrition is limited to anti-nutritional factors, which might impair gut morphology and function. This study investigated the effect of feeding raw or differently processed peas compared with feeding a soybean meal-based control diet (C) on intestinal morphology and nutrient transport in broilers. A total of 360 day-old broiler chicks were fed with one of the following diets: The C diet, and 3 diets containing raw peas (RP), fermented peas (FP) and enzymatically pre-digested peas (EP), each supplying 30% of dietary crude protein. After 35 d, jejunal samples of broilers were taken for analyzing histomorphological parameters, active glucose transport in Ussing chambers and the expression of genes related to glucose absorption, intestinal permeability and cell maturation. Villus length (P = 0.017) and crypt depth (P = 0.009) of EP-fed broilers were shorter compared to birds received C. The villus surface area was larger in broilers fed C compared to those fed with the pea-containing feed (P = 0.005). Glucose transport was higher for broilers fed C in comparison to birds fed with the EP diet (P = 0.044). The sodium-dependent glucose co-transporter 1 (SGLT-1) expression was down-regulated in RP (P = 0.028) and FP (P = 0.015) fed broilers. Correlation analyses show that jejunal villus length negatively correlates with the previously published number of jejunal intraepithelial T cells (P = 0.014) and that jejunal glucose transport was negatively correlated with the occurrence of jejunal intraepithelial leukocytes (P = 0.041). To conclude, the feeding of raw and processed pea containing diets compared to a soybean based diet reduced the jejunal mucosal surface area of broilers, which on average was accompanied by lower glucose transport capacities. These morphological and functional alterations were associated with observed mucosal immune

Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.

Science.gov (United States)

Tang, H L; Li, D D; Zhang, J J; Hsu, Y H; Wang, T S; Zhai, S D; Song, Y Q

2016-12-01

To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors. Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted. © 2016 John Wiley & Sons Ltd.

Approaching to DM2 through sodium-glucose cotransporter-2: does it make sense?

Science.gov (United States)

Segura, Julián

2016-11-01

The kidney is involved in glucose homeostasis through three main mechanisms: renal gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most relevant physiological functions of the kidney, through which filtered glucose is fully recovered, urine is free of glucose, and calorie loss is prevented. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where GLUT2 and SGLT2 transporters are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters. In patients with hyperglycaemia, the kidney continues reabsorbing glucose, and hyperglycaemia is maintained. Most renal glucose reabsorption is mediated by the SGLT2 transporter. Several experimental and clinical studies suggest that pharmacological blockade of this transporter might be beneficial in the management of hyperglycemia in patients with type 2 diabetes. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Prenatal Exposure to Sodium Arsenite Alters Placental Glucose 1, 3, and 4 Transporters in Balb/c Mice

Directory of Open Access Journals (Sweden)

Daniela Sarahí Gutiérrez-Torres

2015-01-01

Full Text Available Inorganic arsenic (iAs exposure induces a decrease in glucose type 4 transporter (GLUT4 expression on the adipocyte membrane, which may be related to premature births and low birth weight infants in women exposed to iAs at reproductive age. The aim of this study was to analyze the effect of sodium arsenite (NaAsO2 exposure on GLUT1, GLUT3, and GLUT4 protein expression and on placental morphology. Female Balb/c mice (n=15 were exposed to 0, 12, and 20 ppm of NaAsO2 in drinking water from 8th to 18th day of gestation. Morphological changes and GLUT1, GLUT3, and GLUT4 expression were evaluated in placentas by immunohistochemical and image analysis and correlated with iAs and arsenical species concentration, which were quantified by atomic absorption spectroscopy. NaAsO2 exposure induced a significant decrease in fetal and placental weight (P<0.01 and increases in infarctions and vascular congestion. Whereas GLUT1 expression was unchanged in placentas from exposed group, GLUT3 expression was found increased. In contrast, GLUT4 expression was significantly lower (P<0.05 in placentas from females exposed to 12 ppm. The decrease in placental GLUT4 expression might affect the provision of adequate fetal nutrition and explain the low fetal weight observed in the exposed groups.

Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

Science.gov (United States)

Tang, Huilin; Cui, Wei; Li, Dandan; Wang, Tiansheng; Zhang, Jingjing; Zhai, Suodi; Song, Yiqing

2017-01-01

Given inconsistent trial results of sodium-glucose cotransporter 2 (SGLT2) inhibitors in addition to insulin therapy for treating type 2 diabetes mellitus (T2DM), a meta-analysis was performed to evaluate the efficacy and safety of this combination for T2DM by searching available randomized trials from PubMed, Embase, CENTRAL and ClinicalTrials.gov. Our meta-analysis included seven eligible placebo-controlled trials involving 4235 patients. Compared with placebo, SGLT2 inhibitor treatment was significantly associated with a mean reduction in HbA1c of -0.56%, fasting plasma glucose of -0.95 mmol/L, body weight of -2.63 kg and insulin dose of -8.79 IU, but an increased risk of drug-related adverse events by 36%, urinary tract infections by 29% and genital infections by 357%. No significant increase was observed in risk of overall adverse events [risk ratio (RR), 1.00], serious adverse events (RR, 0.90), adverse events leading to discontinuation (RR, 1.16), hypoglycaemia events (RR, 1.07) and severe hypoglycaemia events (RR, 1.24). No diabetic ketoacidosis events were reported. Further studies are needed to establish optimal combination type and dose. © 2016 John Wiley & Sons Ltd.

Glucose transport and milk secretion during manipulated plasma insulin and glucose concentrations and during LPS-induced mastitis in dairy cows.

Science.gov (United States)

Gross, J J; van Dorland, H A; Wellnitz, O; Bruckmaier, R M

2015-08-01

In dairy cows, glucose is essential as energy source and substrate for milk constituents. The objective of this study was to investigate effects of long-term manipulated glucose and insulin concentrations in combination with a LPS-induced mastitis on mRNA abundance of glucose transporters and factors involved in milk composition. Focusing on direct effects of insulin and glucose without influence of periparturient endocrine adaptations, 18 dairy cows (28 ± 6 weeks of lactation) were randomly assigned to one of three infusion treatments for 56 h (six animals each). Treatments included a hyperinsulinemic hypoglycaemic clamp (HypoG), a hyperinsulinemic euglycaemic clamp (EuG) and a control group (NaCl). After 48 h of infusions, an intramammary challenge with LPS from E. coli was performed and infusions continued for additional 8 h. Mammary gland biopsies were taken before, at 48 (before LPS challenge) and at 56 h (after LPS challenge) of infusion, and mRNA abundance of genes involved in mammary gland metabolism was measured by RT-qPCR. During the 48 h of infusions, mRNA abundance of glucose transporters GLUT1, 3, 4, 8, 12, SGLT1, 2) was not affected in HypoG, while they were downregulated in EuG. The mRNA abundance of alpha-lactalbumin, insulin-induced gene 1, κ-casein and acetyl-CoA carboxylase was downregulated in HypoG, but not affected in EuG. Contrary during the intramammary LPS challenge, most of the glucose transporters were downregulated in NaCl and HypoG, but not in EuG. The mRNA abundance of glucose transporters in the mammary gland seems not to be affected by a shortage of glucose, while enzymes and milk constituents directly depending on glucose as a substrate are immediately downregulated. During LPS-induced mastitis in combination with hypoglycaemia, mammary gland metabolism was more aligned to save glucose for the immune system compared to a situation without limited glucose availability during EuG. Journal of Animal Physiology and Animal

Glucose transporters are expressed in taste receptor cells.

Science.gov (United States)

Merigo, Flavia; Benati, Donatella; Cristofoletti, Mirko; Osculati, Francesco; Sbarbati, Andrea

2011-08-01

In the intestine, changes of sugar concentration generated in the lumen during digestion induce adaptive responses of glucose transporters in the epithelium. A close matching between the intestinal expression of glucose transporters and the composition and amount of the diet has been provided by several experiments. Functional evidence has demonstrated that the regulation of glucose transporters into enterocytes is induced by the sensing of sugar of the enteroendocrine cells through activation of sweet taste receptors (T1R2 and T1R3) and their associated elements of G-protein-linked signaling pathways (e.g. α-gustducin, phospholipase C β type 2 and transient receptor potential channel M5), which are signaling molecules also involved in the perception of sweet substances in the taste receptor cells (TRCs) of the tongue. Considering this phenotypical similarity between the intestinal cells and TRCs, we evaluated whether the TRCs themselves possess proteins of the glucose transport mechanism. Therefore, we investigated the expression of the typical intestinal glucose transporters (i.e. GLUT2, GLUT5 and SGLT1) in rat circumvallate papillae, using immunohistochemistry, double-labeling immunofluorescence, immunoelectron microscopy and reverse transcriptase-polymerase chain reaction analysis. The results showed that GLUT2, GLUT5 and SGLT1 are expressed in TRCs; their immunoreactivity was also observed in cells that displayed staining for α-gustducin and T1R3 receptor. The immunoelectron microscopic results confirmed that GLUT2, GLUT5 and SGLT1 were predominantly expressed in cells with ultrastructural characteristics of chemoreceptor cells. The presence of glucose transporters in TRCs adds a further link between chemosensory information and cellular responses to sweet stimuli that may have important roles in glucose homeostasis, contributing to a better understanding of the pathways implicated in glucose metabolism. © 2011 The Authors. Journal of Anatomy © 2011

Opium can differently alter blood glucose, sodium and potassium in male and female rats.

Science.gov (United States)

Karam, Gholamreza Asadi; Rashidinejad, Hamid Reza; Aghaee, Mohammad Mehdi; Ahmadi, Jafar; Rahmani, Mohammad Reza; Mahmoodi, Mehdi; Azin, Hosein; Mirzaee, Mohammad Reza; Khaksari, Mohammad

2008-04-01

To determine the effects of opium on serum glucose, potassium and sodium in male and female Wistar rat, opium solution (60 mg/kg) injected intraperitoneally and the same volume of distilled water was used as control (7 rats in each group). Blood samples were collected at 0, 30, 60, 120, 240 and 360 minutes after injection from orbit cavity and the values of serum glucose, sodium (Na(+)) and potassium (K(+)) were measured. The data were then analyzed by the repeated measure ANOVA based on sex and case-control group. P opium solution injection, in female rats compared to a control group. However, the male rats had this rise at 30, 60 and 120 minutes after opium solution injection compared to control group. While serum glucose in male rats was significantly higher than females at 30, 60 and 120 minutes, this value was higher in the female rats at 360 minutes. Therefore, serum glucose alterations following opium injection was significantly different in groups and in the sexes at different times. Sodium (Na(+)) rose at 60, 240 and 360 minutes significantly in all rats compared to control group. However, sodium alteration following opium injection was significantly different only between treated and control groups but sex-independent at all times. Potassium (K(+)) increased significantly at 60, 120, 240 and 360 minutes in male rats, compared to a control group. In female rats K(+) significantly raised at 30, 120, 240 and 360 minutes. Therefore, the alteration of K(+) in male and female rats was found time dependent and sex independent. According to our results, opium increased serum glucose in male and female rats differently, and it interferes with metabolic pathways differently on a gender dependent basis. Opium raised serum Na(+) and K(+), thus it interfere with water regulation and blood pressure via different mechanism.

Modeling of under-expanded reactive CO2-into-sodium jets, in the frame of sodium fast reactors

International Nuclear Information System (INIS)

Vivaldi, D.

2013-01-01

This PhD work was motivated by the investigations in the frame of supercritical CO 2 Brayton cycles as possible energy conversion cycles for the Sodium-cooled Fast nuclear Reactors (SFRs). This technology represents an alternative to conventional steam Rankine cycles, with the main advantage represented by the elimination of the accidental sodium-water reaction scenario. Nevertheless, CO 2 chemically reacts with sodium, through an exothermic reaction leading to solid reaction products, mainly sodium carbonate. Following an accidental leakage inside the sodium-CO 2 heat exchanger of a SFR, the CO 2 , having an operating pressure of about 200 bars, would be injected into the low-operating pressure liquid sodium, creating an under-expanded reactive CO 2 -into-sodium jet. The under-expanded jet features a sonic gas injection velocity and an under-expansion in the first region downstream the leakage, where the CO 2 is accelerated to supersonic velocities. The exothermic reaction between the CO 2 and the sodium causes an increasing of the temperature inside the heat exchanger. An experimental facility was built at CEA Cadarache, for the realization of CO 2 -into-sodium jets: this facility has provided preliminary results in terms of temperature variations inside the jet due to the exothermic reaction. However, this type of experimental tests are complicated to realize and to analyse, due to the technical difficulties of realizing the contact between CO 2 and sodium, and to the incertitude of temperature measurement inside a two-phase high velocity jet. It follows that a numerical model of this kind of jets is required, in order to understand the CO 2 -sodium kinetics of reaction inside the jet and being able to transpose the phenomenon to relevant SFR sodium-CO 2 heat exchangers. This would allow to understand the consequences of a leakage inside a sodium-CO 2 heat exchanger, in terms of, for instance, temperature profiles inside the heat exchanger and on tube surfaces

Endocrine control of active sodium transport across frog skin

International Nuclear Information System (INIS)

Maetz, J.

1959-01-01

I. Action of the neurohypophyseal peptides on sodium transport. 1) On Rana Esculenta, oxytocin alone is active on the sodium transport (not vaso pressin). 2) The post hypophysis of R.e. contains an hormonal factor even more specific on Na transport (12 times more active than oxytocin). 3) This new factor must be closely related to oxytocin. II. Action of the adrenal corticoids. 1) The skin of frogs adapted to a salt-rich external medium, shows a considerable diminution in sodium uptake. 2) This decreased sodium uptake is brought back to normal by the injections of aldosterone. 3) This suggests that salt loading of amphibians (as well as mammals) inhibits the mineralocorticoid activity of the adrenals. (author) [fr

Glucose transporter 1 localisation throughout pregnancy in the carnivore placenta

DEFF Research Database (Denmark)

Wooding, F.B.P.; Dantzer, Vibeke; Klisch, K.

2007-01-01

Glucose is one of the major fetal nutrients. Maternofetal transfer requires transport across the several placental membranes. This transfer is mediated by one or more of the fourteen known isoforms of glucose transporter. So far only Glucose Transporters 1 and 3 (GT1, GT3) have been shown to be l...

Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1.

Science.gov (United States)

Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian; Richter, Erik A; Jensen, Thomas E

2015-02-01

Rac1 regulates stretch-stimulated (i.e. mechanical stress) glucose transport in muscle. Actin depolymerization decreases stretch-induced glucose transport in skeletal muscle. Rac1 is a required part of the mechanical stress-component of the contraction-stimulus to glucose transport in skeletal muscle. An alternative to the canonical insulin signalling pathway for glucose transport is muscle contraction/exercise. Mechanical stress is an integrated part of the muscle contraction/relaxation cycle, and passive stretch stimulates muscle glucose transport. However, the signalling mechanism regulating stretch-stimulated glucose transport is not well understood. We recently reported that the actin cytoskeleton regulating GTPase, Rac1, was activated in mouse muscle in response to stretching. Rac1 is a regulator of contraction- and insulin-stimulated glucose transport, however, its role in stretch-stimulated glucose transport and signalling is unknown. We therefore investigated whether stretch-induced glucose transport in skeletal muscle required Rac1 and the actin cytoskeleton. We used muscle-specific inducible Rac1 knockout mice as well as pharmacological inhibitors of Rac1 and the actin cytoskeleton in isolated soleus and extensor digitorum longus muscles. In addition, the role of Rac1 in contraction-stimulated glucose transport during conditions without mechanical load on the muscles was evaluated in loosely hanging muscles and muscles in which cross-bridge formation was blocked by the myosin ATPase inhibitors BTS and Blebbistatin. Knockout as well as pharmacological inhibition of Rac1 reduced stretch-stimulated glucose transport by 30-50% in soleus and extensor digitorum longus muscle. The actin depolymerizing agent latrunculin B similarly decreased glucose transport in response to stretching by 40-50%. Rac1 inhibition reduced contraction-stimulated glucose transport by 30-40% in tension developing muscle but did not affect contraction-stimulated glucose transport in

Distribution of glucose transporters in renal diseases

OpenAIRE

Szablewski, Leszek

2017-01-01

Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three famil...

Relationship between plasma growth hormone concentration and cellular sodium transport in acromegaly

Energy Technology Data Exchange (ETDEWEB)

Herlitz, H.; Jonsson, O.; Bengtsson, B.-Aa. (Departments of Nephrology, Urology and Endocrinology, University of Goeteborg, Goeteborg (Sweden))

1992-01-01

We investigated the relationship between mean plasma growth hormone (GH) concentration and cellular sodium transport in untreated and treated acromegaly. Seventeen patients (age 55 [+-] 3 years) with active acromegaly were studied with respect to plasma GH (mean of 24 h GH profile) and erythrocyte electrolyte content as well as transmembrane sodium transport. The patients were reinvestigated two weeks after successful surgery (N = 14) and again after one year (N = 13). Erythrocyte electrolytes were analyzed by flame photometry and sodium influx and efflux rate constant determined by in vitro incubation using a modified Keyne's formula. In patients with active acromegaly there was a significant positive correlation between IGF-1 and cellular sodium transport, while GH tended to show a negative relatonship to the same parameter. After successful treatment, both IGF-1 and GH disclosed a positive relationship to cellular sodium transport. After one year, a significant increase in erythrocyte sodium content was seen in the patients compared to the preoperative situation. In conclusion, if this is a generalized phenomonen the results are compatible with a sodium-retaining effect of GH via stimulation of transmembrane sodium transport. In active acromegaly this may be counteracted by a sodium transport inhibitor giving the reverse relationship between GH and cellular sodium transport. (au).

Simultaneous measurement of glucose transport and utilization in the human brain

Science.gov (United States)

Shestov, Alexander A.; Emir, Uzay E.; Kumar, Anjali; Henry, Pierre-Gilles; Seaquist, Elizabeth R.

2011-01-01

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, KMt and Vmaxt, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMRglc) obtained from other tracer studies, such as 13C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state 1H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ∼17 mmol/l for ∼2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMRglc, this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain. PMID:21791622

Intestinal glucose transport and salinity adaptation in a euryhaline teleost

International Nuclear Information System (INIS)

Reshkin, S.J.; Ahearn, G.A.

1987-01-01

Glucose transport by upper and lower intestinal brush-border membrane vesicles of the African tilapia (Oreochromis mossambicus) was characterized in fish acclimated to either freshwater of full-strength sea water. D-[ 3 H]-glucose uptake by vesicles was stimulated by a transmembrane Na gradient, was electrogenic, and was enhanced by countertransport of either D-glucose or D-galactose. Glucose transport was greater in the upper intestine than in the lower intestine and in sea water animals rather than in fish acclimated to freshwater. Glucose influx (10-s uptake) involved both saturable and nonsaturable transport components. Sea water adaptation increased apparent glucose influx K/sub t/, J/sub max/, apparent diffusional permeability (P), and the apparent Na affinity of the cotransport system in both intestinal segments, but the stoichiometry of Na-glucose transfer (1:1) was unaffected by differential saline conditions or gut region. It is suggested that increased sugar transport in sea water animals is due to the combination of enhanced Na-binding properties and an increase in number or transfer rate of the transport proteins. Freshwater animals compensate for reduced Na affinity of the coupled process by markedly increasing the protein affinity for glucose

Glucose transport machinery reconstituted in cell models.

Science.gov (United States)

Hansen, Jesper S; Elbing, Karin; Thompson, James R; Malmstadt, Noah; Lindkvist-Petersson, Karin

2015-02-11

Here we demonstrate the production of a functioning cell model by formation of giant vesicles reconstituted with the GLUT1 glucose transporter and a glucose oxidase and hydrogen peroxidase linked fluorescent reporter internally. Hence, a simplified artificial cell is formed that is able to take up glucose and process it.

Radiochemical measurement of mass transport in sodium

International Nuclear Information System (INIS)

Cooper, M.H.; Chiang, S.H.

1976-01-01

Mass transport processes in the sodium coolant of Liquid Metal Fast Breeder Reactors (LMFBRs) are significant in determining rates of corrosion and deposition of radioactive nuclides from the fuel cladding, deposition and cold trapping of fission products from defect or failed fuel, carbon and nitrogen redistribution in the containment materials, and removal of impurities by cold trapping or hot trapping. Mass transport between rotating, concentric cylinders in molten sodium has been investigated using a unique radiochemical method. Long-lived (33 year) cesium-137, dissolved in the sodium, decays radioactively emitting a beta to barium-137m, which decays with a short half-life (2.6 minutes) emitting a gamma. Cesium is weakly adsorbed and remains in solution, while the barium is strongly adsorbed on the stainless steel surfaces. Hence, by measuring the barium-137m activity on movable stainless steel surfaces, one can calculate the mass transport to that surface. Mass transfer coefficients in sodium measured by this method are in agreement with published heat transfer correlations when the effect of the volumetric mass source is taken into account. Hence, heat transfer correlations can be confidently utilized by analogy in estimating mass transfer in liquid-metal systems

Diabetic Hyperglycemia: Link to Impaired Glucose Transport in Pancreatic β Cells

Science.gov (United States)

Unger, Roger H.

1991-03-01

Glucose uptake into pancreatic β cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal β-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of β cells to hyperglycemia may improve the management and prevention of diabetes.

Molecular cloning and characterization of glucose transporter 1 ...

African Journals Online (AJOL)

Glucose transporter type-1 (glut1) and citrate synthase plays crucial role in glucose transport and regulation of tricarboxylic acid cycle (TCA) cycle in mammalian energy metabolism. The present study was aimed to clone and characterize glut1 and citrate synthase cDNA in water buffalo (Bubalus bubalis). Total of 90 ...

Functional interaction between CFTR and the sodium-phosphate co-transport type 2a in Xenopus laevis oocytes.

Directory of Open Access Journals (Sweden)

Naziha Bakouh

Full Text Available A growing number of proteins, including ion transporters, have been shown to interact with Cystic Fibrosis Transmembrane conductance Regulator (CFTR. CFTR is an epithelial chloride channel that is involved in Cystic Fibrosis (CF when mutated; thus a better knowledge of its functional interactome may help to understand the pathophysiology of this complex disease. In the present study, we investigated if CFTR and the sodium-phosphate co-transporter type 2a (NPT2a functionally interact after heterologous expression of both proteins in Xenopus laevis oocytes.NPT2a was expressed alone or in combination with CFTR in X. laevis oocytes. Using the two-electrode voltage-clamp technique, the inorganic phosphate-induced current (IPi was measured and taken as an index of NPT2a activity. The maximal IPi for NPT2a substrates was reduced when CFTR was co-expressed with NPT2a, suggesting a decrease in its expression at the oolemna. This was consistent with Western blot analysis showing reduced NPT2a plasma membrane expression in oocytes co-expressing both proteins, whereas NPT2a protein level in total cell lysate was the same in NPT2a- and NPT2a+CFTR-oocytes. In NPT2a+CFTR- but not in NPT2a-oocytes, IPi and NPT2a surface expression were increased upon PKA stimulation, whereas stimulation of Exchange Protein directly Activated by cAMP (EPAC had no effect. When NPT2a-oocytes were injected with NEG2, a short amino-acid sequence from the CFTR regulatory domain that regulates PKA-dependent CFTR trafficking to the plasma membrane, IPi values and NPT2a membrane expression were diminished, and could be enhanced by PKA stimulation, thereby mimicking the effects of CFTR co-expression.We conclude that when both CFTR and NPT2a are expressed in X. laevis oocytes, CFTR confers to NPT2a a cAMPi-dependent trafficking to the membrane. This functional interaction raises the hypothesis that CFTR may play a role in phosphate homeostasis.

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

Science.gov (United States)

Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

2012-01-01

The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain. PMID:23202918

Sodium-Glucose Linked Transporter-2 Inhibitors in Chronic Kidney Disease

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L. Zanoli

2015-01-01

Full Text Available SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD.

Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes

International Nuclear Information System (INIS)

Carter-Su, C.; Okamoto, K.

1987-01-01

The ability of glucocorticoids to modify the effect of insulin on glucose (L-1- 3 H(N)]glucose and D-[ 14 C-U]glucose) transport was investigated in both intact isolated rat adipocytes and in membranes isolated from hormone-treated adipocytes. In intact adipocytes, dexamethasone, a potent synthetic glucocorticoid, inhibited insulin-stimulated 3-O-methylglucose transport at all concentrations of insulin tested. Insulin sensitivity, as well as the maximal response to insulin, was decreased by dexamethasone in the absence of a change in 125 I insulin binding. The inhibition was observed regardless of which hormone acted first, was blocked by actinomycin D, and resulted from a decrease in V/sub max/ rather than an increase in K/sub t/ of transport. In plasma membranes isolated from insulin-treated adipocytes, glucose transport activity and the amount of glucose transporter covalently labeled with [ 3 H]cytochalasin B were increased in parallel in a dose-dependent fashion. The amount of labeled transporter in a low-density microsomal fraction (LDMF) was decreased in a reciprocal fashion. In contrast, addition of dexamethasone to insulin-stimulated cells caused decreases in both transport activity and amount of labeled transporter in the plasma membranes. This was accompanied by a small increase in the amount of [ 3 H]cytochalasin B incorporated into the glucose transporter in the LDMF. These results are consistent with both insulin and glucocorticoids altering the distribution of glucose transporters between the plasma membrane and LDMF, in opposite directions

Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

Science.gov (United States)

Besson, Marie Thérèse; Alegría, Karin; Garrido-Gerter, Pamela; Barros, Luis Felipe; Liévens, Jean-Charles

2015-01-01

Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP) impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to mediate the hGluT3

Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

Directory of Open Access Journals (Sweden)

Marie Thérèse Besson

Full Text Available Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93. We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD, the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to

Reduced Expression of the Liver/Beta-Cell Glucose Transporter Isoform in Glucose-Insensitive Pancreatic Beta Cells of Diabetic Rats

Science.gov (United States)

Thorens, Bernard; Weir, Gordon C.; Leahy, John L.; Lodish, Harvey F.; Bonner-Weir, Susan

1990-09-01

Rats injected with a single dose of streptozocin at 2 days of age develop non-insulin-dependent diabetes 6 weeks later. The pancreatic beta islet cells of these diabetic rats display a loss of glucose-induced insulin secretion while maintaining sensitivity to other secretagogues such as arginine. We analyzed the level of expression of the liver/beta-cell glucose transporter isoform in diabetic islets by immunofluorescence staining of pancreas sections and by Western blotting of islet lysates. Islets from diabetic animals have a reduced expression of this beta-cell-specific glucose transporter isoform and the extent of reduction is correlated with the severity of hyperglycemia. In contrast, expression of this transporter isoform in liver is minimally modified by the diabetes. Thus a decreased expression of the liver/beta-cell glucose transporter isoform in beta cells is associated with the impaired glucose sensing characteristic of diabetic islets; our data suggest that this glucose transporter may be part of the beta-cell glucose sensor.

Cellular and molecular cues of glucose sensing in the rat olfactory bulb

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Dolly eAl Koborssy

2014-10-01

Full Text Available In the brain, glucose homeostasis of extracellular fluid is crucial to the point that systems specifically dedicated to glucose sensing are found in areas involved in energy regulation and feeding behavior. Olfaction is a major sensory modality regulating food consumption. Nutritional status in turn modulates olfactory detection. Recently it has been proposed that some olfactory bulb (OB neurons respond to glucose similarly to hypothalamic neurons. However, the precise molecular cues governing glucose sensing in the OB are largely unknown. To decrypt these molecular mechanisms, we first used immunostaining to demonstrate a strong expression of two neuronal markers of glucose-sensitivity, insulin-dependent glucose transporter type 4 (GLUT4, and sodium glucose co-transporter type 1 (SGLT1 in specific OB layers. We showed that expression and mapping of GLUT4 but not SGLT1 were feeding state-dependent. In order to investigate the impact of metabolic status on the delivery of blood-borne glucose to the OB, we measured extracellular fluid glucose concentration using glucose biosensors simultaneously in the OB and cortex of anesthetized rats. We showed that glucose concentration in the OB is higher than in the cortex, that metabolic steady-state glucose concentration is independent of feeding state in the two brain areas, and that acute changes in glycemic conditions affect bulbar glucose concentration alone. These data provide new evidence of a direct relationship between the OB and peripheral metabolism, and emphasize the importance of glucose for the OB network, providing strong arguments toward establishing the OB as a glucose-sensing organ.

Steady-state cerebral glucose concentrations and transport in the human brain

OpenAIRE

Gruetter, R.; Ugurbil, K.; Seaquist, E. R.

1998-01-01

Understanding the mechanism of brain glucose transport across the blood- brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport nave been generally described using standard Michaelis-Menten kinetics. These models predict that the steady- state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, K(t). In experiments wh...

Septal co-infusions of glucose with the benzodiazepine agonist chlordiazepoxide impair memory, but co-infusions of glucose with the opiate morphine do not.

Science.gov (United States)

Krebs-Kraft, Desiree L; Parent, Marise B

2010-03-30

We have found repeatedly that medial septal (MS) infusions of glucose impair memory when co-infused with the gamma-amino butyric acid (GABA) agonist muscimol. The present experiments sought to determine whether the memory-impairing effects of this concentration of glucose would generalize to another GABA(A) receptor agonist and to an agonist from another neurotransmitter system that is known to impair memory. Specifically, we determined whether the dose of glucose that produces memory deficits when combined with muscimol in the MS would also impair memory when co-infused with the GABA(A) receptor modulator chlordiazepoxide (CDP) or the opiate morphine. Male Sprague-Dawley rats were given MS co-infusions and then 15 min later tested for spontaneous alternation or given shock avoidance training (retention tested 48 h later). The results showed that MS infusions of the higher dose of glucose with morphine did not produce memory deficits, whereas, the performance of rats given MS co-infusions of CDP with glucose was impaired. These findings suggest that the memory-impairing effects of brain glucose administration may involve an interaction with the GABA(A) receptor. (c) 2009 Elsevier Inc. All rights reserved.

Control of sodium vapor transport in annuli

International Nuclear Information System (INIS)

Meadows, G.E.; Bohringer, A.P.

1983-11-01

The method used to control sodium vapor transport in the annuli of various components at the Fast Flux Test Facility (FFTF) is a downward purge of the annuli with high purity argon. The purge rates for the FFTF were selected by calculating the gas velocity required to overcome thermal convection transport in the annuli. To evaluate the effectiveness of the gas purge, laboratory apparatus was fabricated which simulated selected annuli in the FFTF In-Vessel Handling Machine (IVHM) and the Instrument Tree (IT) annuli. Tests were conducted at temperatures similar to FFTF conditions. Gas purge rates ranged from zero to 130% of FFTF flow rates. Test results show the effectiveness of a high purity gas purge in decreasing the accumulation of sodium vapor deposits in an annulus. The presence of water vapor and oxygen in the purge gas increased the sodium deposition rate by a factor of three over other tests usig high purity argon. The presence of a vapor control collar used in the IT annulus was shown to be beneficial for controlling vapor transport into the upper region of the annulus

Glucose transporter of the human brain and blood-brain barrier

International Nuclear Information System (INIS)

Kalaria, R.N.; Gravina, S.A.; Schmidley, J.W.; Perry, G.; Harik, S.I.

1988-01-01

We identified and characterized the glucose transporter in the human cerebral cortex, cerebral microvessels, and choroid plexus by specific D-glucose-displaceable [3H]cytochalasin B binding. The binding was saturable, with a dissociation constant less than 1 microM. Maximal binding capacity was approximately 7 pmol/mg protein in the cerebral cortex, approximately 42 pmol/mg protein in brain microvessels, and approximately 27 pmol/mg protein in the choroid plexus. Several hexoses displaced specific [3H]cytochalasin B binding to microvessels in a rank-order that correlated well with their known ability to cross the blood-brain barrier; the only exception was 2-deoxy-D-glucose, which had much higher affinity for the glucose transporter than the natural substrate, D-glucose. Irreversible photoaffinity labeling of the glucose transporter of microvessels with [3H]cytochalasin B, followed by solubilization and polyacrylamide gel electrophoresis, labeled a protein band with an average molecular weight of approximately 55,000. Monoclonal and polyclonal antibodies specific to the human erythrocyte glucose transporter immunocytochemically stained brain blood vessels and the few trapped erythrocytes in situ, with minimal staining of the neuropil. In the choroid plexus, blood vessels did not stain, but the epithelium reacted positively. We conclude that human brain microvessels are richly endowed with a glucose transport moiety similar in molecular weight and antigenic characteristics to that of human erythrocytes and brain microvessels of other mammalian species

Effect of erythropoietin on the glucose transport of rat erythrocytes and bone marrow cells

International Nuclear Information System (INIS)

Ghosal, J.; Chakraborty, M.; Biswas, T.; Ganguly, C.K.; Datta, A.G.

1987-01-01

The effect of Ep on radioactive glucose and methyl-alpha-D-glucoside transport by rat erythrocytes and bone marrow cells were studied. There is initial linearity followed by saturation kinetics of [ 14 C]glucose transport by the erythrocytes of starved and starved plus Ep-treated rats at different concentrations of glucose. Starvation caused slight inhibition of glucose transport which increased markedly on Ep administration to starved rats. Normal animals failed to show any significant change in glucose transport after Ep treatment. Methyl-alpha-D-glucoside inhibited the Ep-stimulated glucose transport significantly. Ep also stimulated the transport of radioactive methyl-alpha-D-glucoside which was competitively inhibited in presence of D-glucose. Glucose transport in erythrocytes was found to be sensitive to metabolic inhibitors like azide and DNP. A sulfhydryl reagent and ouabain also inhibited the transport process. Ep stimulated glucose and methyl-alpha-D-glucoside transport in the bone marrow cells of starved rats. The sugar analog competitively inhibited the glucose transport in bone marrow cells and vice versa

Simultaneous measurement of glucose transport and utilization in the human brain

OpenAIRE

Shestov, Alexander A.; Emir, Uzay E.; Kumar, Anjali; Henry, Pierre-Gilles; Seaquist, Elizabeth R.; Öz, Gülin

2011-01-01

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, KMt and Vmaxt, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose tra...

Transport equations in an enzymatic glucose fuel cell

Science.gov (United States)

Jariwala, Soham; Krishnamurthy, Balaji

2018-01-01

A mathematical model is developed to study the effects of convective flux and operating temperature on the performance of an enzymatic glucose fuel cell with a membrane. The model assumes isothermal operating conditions and constant feed rate of glucose. The glucose fuel cell domain is divided into five sections, with governing equations describing transport characteristics in each region, namely - anode diffusion layer, anode catalyst layer (enzyme layer), membrane, cathode catalyst layer and cathode diffusion layer. The mass transport is assumed to be one-dimensional and the governing equations are solved numerically. The effects flow rate of glucose feed on the performance of the fuel cell are studied as it contributes significantly to the convective flux. The effects of operating temperature on the performance of a glucose fuel cell are also modeled. The cell performances are compared using cell polarization curves, which were found compliant with experimental observations.

Facile synthesis of ultrafine Co3O4 nanocrystals embedded carbon matrices with specific skeletal structures as efficient non-enzymatic glucose sensors

International Nuclear Information System (INIS)

Li, Mian; Han, Ce; Zhang, Yufan; Bo, Xiangjie; Guo, Liping

2015-01-01

Highlights: • Novel hyperfine Co 3 O 4 nanocrystals decorated porous carbon matrixes. • Facile synthesis without use of any harmful dispersing reagents or surfactants. • High dispersion degree of Co 3 O 4 nanocrystals and excellent e − transport rates. • A large current sensitivity of 955.9 μA cm −2 mM −1 toward glucose. • Excellent anti-interference and stability for glucose detection. - Abstract: A facile, effective, and environmentally friendly method has been adopted for the first time to prepare tiny Co 3 O 4 nanocrystals embedded carbon matrices without using surfactants, harmful organic reagents or extreme conditions. Structural characterizations reveal that the size-controlled Co 3 O 4 nanocrystals are uniformly dispersed on carbon matrices. Electrochemical measurements reveal that Co 3 O 4 -ordered mesoporous carbon (OMC) can more efficiently catalyze glucose oxidation and acquire better detection parameters compared with those for the Co 3 O 4 -macroporous carbon, Co 3 O 4 -reduced graphene oxide, and free Co 3 O 4 nanoparticles (NPs) (such as: the large sensitivity (2597.5 μA cm −2 mM −1 between 0 and 0.8 mM and 955.9 μA cm −2 mM −1 between 0.9 and 7.0 mM), fast response time, wide linear range, good stability, and surpassingly selective capability to electroactive molecules or Cl − ). Such excellent performances are attributed to the synergistic effect of the following three factors: (1) the high catalytic sites provided by the uniformly dispersed and size-controlled Co 3 O 4 nanocrystals embedded on OMC; (2) the excellent reactant transport efficiency caused by the abundant mesoporous structures of OMC matrix: (3) the improved electron transport in high electron transfer rate (confinement of the Co 3 O 4 NPs in nanoscale spaces ensured intimate contact between Co 3 O 4 nanocrystals and the conducting OMC matrix). The superior catalytic activity and selectivity make Co 3 O 4 -OMC very promising for application in direct

Prenatal programming of rat cortical collecting tubule sodium transport.

Science.gov (United States)

Cheng, Chih-Jen; Lozano, German; Baum, Michel

2012-03-15

Prenatal insults have been shown to lead to elevated blood pressure in offspring when they are studied as adults. Prenatal administration of dexamethasone and dietary protein deprivation have demonstrated that there is an increase in transporter abundance for a number of nephron segments but not the subunits of the epithelial sodium channel (ENaC) in the cortical collecting duct. Recent studies have shown that aldosterone is elevated in offspring of protein-deprived mothers when studied as adults, but the physiological importance of the increase in serum aldosterone is unknown. As an indirect measure of ENaC activity, we compared the natriuretic response to benzamil in offspring of mothers who ate a low-protein diet (6%) with those who ate a normal diet (20%) for the last half of pregnancy. The natriuretic response to benzamil was greater in the 6% group (821.1 ± 161.0 μmol/24 h) compared with the 20% group (279.1 ± 137.0 μmol/24 h), consistent with greater ENaC activity in vivo (P sodium transport (-1.9 ± 3.1 pmol·mm(-1)·min(-1)), the offspring of rats that ate a 6% protein diet during the last half of pregnancy had a net sodium flux of 10.7 ± 2.6 pmol·mm(-1)·min(-1) (P = 0.01) in tubules perfused in vitro. Sodium transport was measured using ion-selective electrodes, a novel technique allowing measurement of sodium in nanoliter quantities of fluid. Thus we directly demonstrate that there is prenatal programming of cortical collecting duct sodium transport.

Glucose transporters: expression, regulation and cancer

Directory of Open Access Journals (Sweden)

RODOLFO A. MEDINA

2002-01-01

Full Text Available Mammalian cells depend on glucose as a major substrate for energy production. Glucose is transported into the cell via facilitative glucose transporters (GLUT present in all cell types. Many GLUT isoforms have been described and their expression is cell-specific and subject to hormonal and environmental control. The kinetic properties and substrate specificities of the different isoforms are specifically suited to the energy requirements of the particular cell types. Due to the ubiquitousness of these transporters, their differential expression is involved in various disease states such as diabetes, ischemia and cancer. The majority of cancers and isolated cancer cell lines over-express the GLUT family members which are present in the respective tissue of origin under non-cancerous conditions. Moreover, due to the requirement of energy to feed uncontrolled proliferation, cancer cells often express GLUTs which under normal conditions would not be present in these tissues. This over-expression is predominantly associated with the likelihood of metastasis and hence poor patient prognosis. This article presents a review of the current literature on the regulation and expression of GLUT family members and has compiled clinical and research data on GLUT expression in human cancers and in isolated human cancer cell lines.

Transcript levels of members of the SLC2 and SLC5 families of glucose transport proteins in eel swimbladder tissue: the influence of silvering and the influence of a nematode infection.

Science.gov (United States)

Schneebauer, Gabriel; Mauracher, David; Fiechtner, Birgit; Pelster, Bernd

2018-04-01

The rate of glucose metabolism has been shown to be correlated to glucose uptake in swimbladder gas gland cells. Therefore, it is assumed that in the European eel silvering, i.e., the preparation of the eel for the spawning migration to the Sargasso Sea, coincides with an enhanced capacity for glucose uptake. To test this hypothesis expression of all known glucose transport proteins has been assessed at the transcript level in yellow and in silver eels, and we also included Anguillicola crassus infected swimbladders. Glucose uptake by rete mirabile endothelial cells could be crucial for the countercurrent exchange capacity of the rete. Therefore, this tissue was also included in our analysis. The results revealed expression of ten different members of the slc2 family of glucose transporters, of four slc5 family members, and of kiaa1919 in gas gland tissue. Glucose transporters of the slc2 family were expressed at very high level, and slc2a1b made up about 80% of all slc2 family members, irrespective of the developmental state or the infection status of the eel. Overall, the slc5 family contributed to only about 8% of all detected glucose transport transcripts in gas gland tissue, and the slc2 family to more than 85%. In rete capillaries, the contribution of sodium-dependent glucose transporters was significantly higher, leaving only 66% for the slc2 family of glucose transporters. Neither silvering nor the infection status had a significant effect on the expression of glucose transporters in swimbladder gas gland tissue, suggesting that glucose metabolism of eel gas gland cells may not be related to transcriptional changes of glucose transport proteins.

An evolved xylose transporter from Zymomonas mobilis enhances sugar transport in Escherichia coli

Directory of Open Access Journals (Sweden)

Zhang Jingqing

2009-12-01

Full Text Available Abstract Background Xylose is a second most abundant sugar component of lignocellulose besides glucose. Efficient fermentation of xylose is important for the economics of biomass-based biorefineries. However, sugar mixtures are sequentially consumed in xylose co-fermentation with glucose due to carbon catabolite repression (CCR in microorganisms. As xylose transmembrance transport is one of the steps repressed by CCR, it is therefore of interest to develop a transporter that is less sensitive to the glucose inhibition or CCR. Results The glucose facilitator protein Glf transporter from Zymomonas mobilis, also an efficient transporter for xylose, was chosen as the target transporter for engineering to eliminate glucose inhibition on xylose uptake. The evolution of Glf transporter was carried out with a mixture of glucose and xylose in E. coli. Error-prone PCR and random deletion were employed respectively in two rounds of evolution. Aided by a high-throughput screening assay using xylose analog p-nitrophenyl-β-D-xylopyranoside (pNPX in 96-well plates, a best mutant 2-RD5 was obtained that contains several mutations, and a deletion of 134 residues (about 28% of total residues, or three fewer transmembrane sections (TMSs. It showed a 10.8-fold improvement in terms of pNPX transport activity in the presence of glucose. The fermentation performance results showed that this mutant improved xylose consumption by 42% with M9 minimal medium containing 20 g L-1 xylose only, while with the mixture sugar of xylose and glucose, 28% more glucose was consumed, but no obvious co-utilization of xylose was observed. Further glucose fed-batch experiments suggested that the intracellular metabolism of xylose was repressed by glucose. Conclusions Through random mutagenesis and partial deletion coupled with high-throughput screening, a mutant of the Glf transporter (2-RD5 was obtained that relieved the inhibition of xylose transport by glucose. The fermentation

Validation of 123I-6-deoxy-6-iodo-D-glucose (6-DIC) as tracer for the in-vivo glucose transport

International Nuclear Information System (INIS)

Perret, P.; Ghezzi, C.; Mathieu, J.P.; Morin, C.; Vidal, M.; Comet, M.; Fagret, D.

1997-01-01

The evaluation of the glucose transport is very important clinically because alterations of this transport were described in numerous pathologies, in neurology, oncology and endocrinology. A new analog of the 123 I-labelled has been synthesized: 123 I-6-deoxy-6-iodo-D-glucose (6-DIG). Its in-vitro biological behaviour is similar to that of 3-O-methyl-D-glucose (3-OMG), the reference tracer of glucose transport. The aim of the study was to determine if it is possible to make evident by 6-DIG a variations of in-vivo glucose transport. The studies were effected on a model of homozygote mice (db/db), genetically diabetic (NIDDM), presenting a severe insulin-resistance, characterized by deficient glucose transport in response to insulin. The studies of 6-DIG biodistribution (5 nmol/mouse) with (1.5 UI/Kg) or without exogenous insulin, were conducted in diabetic mice (db/db) and in non-diabetic (db/+) control mice. The results show that the capture of 6-DIG, as well as that of glucose, increases (by 30%) in response to insulin in most of insulin-sensitive tissues in control mice. In the insulin-resistant and hyperglycemic db/db mouse, the capture of 6-DIG is not modified, no matter whether the exogenous insulin is present. In conclusion, the 6-DIG is able to make evident a lack of glucose transport in heart, diaphragm and skeletal muscle in diabetic mouse and a physiological variation of this transport in response to insulin, in the control mouse. This result should be stressed because for the first time it is possible to evidence in-vivo variations into glucose transport with a iodated molecule

Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect.

Science.gov (United States)

Kalra, Sanjay; Jain, Arpit; Ved, Jignesh; Unnikrishnan, A G

2016-01-01

This review discusses two distinct, yet related, mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibition: Calorie restriction mimicry (CRM) and pro-ketogenic effect, which may explain their cardiovascular benefits. We term these adaptive CRM and pro-ketogenic effects of SGLT2 inhibition, the Robin Hood hypothesis. In English history, Robin Hood was a "good person," who stole from the rich and helped the poor. He supported redistribution of resources as he deemed fit for the common good. In a similar fashion, SGLT2 inhibition provides respite to the overloaded glucose metabolism while utilizing lipid stores for energy production.

Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect

Directory of Open Access Journals (Sweden)

Sanjay Kalra

2016-01-01

Full Text Available This review discusses two distinct, yet related, mechanisms of sodium-glucose cotransporter 2 (SGLT2 inhibition: Calorie restriction mimicry (CRM and pro-ketogenic effect, which may explain their cardiovascular benefits. We term these adaptive CRM and pro-ketogenic effects of SGLT2 inhibition, the Robin Hood hypothesis. In English history, Robin Hood was a "good person," who stole from the rich and helped the poor. He supported redistribution of resources as he deemed fit for the common good. In a similar fashion, SGLT2 inhibition provides respite to the overloaded glucose metabolism while utilizing lipid stores for energy production.

Endocrine control of active sodium transport across frog skin; Le controle endocrinien du transport actif de sodium a travers la peau de grenouille

Energy Technology Data Exchange (ETDEWEB)

Maetz, J. [Commissariat a l' Energie Atomique, Saclay (France).Centre d' Etudes Nucleaires

1959-07-01

I. Action of the neurohypophyseal peptides on sodium transport. 1) On Rana Esculenta, oxytocin alone is active on the sodium transport (not vaso pressin). 2) The post hypophysis of R.e. contains an hormonal factor even more specific on Na transport (12 times more active than oxytocin). 3) This new factor must be closely related to oxytocin. II. Action of the adrenal corticoids. 1) The skin of frogs adapted to a salt-rich external medium, shows a considerable diminution in sodium uptake. 2) This decreased sodium uptake is brought back to normal by the injections of aldosterone. 3) This suggests that salt loading of amphibians (as well as mammals) inhibits the mineralocorticoid activity of the adrenals. (author) [French] I. Action des peptides neurohypophysaires chez Rana esculenta. 1) Le transport actif de Na est sensible a l'action de l'ocytocine mais non a l'hormone antidiuretique. 2) La posthypophyse de ces grenouilles contient un facteur plus specifique encore, puisque 12 fois plus actif que l'ocytocine. 3) Ce facteur est cependant tres voisin de l'ocytocine au point de vue chimique. lI. Action des corticoides surrenaliens chez Rana Esculenta. 1) L'adaptation des grenouilles a un milieu riche en sel a pour effet une diminution considerable du transport actif de sodium, visible in vivo et in vitro. 2) L'injection d'aldosterone a des grenouilles adaptees dans ces conditions restaure le transport actif a un niveau comparable a celui que l'on observe chez les animaux conserves dans de l'eau courante. 3) Ces faits suggerent que la surcharge en NaCI produirait chez les amphibiens, comme chez les mammiferes, une mise au repos de la fonction mineralotrope de la surrenale. (auteur)

Endocrine control of active sodium transport across frog skin; Le controle endocrinien du transport actif de sodium a travers la peau de grenouille

Energy Technology Data Exchange (ETDEWEB)

Maetz, J [Commissariat a l' Energie Atomique, Saclay (France).Centre d' Etudes Nucleaires

1959-07-01

I. Action of the neurohypophyseal peptides on sodium transport. 1) On Rana Esculenta, oxytocin alone is active on the sodium transport (not vaso pressin). 2) The post hypophysis of R.e. contains an hormonal factor even more specific on Na transport (12 times more active than oxytocin). 3) This new factor must be closely related to oxytocin. II. Action of the adrenal corticoids. 1) The skin of frogs adapted to a salt-rich external medium, shows a considerable diminution in sodium uptake. 2) This decreased sodium uptake is brought back to normal by the injections of aldosterone. 3) This suggests that salt loading of amphibians (as well as mammals) inhibits the mineralocorticoid activity of the adrenals. (author) [French] I. Action des peptides neurohypophysaires chez Rana esculenta. 1) Le transport actif de Na est sensible a l'action de l'ocytocine mais non a l'hormone antidiuretique. 2) La posthypophyse de ces grenouilles contient un facteur plus specifique encore, puisque 12 fois plus actif que l'ocytocine. 3) Ce facteur est cependant tres voisin de l'ocytocine au point de vue chimique. lI. Action des corticoides surrenaliens chez Rana Esculenta. 1) L'adaptation des grenouilles a un milieu riche en sel a pour effet une diminution considerable du transport actif de sodium, visible in vivo et in vitro. 2) L'injection d'aldosterone a des grenouilles adaptees dans ces conditions restaure le transport actif a un niveau comparable a celui que l'on observe chez les animaux conserves dans de l'eau courante. 3) Ces faits suggerent que la surcharge en NaCI produirait chez les amphibiens, comme chez les mammiferes, une mise au repos de la fonction mineralotrope de la surrenale. (auteur)

Reducing biomass recalcitrance via mild sodium carbonate pretreatment.

Science.gov (United States)

Mirmohamadsadeghi, Safoora; Chen, Zhu; Wan, Caixia

2016-06-01

This study examined the effects of mild sodium carbonate (Na2CO3) pretreatment on enzymatic hydrolysis of different feedstocks (i.e., corn stover, Miscanthus, and switchgrass). The results showed that sodium carbonate pretreatment markedly enhanced the sugar yields of the tested biomass feedstocks. The pretreated corn stover, Miscanthus, and switchgrass gave the glucose yields of 95.1%, 62.3%, and 81.3%, respectively, after enzymatic hydrolysis. The above glucose yields of pretreated feedstocks were 2-4 times that of untreated ones. The pretreatment also enhanced the xylose yields, 4 times for corn stover and 20 times for both Miscanthus and switchgrass. Sodium carbonate pretreatment removed 40-59% lignin from the tested feedstocks while preserving most of cellulose (sodium carbonate pretreatment was effective for reducing biomass recalcitrance and subsequently improving the digestibility of lignocellulosic biomass. Copyright © 2016 Elsevier Ltd. All rights reserved.

Orexins control intestinal glucose transport by distinct neuronal, endocrine and direct epithelial pathways. : Orexins regulate intestinal glucose absorption

OpenAIRE

Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

2007-01-01

International audience; Objective : Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and OxB on intestinal glucose transport in the rat. Research Design and Methods : Injection of orexins led to a decrease in the blood glucose level in OGTT. Effects of orexins on glucose entry were analysed in Ussing chamber using the Na+-dependent increase in short-circuit current to quantify jejunal glucose transport. Results & Conclusions : The rapid an...

Environmental, health, and safety issues of sodium-sulfur batteries for electric and hybrid vehicles. Volume 3, Transport of sodium-sulfur and sodium-metal-chloride batteries

Energy Technology Data Exchange (ETDEWEB)

Hammel, C J

1992-09-01

This report examines the shipping regulations that govern the shipment of dangerous goods. Since the elemental sodium contained in both sodium-sulfur and sodium-metal-chloride batteries is classified as a dangerous good, and is listed on both the national and international hazardous materials listings, both national and international regulatory processes are considered in this report The interrelationships as well as the differences between the two processes are highlighted. It is important to note that the transport regulatory processes examined in this report are reviewed within the context of assessing the necessary steps needed to provide for the domestic and international transport of sodium-beta batteries. The need for such an assessment was determined by the Shipping Sub-Working Group (SSWG) of the EV Battery Readiness Working Group (Working Group), created in 1990. The Working Group was created to examine the regulatory issues pertaining to in-vehicle safety, shipping, and recycling of sodium-sulfur batteries, each of which is addressed by a sub-working group. The mission of the SSWG is to establish basic provisions that will ensure the safe and efficient transport of sodium-beta batteries. To support that end, a proposal to the UN Committee of Experts was prepared by the SSWG, with the goal of obtaining a proper shipping name and UN number for sodium-beta batteries and to establish the basic transport requirements for such batteries (see the appendix for the proposal as submitted). It is emphasized that because batteries are large articles containing elemental sodium and, in some cases, sulfur, there is no existing UN entry under which they can be classified and for which modal transport requirements, such as the use of packaging appropriate for such large articles, are provided for. It is for this reason that a specific UN entry for sodium-beta batteries is considered essential.

Monju secondary heat transport system sodium leak

International Nuclear Information System (INIS)

Suzuki, Takeo; Hiroi, Hiroshi; Usami, Shin; Iwata, Koji.

1996-01-01

On December 8, 1995, the sodium leakage from the secondary heat transport system (SHTS) occurred in the piping room of the reactor auxiliary building in Monju. The secondary sodium leaked through a temperature sensor, due to the breakaway of the tip of the well tube of the sensor installed near the outlet of the intermediate heat exchanger (IHX) in the C loop of SHTS. The reactor core remained cooled and thus, from the viewpoint of radiological hazards, the safety of the reactor was secured. There were no adverse effects for operating personnel or the surrounding environment. The cause of the well tube failure is considered to result from high cycle fatigue due to flow induced vibrations. Delay in draining the sodium from the leaking loop increased the consequential effects from sodium combustion products. (author)

Study of mechanisms and kinetics of Sodium-CO2 interactions. Contribution to the evaluation of an energy conversion system with supercritical CO2 for sodium fast breeder reactors

International Nuclear Information System (INIS)

Gicquel, L.

2010-01-01

This PhD study consisted in studying reactive mechanisms and kinetics of sodium-CO 2 interactions, in the frame of the assessment of an energy conversion system with supercritical CO 2 for fast breeder reactors cooled by sodium. The approach was the following. First of all, the interactions between sodium and CO 2 have been brought to light by laboratory experiments associated with products analysis. They have enabled the establishment of a coherent mechanism, in agreement with literature data, and gave preliminary indications on the reaction kinetics. In order to estimate a more detailed reaction kinetics, we tried to approach the phenomenon that appears in the case of a leak in a sodium-CO 2 heat exchanger. Geometry of such heat exchangers is not fixed for the moment, even if the development of compact exchangers is foreseen. Then, free jets of CO 2 in liquid sodium have been modeled in order to obtain, by identification, kinetics parameters of the reaction. Those parameters, estimated with such a geometry, will remain valid with a much complex geometry, that will better represent the real exchanger. An experimental bench has been defined and built to realize those jets. The first laboratory experiments have concluded in the existence of different reactive mechanisms according to the temperature level. A threshold has been brought to light around 500 C. Below this one, reaction appears moderated, or even, slow, with a medium exothermicity, and appears after an induction period that depends on the temperature,and which duration could reach several hours. At contrary, above this threshold, it seems rapid and more exothermic. Below 500 C, sodium oxalate is produced, and then reacts with sodium in an exothermic way, following the reactions: CO 2 + Na →1/4 Na 2 C 2 O 4 + 1/4 CO + 1/4 Na 2 CO 3 (5) 4 Na + Na 2 C 2 O 4 → 3 Na 2 O + CO + C (6) Above 500 C, sodium carbonate is produced, and can then possibly react with sodium in an endothermic way, following the

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

OpenAIRE

Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

2012-01-01

The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s dis...

Red blood cell sodium transport in patients with cirrhosis

DEFF Research Database (Denmark)

Henriksen, Ulrik Lütken; Kiszka-Kanowitz, Marianne; Bendtsen, Flemming

2016-01-01

Patients with advanced cirrhosis have abnormal sodium homoeostasis. The study was undertaken to quantify the sodium transport across the plasma membrane of red blood cells (RBC) in patients with cirrhosis. RBC efflux and influx of sodium were studied in vitro with tracer (22) Na(+) according...... to linear kinetics in 24 patients with cirrhosis and 14 healthy controls. The sodium efflux was modified by ouabain (O), furosemide (F) and a combination of O and F (O + F). RBC sodium was significantly decreased (4·6 versus control 6·3 mmol l(-1) , Psodium (r = 0·57, P......sodium efflux was higher in patients with cirrhosis (+46%, Psodium buffers showed that the F-insensitive sodium efflux was twice as high in cirrhosis as in controls (P = 0...

Effective Peroxidase-Like Activity of Co-Aminoclay [CoAC] and Its Application for Glucose Detection

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Han Pill Song

2018-02-01

Full Text Available In this study, we describe a novel peroxidase-like activity of Co-aminoclay [CoAC] present at pH ~5.0 and its application to fluorescent biosensor for the determination of H2O2 and glucose. It is synthesized with aminoclays (ACs entrapping cationic metals such as Fe, Cu, Al, Co., Ce, Ni, Mn, and Zn to find enzyme mimicking ACs by sol–gel ambient conditions. Through the screening of catalytic activities by the typical colorimetric reaction employing 2,2′-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic aciddiammonium salt (ABTS as a substrate with or without H2O2, Fe, Cu, and CoACs are found to exhibit peroxidase-like activity, as well as oxidase-like activity was observed from Ce and MnACs. Among them, CoAC shows exceptionally high peroxidase-like activity, presumably due to its ability to induce electron transfer between substrates and H2O2. CoAC is then used to catalyze the oxidation of Amplex® UltraRed (AUR into a fluorescent end product, which enables a sensitive fluorescent detection of H2O2. Moreover, a highly sensitive and selective glucose biosensing strategy is developed, based on enzyme cascade reaction between glucose oxidase (GOx and CoAC. Using this strategy, a highly linear fluorescence enhancement is verified when the concentration of glucose is increased in a wide range from 10 μM to 1 mM with a lower detection limit of 5 μM. The practical diagnostic capability of the assay system is also verified by its use to detect glucose in human blood serum. Based on these results, it is anticipated that CoAC can serve as potent peroxidase mimetics for the detection of clinically important target molecules.

Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA

International Nuclear Information System (INIS)

Permutt, M.A.; Koranyi, L.; Keller, K.; Lacy, P.E.; Scharp, D.W.; Mueckler, M.

1989-01-01

Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-K m , low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. The authors isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus

Thermodynamic and transport properties of sodium liquid and vapor

International Nuclear Information System (INIS)

Fink, J.K.; Leibowitz, L.

1995-01-01

Data have been reviewed to obtain thermodynamically consistent equations for thermodynamic and transport properties of saturated sodium liquid and vapor. Recently published Russian recommendations and results of equation of state calculations on thermophysical properties of sodium have been included in this critical assessment. Thermodynamic properties of sodium liquid and vapor that have been assessed include: enthalpy, heat capacity at constant pressure, heat capacity at constant volume, vapor pressure, boiling point, enthalpy of vaporization, density, thermal expansion, adiabatic and isothermal compressibility, speed of sound, critical parameters, and surface tension. Transport properties of liquid sodium that have been assessed include: viscosity and thermal conductivity. For each property, recommended values and their uncertainties are graphed and tabulated as functions of temperature. Detailed discussions of the analyses and determinations of the recommended equations include comparisons with recommendations given in other assessments and explanations of consistency requirements. The rationale and methods used in determining the uncertainties in the recommended values are also discussed

Use of glucose as reductant to recover Co from spent lithium ions batteries.

Science.gov (United States)

Meng, Qi; Zhang, Yingjie; Dong, Peng

2017-06-01

A hydrometallurgical leaching process has been developed for recovery of Co and Li from cathode material (LiCoO 2 ) collected from spent LIBs using a mix solution of glucose and phosphoric acid. The spent LiCoO 2 before and after leaching process are analyzed by scanning electron microscopy. A leaching rate of about 98% Co and nearly 100% Li is presented with 1.5mol/L phosphoric acid and 0.02mol/L glucose at 80°C in about 2h. During leaching process, glucose was oxidized into monocarboxylic acid with reduction of Co(III) to Co(II). Co in solution was recovered as Co-oxalate after leaching process. Using glucose as reductant to dissolve LiCoO 2 with chelating agent of phosphoric acid is achieved here. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

Science.gov (United States)

Fidler, Trevor P; Middleton, Elizabeth A; Rowley, Jesse W; Boudreau, Luc H; Campbell, Robert A; Souvenir, Rhonda; Funari, Trevor; Tessandier, Nicolas; Boilard, Eric; Weyrich, Andrew S; Abel, E Dale

2017-09-01

On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets. Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on α-granule membranes and under basal conditions facilitates glucose uptake into α-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased α-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis. GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes α-granule release, platelet activation, and postactivation functions. © 2017 American Heart Association, Inc.

Aspergillus niger membrane-associated proteome analysis for the identification of glucose transporters.

Science.gov (United States)

Sloothaak, J; Odoni, D I; de Graaff, L H; Martins Dos Santos, V A P; Schaap, P J; Tamayo-Ramos, J A

2015-01-01

The development of biological processes that replace the existing petrochemical-based industry is one of the biggest challenges in biotechnology. Aspergillus niger is one of the main industrial producers of lignocellulolytic enzymes, which are used in the conversion of lignocellulosic feedstocks into fermentable sugars. Both the hydrolytic enzymes responsible for lignocellulose depolymerisation and the molecular mechanisms controlling their expression have been well described, but little is known about the transport systems for sugar uptake in A. niger. Understanding the transportome of A. niger is essential to achieve further improvements at strain and process design level. Therefore, this study aims to identify and classify A. niger sugar transporters, using newly developed tools for in silico and in vivo analysis of its membrane-associated proteome. In the present research work, a hidden Markov model (HMM), that shows a good performance in the identification and segmentation of functionally validated glucose transporters, was constructed. The model (HMMgluT) was used to analyse the A. niger membrane-associated proteome response to high and low glucose concentrations at a low pH. By combining the abundance patterns of the proteins found in the A. niger plasmalemma proteome with their HMMgluT scores, two new putative high-affinity glucose transporters, denoted MstG and MstH, were identified. MstG and MstH were functionally validated and biochemically characterised by heterologous expression in a S. cerevisiae glucose transport null mutant. They were shown to be a high-affinity glucose transporter (K m = 0.5 ± 0.04 mM) and a very high-affinity glucose transporter (K m = 0.06 ± 0.005 mM), respectively. This study, focusing for the first time on the membrane-associated proteome of the industrially relevant organism A. niger, shows the global response of the transportome to the availability of different glucose concentrations. Analysis of the A. niger

Seeking effective dyes for a mediated glucose-air alkaline battery/fuel cell

Science.gov (United States)

Eustis, Ross; Tsang, Tsz Ming; Yang, Brigham; Scott, Daniel; Liaw, Bor Yann

2014-02-01

A significant level of power generation from an abiotic, air breathing, mediated reducing sugar-air alkaline battery/fuel cell has been achieved in our laboratories at room temperature without complicated catalysis or membrane separation in the reaction chamber. Our prior studies suggested that mass transport limitation by the mediator is a limiting factor in power generation. New and effective mediators were sought here to improve charge transfer and power density. Forty-five redox dyes were studied to identify if any can facilitate mass transport in alkaline electrolyte solution; namely, by increasing the solubility and mobility of the dye, and the valence charge carried per molecule. Indigo dyes were studied more closely to understand the complexity involved in mass transport. The viability of water-miscible co-solvents was also explored to understand their effect on solubility and mass transport of the dyes. Using a 2.0 mL solution, 20% methanol by volume, with 100 mM indigo carmine, 1.0 M glucose and 2.5 M sodium hydroxide, the glucose-air alkaline battery/fuel cell attained 8 mA cm-2 at short-circuit and 800 μW cm-2 at the maximum power point. This work shall aid future optimization of mediated charge transfer mechanism in batteries or fuel cells.

Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

Science.gov (United States)

Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.

2012-01-01

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363

Effects of sodium bicarbonate on the end-tidal CO2, PaCO2, HCO3-, PH and cerebral blood flow

International Nuclear Information System (INIS)

Komatani, Akio; Akutsu, Tooru; Yoshida, Michihiko; Yamaguchi, Koichi; Seo, Hiroshi

1992-01-01

To estimate the quantitative reactivity of cerebral blood flow (CBF), the effects of sodium bicarbonate on the end-tidal CO 2 , arterial partial pressure of CO 2 (PaCO 2 ), HCO 3 - , pH and CBF were examined. The CBF was measured by 133 Xe inhalation method with ring type SPECT (HEADTOME). Activation study with sodium bicarbonate administration was performed after 30 minutes of resting study, and the reactivity of each parameters was investigated. The arterial HCO 3 - and pH increased with similar reactivity, but PaCO 2 , end-tidal CO 2 and CBF in the non-injured hemisphere changed with irregular reactivity. The excellent correlation between PaCO 2 and end-tidal CO 2 was vanished by the administration of sodium bicarbonate. The reactivity of CBF did not correlate with reactivity of PaCO 2 and end-tidal CO 2 , but correlated with arterial HCO 3 - and pH. Thus the measurement of arterial HCO 3 - and pH may be indispensable to estimate the CBF reactivity with the administration of sodium bicarbonate. (author)

Facile synthesis of ultrafine Co{sub 3}O{sub 4} nanocrystals embedded carbon matrices with specific skeletal structures as efficient non-enzymatic glucose sensors

Energy Technology Data Exchange (ETDEWEB)

Li, Mian; Han, Ce; Zhang, Yufan; Bo, Xiangjie, E-mail: baoxj133@nenu.edu.cn; Guo, Liping, E-mail: guolp078@nenu.edu.cn

2015-02-25

Highlights: • Novel hyperfine Co{sub 3}O{sub 4} nanocrystals decorated porous carbon matrixes. • Facile synthesis without use of any harmful dispersing reagents or surfactants. • High dispersion degree of Co{sub 3}O{sub 4} nanocrystals and excellent e{sup −} transport rates. • A large current sensitivity of 955.9 μA cm{sup −2} mM{sup −1} toward glucose. • Excellent anti-interference and stability for glucose detection. - Abstract: A facile, effective, and environmentally friendly method has been adopted for the first time to prepare tiny Co{sub 3}O{sub 4} nanocrystals embedded carbon matrices without using surfactants, harmful organic reagents or extreme conditions. Structural characterizations reveal that the size-controlled Co{sub 3}O{sub 4} nanocrystals are uniformly dispersed on carbon matrices. Electrochemical measurements reveal that Co{sub 3}O{sub 4}-ordered mesoporous carbon (OMC) can more efficiently catalyze glucose oxidation and acquire better detection parameters compared with those for the Co{sub 3}O{sub 4}-macroporous carbon, Co{sub 3}O{sub 4}-reduced graphene oxide, and free Co{sub 3}O{sub 4} nanoparticles (NPs) (such as: the large sensitivity (2597.5 μA cm{sup −2} mM{sup −1} between 0 and 0.8 mM and 955.9 μA cm{sup −2} mM{sup −1} between 0.9 and 7.0 mM), fast response time, wide linear range, good stability, and surpassingly selective capability to electroactive molecules or Cl{sup −}). Such excellent performances are attributed to the synergistic effect of the following three factors: (1) the high catalytic sites provided by the uniformly dispersed and size-controlled Co{sub 3}O{sub 4} nanocrystals embedded on OMC; (2) the excellent reactant transport efficiency caused by the abundant mesoporous structures of OMC matrix: (3) the improved electron transport in high electron transfer rate (confinement of the Co{sub 3}O{sub 4} NPs in nanoscale spaces ensured intimate contact between Co{sub 3}O{sub 4} nanocrystals and the

Preparation and Characterization of Nanoparticles Made from Co-Incubation of SOD and Glucose

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Liping Cai

2017-12-01

Full Text Available The attractive potential of natural superoxide dismutase (SOD in the fields of medicine and functional food is limited by its short half-life in circulation and poor permeability across the cell membrane. The nanoparticle form of SOD might overcome these limitations. However, most preparative methods have disadvantages, such as complicated operation, a variety of reagents—some of them even highly toxic—and low encapsulation efficiency or low release rate. The aim of this study is to present a simple and green approach for the preparation of SOD nanoparticles (NPs by means of co-incubation of Cu/Zn SOD with glucose. This method was designed to prepare nanoscale aggregates based on the possible inhibitory effect of Maillard reaction on heating-induced aggregation during the co-incubation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE results indicated that the Maillard reaction occurred during the co-incubation process. It was found that enzymatically active NPs of Cu/Zn SOD were simultaneously generated during the reaction, with an average particle size of 175.86 ± 0.71 nm, and a Zeta potential of −17.27 ± 0.59 mV, as established by the measurement of enzymatic activity, observations using field emission scanning electron microscope, and analysis of dynamic light scattering, respectively. The preparative conditions for the SOD NPs were optimized by response surface design to increase SOD activity 20.43 fold. These SOD NPs showed storage stability for 25 days and better cell uptake efficacy than natural SOD. Therefore, these NPs of SOD are expected to be a potential drug candidate or functional food factor. To our knowledge, this is the first report on the preparation of nanoparticles possessing the bioactivity of the graft component protein, using the simple and green approach of co-incubation with glucose, which occurs frequently in the food industry during thermal processing.

Renoprotective Effects of SGLT2 Inhibitors: Beyond Glucose Reabsorption Inhibition.

Science.gov (United States)

Tsimihodimos, V; Filippatos, T D; Filippas-Ntekouan, S; Elisaf, M

2017-01-01

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain

Science.gov (United States)

Marin-Valencia, Isaac; Good, Levi B; Ma, Qian; Malloy, Craig R; Pascual, Juan M

2013-01-01

It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-13C3]heptanoate was examined in the normal mouse brain and in G1D by 13C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism. PMID:23072752

Sugar transporter genes of the brown planthopper, Nilaparvata lugens: A facilitated glucose/fructose transporter.

Science.gov (United States)

Kikuta, Shingo; Kikawada, Takahiro; Hagiwara-Komoda, Yuka; Nakashima, Nobuhiko; Noda, Hiroaki

2010-11-01

The brown planthopper (BPH), Nilaparvata lugens, attacks rice plants and feeds on their phloem sap, which contains large amounts of sugars. The main sugar component of phloem sap is sucrose, a disaccharide composed of glucose and fructose. Sugars appear to be incorporated into the planthopper body by sugar transporters in the midgut. A total of 93 expressed sequence tags (ESTs) for putative sugar transporters were obtained from a BPH EST database, and 18 putative sugar transporter genes (Nlst1-18) were identified. The most abundantly expressed of these genes was Nlst1. This gene has previously been identified in the BPH as the glucose transporter gene NlHT1, which belongs to the major facilitator superfamily. Nlst1, 4, 6, 9, 12, 16, and 18 were highly expressed in the midgut, and Nlst2, 7, 8, 10, 15, 17, and 18 were highly expressed during the embryonic stages. Functional analyses were performed using Xenopus oocytes expressing NlST1 or 6. This showed that NlST6 is a facilitative glucose/fructose transporter that mediates sugar uptake from rice phloem sap in the BPH midgut in a manner similar to NlST1. Copyright © 2010 Elsevier Ltd. All rights reserved.

AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

Science.gov (United States)

de Laat, M A; Robinson, M A; Gruntmeir, K J; Liu, Y; Soma, L R; Lacombe, V A

2015-09-01

Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P managing IR requires investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Proton Transport Chains in Glucose Metabolism: Mind the Proton

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Dirk Roosterman

2018-06-01

Full Text Available The Embden–Meyerhof–Parnas (EMP pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CH3CH(OHCOOH]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CH3COCOO-. We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway. In this review, we consider the flow of metabolites to be coupled to a flow of energy that is irreversible and sufficient to form ordered structures. This latter principle is highlighted by discussing that lactate dehydrogenase (LDH complexes irreversibly reduce pyruvate/H+ to lactate [CH3CH(OHCOO-], or irreversibly catalyze the opposite reaction, oxidation of lactate to pyruvate/H+. However, both LDH complexes are considered to be driven by postulated proton transport chains. Metabolism of glucose to two lactic acids is introduced as a unidirectional, continuously flowing pathway. In an organism, cell membrane-located proton-linked monocarboxylate transporters catalyze the final step of glycolysis, the release of lactic acid. Consequently, both pyruvate and lactate are discussed as intermediate products of glycolysis and substrates of regulated crosscuts of the glycolytic flow.

Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

Science.gov (United States)

Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

2014-01-01

The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes.

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

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García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W; Pfluger, Paul T; Fernandez, Ana M; Luquet, Serge; Woods, Stephen C; Torres-Alemán, Ignacio; Kahn, C Ronald; Götz, Magdalena; Horvath, Tamas L; Tschöp, Matthias H

2016-08-11

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB. Copyright © 2016 Elsevier Inc. All rights reserved.

A Glimpse of Membrane Transport through Structures-Advances in the Structural Biology of the GLUT Glucose Transporters.

Science.gov (United States)

Yan, Nieng

2017-08-18

The cellular uptake of glucose is an essential physiological process, and movement of glucose across biological membranes requires specialized transporters. The major facilitator superfamily glucose transporters GLUTs, encoded by the SLC2A genes, have been a paradigm for functional, mechanistic, and structural understanding of solute transport in the past century. This review starts with a glimpse into the structural biology of membrane proteins and particularly membrane transport proteins, enumerating the landmark structures in the past 25years. The recent breakthrough in the structural elucidation of GLUTs is then elaborated following a brief overview of the research history of these archetypal transporters, their functional specificity, and physiological and pathophysiological significances. Structures of GLUT1, GLUT3, and GLUT5 in distinct transport and/or ligand-binding states reveal detailed mechanisms of the alternating access transport cycle and substrate recognition, and thus illuminate a path by which structure-based drug design may be applied to help discover novel therapeutics against several debilitating human diseases associated with GLUT malfunction and/or misregulation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Properties of the Sodium Naproxen-Lactose-Tetrahydrate Co-Crystal upon Processing and Storage

DEFF Research Database (Denmark)

Sovago, Ioana; Wang, Wenbo; Qiu, Danwen

2016-01-01

naproxen-lactose-tetrahydrate co-crystal and the co-amorphous mixture of sodium, naproxen, and lactose was investigated. The structure of the co-crystal is described using single-crystal X-ray diffraction. The structural analysis revealed a monoclinic lattice, space group P21, with the asymmetric unit...... containing one molecule of lactose, one of naproxen, sodium, and four water molecules. Upon heating, it was observed that the co-crystal transforms into a co-amorphous system due to the loss of its crystalline bound water. Dehydration and co-amorphization were studied using synchrotron X-ray radiation...... and thermogravimetric analysis (TGA). Subsequently, different processing techniques (ball milling, spray drying, and dehydration) were used to prepare the co-amorphous mixture of sodium, naproxen, and lactose. X-ray powder diffraction (XRPD) revealed the amorphous nature of the mixtures after preparation. Differential...

Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1

DEFF Research Database (Denmark)

Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian

2015-01-01

-stimulated glucose transport and signaling is unknown. We therefore investigated whether stretch-induced glucose transport in skeletal muscle required Rac1 and the actin cytoskeleton. We used muscle specific inducible Rac1 knockout mice as well as pharmacological inhibitors of Rac1 and the actin cytoskeleton...

Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I.

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Marc U Baumann

Full Text Available Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

Differentiation of the insulin-sensitive glucose transporter in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Frost, S.C.; Baly, D.L.; Cushman, S.W.; Lane, M.D.; Simpson, I.A.

1986-01-01

3T3-L1 fibroblasts differentiate in culture to resemble adipocytes both morphologically and biochemically. Insulin-sensitive glucose transport, as measured by 2-deoxy-[1- 14 C]- glucose uptake in the undifferentiated cell is small (2X). In contrast, the rate of glucose transport in fully differentiated cells is elevated 15-fold over basal in the presence of insulin. To determine if this is due to an increase in the number of transporters/cell or accessibility to the transporters, the number of transporters was measured in subcellular fractions over differentiation using a 3 H-cytochalasin B binding assay. The increase in the rate of insulin-sensitive glucose transport directly parallels an increase in the number of transporters which reside in an insulin-responsive intracellular compartment. This observation was confirmed by identifying the transporters by immunoblotting using an antibody generated against the human erythrocyte transporter. The molecular weight of this transporter increases over differentiation from a single band of 40kDa to a heterogeneous triplet of 40, 44 and 48kDa. These data suggest that the transporter undergoes differential processing and that the functional, insulin-responsive transporter may be different from the insulin-insensitive (basal) transporter

Sodium-glucose cotransporter 2 inhibitor use: A pharmaco-ergonomic qualification tool

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Sanjay Kalra

2017-01-01

Full Text Available Pharmaco-ergonomics implies tailoring the drug therapy to an individual patient's requirement(s. The development of sodium-glucose cotransporter 2 inhibitor (SGLT2-i agents has impelled multiple clinical considerations, in the management of type-2 diabetes. This paper attempts to summarize the pharmaco-ergonomic considerations for these agents, in the form of an SGLT2-i qualification tool, based on a clinical score. This tool may serve as a simple and inexpensive practical guide, to optimize the risk-benefit considerations for SGLT2-i agents.

Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

International Nuclear Information System (INIS)

Blomqvist, G.; Widen, L.; Hellstrand, E.; Gutniak, M.; Grill, V.

1991-01-01

The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using D-glucose 11 C(ul) as tracer. To rule out any effects of insulin, the plasma insulin concentration was maintained at the same level under normo- and hypoglycaemic conditions. Reduction of blood glucose by 55% increased the glucose clearance through the blood-brain barrier by 50% and reduced brain glucose consumption by 40%. Blood flow was not affected. The results are consistent with facilitated transport of glucose from blood to brain in humans. The maximal transport rate of glucose from blood to brain was found to be 62±19 (mean±SEM) μmol hg -1 min -1 , and the half-saturation constant was found to be 4.1±3.2 mM. (orig.)

Glucose & sodium chloride induced biofilm production & ica operon in clinical isolates of staphylococci

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Astha Agarwal

2013-01-01

Full Text Available Background & objectives: All colonizing and invasive staphylococcal isolates may not produce biofilm but may turn biofilm producers in certain situations due to change in environmental factors. This study was done to test the hypothesis that non biofilm producing clinical staphylococci isolates turn biofilm producers in presence of sodium chloride (isotonic and high concentration of glucose, irrespective of presence or absence of ica operon. Methods: Clinical isolates of 100 invasive, 50 colonizing and 50 commensal staphylococci were tested for biofilm production by microtiter plate method in different culture media (trypticase soy broth alone or supplemented with 0.9% NaCl/ 5 or 10% glucose. All isolates were tested for the presence of ica ADBC genes by PCR. Results: Biofilm production significantly increased in the presence of glucose and saline, most, when both glucose and saline were used together. All the ica positive staphylococcal isolates and some ica negative isolates turned biofilm producer in at least one of the tested culture conditions. Those remained biofilm negative in different culture conditions were all ica negative. Interpretation & conclusions: The present results showed that the use of glucose or NaCl or combination of both enhanced biofilm producing capacity of staphylococcal isolates irrespective of presence or absence of ica operon.

Expression of Na⁺/HCO3^- co-transporter proteins (NBCs) in rat and human skeletal muscle

DEFF Research Database (Denmark)

Kristensen, Jonas Møller; Kristensen, Michael; Juel, Carsten

2004-01-01

AIM: Sodium/bicarbonate co-transport (NBC) has been suggested to have a role in muscle pH regulation. We investigated the presence of NBC proteins in rat and human muscle samples and the fibre type distribution of the identified NBCs. METHODS AND RESULTS: Western blotting of muscle homogenates...... the T-tubules. The two NBCs localized in muscle have distinct fibre type distributions. CONCLUSIONS: Skeletal muscle possesses two variants of the sodium/bicarbonate co-transporter (NBC) isoforms, which have been called NBCe1 and NBCe2....... and sarcolemmal membranes (sarcolemmal giant vesicles) were used to screen for the presence of NBCs. Immunohistochemistry was used for the subcellular localization. The functional test revealed that approximately half of the pH recovery in sarcolemmal vesicles produced from rat muscle is mediated by bicarbonate...

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

Science.gov (United States)

Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

2017-01-01

The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

Sodium Glucose Cotransporter 2 (SGLT2 Plays as a Physiological Glucose Sensor and Regulates Cellular Contractility in Rat Mesangial Cells.

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Masanori Wakisaka

Full Text Available Mesangial cells play an important role in regulating glomerular filtration by altering their cellular tone. We report the presence of a sodium glucose cotransporter (SGLT in rat mesangial cells. This study in rat mesangial cells aimed to evaluate the expression and role of SGLT2.The SGLT2 expression in rat mesangial cells was assessed by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR. Changes in the mesangial cell surface area at different glucose concentrations and the effects of extracellular Na+ and Ca2+ and of SGLT and Na+/Ca2+ exchanger (NCX inhibitors on cellular size were determined. The cellular sizes and the contractile response were examined during a 6-day incubation with high glucose with or without phlorizin, an SGLT inhibitor.Western blotting revealed an SGLT2 band, and RT-PCR analysis of SGLT2 revealed the predicted 422-bp band in both rat mesangial and renal proximal tubular epithelial cells. The cell surface area changed according to the extracellular glucose concentration. The glucose-induced contraction was abolished by the absence of either extracellular Na+ or Ca2+ and by SGLT and NCX inhibitors. Under the high glucose condition, the cell size decreased for 2 days and increased afterwards; these cells did not contract in response to angiotensin II, and the SGLT inhibitor restored the abolished contraction.These data suggest that SGLT2 is expressed in rat mesangial cells, acts as a normal physiological glucose sensor and regulates cellular contractility in rat mesangial cells.

Co-precipitation and solubility studies of cesium, potassium and sodium tetraphenylborate

International Nuclear Information System (INIS)

Peterson, R.A.

1999-01-01

This report contains the results from a study requested by High Level Waste Division on the co-precipitation and solubility of cesium, potassium, and sodium tetraphenylborate. Co-precipitation of cesium (Cs), potassium (K), and sodium (Na) tetraphenylborate (TPB) helps determine the efficiency of reagent usage in the Small Tank Precipitation Process. This process uses NaTPB to remove cesium from waste by means of precipitation. Previous studies by McCabe suggested that if the sodium ion concentration [Na+] increased the rate at which cesium tetraphenylborate (KTPB) in the presence of high [Na+] (∼5M) appears to produce a mixed solid phase composed of NaTPB and KTPB together in the crystal lattice

Effect of physical training on glucose transporter protein and mRNA levels in rat adipocytes

DEFF Research Database (Denmark)

Stallknecht, B; Andersen, P H; Vinten, J

1993-01-01

Physical training increases insulin-stimulated glucose transport and the number of glucose transporters in adipocytes measured by cytochalasin B binding. In the present study we used immunoblotting to measure the abundance of two glucose transporters (GLUT-4, GLUT-1) in white adipocytes from....../or intrinsic activity). GLUT-1 protein and mRNA levels/adipocyte volume did not change with age or training....

Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake.

Science.gov (United States)

Karim, Sumera; Liaskou, Evaggelia; Fear, Janine; Garg, Abhilok; Reynolds, Gary; Claridge, Lee; Adams, David H; Newsome, Philip N; Lalor, Patricia F

2014-12-15

Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease. Copyright © 2014 the American Physiological Society.

Salivary pH after a glucose rinse: effect of a new mucoadhesive spray (Cariex) based on sodium bicarbonate and xylitol.

Science.gov (United States)

Abbate, G M; Levrini, L; Caria, M P

2014-01-01

This study evaluated whether sodium bicarbonate applied on the oral mucosa through a new mucoadhesive spray (Cariex) could control a drop in salivary pH after a glucose rinse, and therefore enhance the buffering potential of saliva. A sample of 50 healthy adults was selected. At day 1, the measurement of salivary pH was performed in the lower fornix in correspondence with the lower molars. Each subject rinsed with 10 ml of a 10% glucose solution and then pH was monitored continually for 40 minutes. At day 2, the same experimental procedure was repeated and three shots of the spray were administered on the oral mucosa. The tested spray is composed of sodium bicarbonate, xylitol, and excipients. Without the mucoadhesive spray, salivary pH became significantly lower following the glucose rinse (p pH remained lower than 6.0 was reduced statistically significantly (p salivary pH was observed for the 40 minutes in which the pH recording was performed. Conclusions: The use of a sodium bicarbonate spray on the mucosa was shown to control the lowering of salivary pH following carbohydrate consumption, and might therefore add to the prevention of caries and dental erosion.

Study of dynamics of glucose-glucose oxidase-ferricyanide reaction

Science.gov (United States)

Nováková, A.; Schreiberová, L.; Schreiber, I.

2011-12-01

This work is focused on dynamics of the glucose-glucose oxidase-ferricyanide enzymatic reaction with or without sodium hydroxide in a continuous-flow stirred tank reactor (CSTR) and in a batch reactor. This reaction exhibits pH-variations having autocatalytic character and is reported to provide nonlinear dynamic behavior (bistability, excitability). The dynamical behavior of the reaction was examined within a wide range of inlet parameters. The main inlet parameters were the ratio of concentrations of sodium hydroxide and ferricyanide and the flow rate. In a batch reactor we observed an autocatalytic drop of pH from slightly basic to medium acidic values. In a CSTR our aim was to find bistability in the presence of sodium hydroxide. However, only a basic steady state was found. In order to reach an acidic steady state, we investigated the system in the absence of sodium hydroxide. Under these conditions the transition from the basic to the acidic steady state was observed when inlet glucose concentration was increased.

Inhibition by nucleosides of glucose-transport activity in human erythrocytes.

OpenAIRE

Jarvis, S M

1988-01-01

The interaction of nucleosides with the glucose carrier of human erythrocytes was examined by studying the effect of nucleosides on reversible cytochalasin B-binding activity and glucose transport. Adenosine, inosine and thymidine were more potent inhibitors of cytochalasin B binding to human erythrocyte membranes than was D-glucose [IC50 (concentration causing 50% inhibition) values of 10, 24, 28 and 38 mM respectively]. Moreover, low concentrations of thymidine and adenosine inhibited D-glu...

Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.

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Ali Ashek

Full Text Available Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage. Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.

Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency.

Science.gov (United States)

Akman, Cigdem Inan; Provenzano, Frank; Wang, Dong; Engelstad, Kristin; Hinton, Veronica; Yu, Julia; Tikofsky, Ronald; Ichese, Masonari; De Vivo, Darryl C

2015-02-01

(18)F fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using (18)F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism. (18)F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results. Visual analysis of the (18)F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score. Quantitative analysis of (18)F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy. Copyright © 2014. Published by Elsevier B.V.

Increased Urinary Extracellular Vesicle Sodium Transporters in Cushing's Syndrome with Hypertension.

Science.gov (United States)

Salih, Mahdi; Bovée, Dominique M; van der Lubbe, Nils; Danser, Alexander H J; Zietse, Robert; Feelders, Richard A; Hoorn, Ewout J

2018-05-02

Increased renal sodium reabsorption contributes to hypertension in Cushing's syndrome (CS). Renal sodium transporters can be analyzed non-invasively in urinary extracellular vesicles (uEVs). To analyze renal sodium transporters in uEVs of patients with CS and hypertension. Observational study. University hospital. uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 CS patients and 7 age-matched healthy subjects. In 7 CS patients uEVs were analyzed before and after treatment. uEV protein abundance. The 10 CS patients were divided in those with suppressed and non-suppressed renin-angiotensin-aldosterone system (RAAS, n = 5/group). CS patients with suppressed RAAS had similar blood pressure but significantly lower serum potassium than CS patients with non-suppressed RAAS. Compared to healthy subjects, only those with suppressed RAAS had higher phosphorylated Na+-K+-Cl- cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl- cotransporter (NCC) in uEVs. Serum potassium but not urinary free cortisol correlated with pNKCC2, pNCC, and NCC in uEVs. Treatment of CS reversed the increases in pNKCC2, NCC, and pNCC. CS increases renal sodium transporter abundance in uEVs especially in patients with hypertension and suppressed RAAS. As potassium has recently been identified as an important driver of NCC activity, low serum potassium may also contribute to increased renal sodium reabsorption and hypertension in CS. These results may also be relevant for hypertension induced by exogenous glucocorticoids.

Insulin, concanavalin A, EGF, IFG-I and vanadate activate de novo phosphatidic acid and diacylglycerol synthesis, C-kinase, and glucose transport in BC3H-1 myocytes

International Nuclear Information System (INIS)

Cooper, D.R.; Hernandez, H.; Konda, T.S.; Standaert, M.S.; Pollet, R.J.; Farese, R.V.

1987-01-01

The authors have reported that insulin stimulates de novo synthesis of phosphatidic acid (PA) which is metabolized directly to diacylglycerol (DG) in BS3H-1 myocytes; this is accompanied by increases in C-kinase activity in membrane and cytosolic extracts. This pathway may be involved in stimulating glucose transport and other metabolic processes. In this study, the authors have compared the effects of concanavalin A, EGF, IGF-I and sodium orthovanadate to insulin on PA/DG synthesis, C-kinase activity and glucose transport. All were found to be effective in stimulating glucose transport. Additionally, all activators rapidly increased the incorporation of [ 3 H]glycerol into DG and total glycerolipids, although none were as effective as insulin, which increased [ 3 H]DG 400% in 1 minute. Increased incorporation into phospholipids and triacylglycerols and to a lesser extent monoacylglycerol was also noted. They examined effects of concanavalin A and EGF on C-kinase activity and found that both agonists, like insulin, increase C-kinase activity in cytosolic and/or membrane fractions. Their findings raise the possibility that activation of receptors having associated tyrosine kinase activity may provoke some cellular responses through de novo PA/GD synthesis and C-kinase activation

Development of computer code on sodium-water reaction products transport

International Nuclear Information System (INIS)

Arikawa, H.; Yoshioka, N.; Suemori, M.; Nishida, K.

1988-01-01

The LMFBR concept eliminating the secondary sodium system has been considered to be one of the most promissing concepts for offering cost reductions. In this reactor concept, the evaluation of effects on reactor core by the sodium-water reaction products (SWRPs) during sodium-water reaction at primary steam generator becomes one of the major safety issues. In this study, the calculation code was developed as the first step of the processes of establishing the evaluation method for SWRP effects. The calculation code, called SPROUT, simulates the SWRPs transport and distribution in primary sodium system using the system geometry, thermal hydraulic data and sodium-water reacting conditions as input. This code principally models SWRPs behavior. The paper contain the modelings for SWRPs behaviors, with solution, precipation, deposition and so on, and the results and discussions of the demonstration calculation for a typical FBR plant eliminating the secondary sodium system

Role of vitamin D on the expression of glucose transporters in L6 myotubes

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Bubblu Tamilselvan

2013-01-01

Full Text Available Altered expression of glucose transporters is a major characteristic of diabetes. Vitamin D has evolved widespread interest in the pathogenesis and prevention of diabetes. The present study was designed to investigate the effect of vitamin D in the overall regulation of muscle cell glucose transporter expression. L6 cells were exposed to type 1 and type 2 diabetic conditions and the effect of calcitriol (1,25, dihydroxy cholicalciferol on the expression of glucose transporters was studied by real time polymerase chain reaction (RT-PCR. There was a significant decrease in glucose transporter type 1 (GLUT1, GLUT4, vitamin D receptor (VDR, and IR expression in type 1 and 2 diabetic model compared to control group. Treatment of myoblasts with 10-7 M calcitriol for 24 h showed a significant increase in GLUT1, GLUT4, VDR, and insulin receptor (IR expression. The results indicate a potential antidiabetic function of vitamin D on GLUT1, GLUT4, VDR, and IR by improving receptor gene expression suggesting a role for vitamin D in regulation of expression of the glucose transporters in muscle cells.

Enhanced glucose yield and structural characterization of corn stover by sodium carbonate pretreatment.

Science.gov (United States)

Kim, Ilgook; Rehman, Muhammad Saif Ur; Han, Jong-In

2014-01-01

Na2CO3 was employed as an efficient yet cheap alkaline catalyst for the pretreatment of corn stover. To systematically obtain an optimal condition, the effects of critical pretreatment parameters including Na2CO3 concentration (2-6%), temperature (120-160 °C), and reaction time (10-30 min) on glucose yield were evaluated in lab-scale using response surface methodology. The best conditions were found to be Na2CO3 of 4.1%, temperature of 142.6 °C, and reaction time of 18.0 min, under which glucose yield reached to 267.5 g/kg biomass. Physical properties, based on scanning electron microscopy (SEM) imagery, surface area, pore volume and size, and crystallinity of pretreated corn stover, were examined. The Na2CO3 pretreatment apparently damaged the surface and altered structural features of corn stover, which resulted in the enhancement of enzymatic of hydrolysis. These results evidently support that Na2CO3 is indeed a robust and feasible catalyst for pretreating lignocellulosic biomass. Copyright © 2013 Elsevier Ltd. All rights reserved.

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle.

Science.gov (United States)

Cervone, Daniel T; Dyck, David J

2017-07-01

Emerging evidence implicates ghrelin, a gut-derived, orexigenic hormone, as a potential mediator of insulin-responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin-stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin-stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser 473 AKT or Thr 172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin-dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle. © 2017 The

Glucose, epithelium, and enteric nervous system: dialogue in the dark.

Science.gov (United States)

Pfannkuche, H; Gäbel, G

2009-06-01

The gastrointestinal epithelium is in close contact with the various components of the chymus, including nutrients, bacteria and toxins. The epithelial barrier has to decide which components are effectively absorbed and which components are extruded. In the small intestine, a nutrient like glucose is mainly absorbed by the sodium linked glucose cotransporter 1 (SGLT1) and the glucose transporter 2 (GLUT2). The expression and activity of both transport proteins is directly linked to the amount of intraluminal glucose. Besides the direct interaction between glucose and the enterocytes, glucose also stimulates different sensory mechanisms within the intestinal wall. The most important types of cells involved in the sensing of intraluminal contents are enteroendocrine cells and neurones of the enteric nervous system. Regarding glucosensing, a distinct type of enteroendocrine cells, the enterochromaffine (EC) cells are involved. Excitation of EC cells by intraluminal glucose results in the release of serotonin (5-HT), which modulates epithelial functions and activates enteric secretomotorneurones. Enteric neurones are not only activated by 5-HT, but also directly by glucose. The activation of different cell types and the subsequent crosstalk between these cells may trigger appropriate absorptive and secretory processes within the intestine.

Preliminary Studies of Two-Phase Reactive Process of Sodium-CO2 in S-CO2 Power Conversion Cycle Coupled to SFR System

International Nuclear Information System (INIS)

Jung, Hwa Young; Ahn, Yoon Han; Lee, You Ho; Lee, Jeong Ik

2013-01-01

As a competing alternative to the steam Rankine cycle, the supercritical CO 2 (S-CO 2 ) Brayton cycle has been highlighted due to its high thermal efficiency, compact turbomachinery and heat exchangers sizes, and the reduced risk of SWRs. While the reduced risk of an SWR is considered as the one of most pronounced benefits of S-CO 2 Brayton cycle, there is still an interaction problem between liquid sodium and CO 2 . Although the chemical interaction between liquid sodium and CO 2 demonstrates less serious potential risks than those of a SWR, the Na/CO 2 interaction should be understood to evaluate safety and reliability of Intermediate Heat eXchanger (IHX). A noticeable characteristic of the reaction environment is that there is a large pressure difference between the liquid sodium and CO 2 side by about 1 and 200 bar, respectively. This would imply that the presence of a micro-crack in a heat exchanger tube will cause a high-pressure leak of CO 2 into liquid sodium side. Although the Na/CO 2 interaction may play an important role in the safety of the SFR reactor system, there has not yet been any research on understanding Na/CO 2 reaction by leakage through IHX. For this problem, the Korea Advanced Institute of Science and Technology (KAIST) research team is studying the mechanism of CO 2 leakage and Na/CO 2 interaction in more details. The KAIST research team developed the MATLAB code, KAIST H XD, which can be used to design and evaluate performance of a heat exchanger of an S-CO 2 cycle. The size of heat exchanger and the amount of CO 2 in the cycle are calculated from the KAIST H XD code to estimate the amount of reaction products in Na/CO 2 interaction as well as liquid sodium

Synthesis of tremella-like CoS and its application in sensing of hydrogen peroxide and glucose

Energy Technology Data Exchange (ETDEWEB)

Wu, Wenqin; Yu, Beibei [Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Ministry of Education, College of Chemistry & Chemical Engineering, Hubei University, Wuhan 430062 (China); Wu, Huimin, E-mail: whm267@hubu.edu.cn [Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Ministry of Education, College of Chemistry & Chemical Engineering, Hubei University, Wuhan 430062 (China); Wang, Shengfu; Xia, Qinghua [Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Ministry of Education, College of Chemistry & Chemical Engineering, Hubei University, Wuhan 430062 (China); Ding, Yu [College of Chemistry and Materials Science, Hubei Engineering University, Xiaogan 432000 (China)

2017-01-01

Different phases of cobalt sulfides have been fabricated by one-pot hydrothermal method. Comparing all of the prepared materials, and the results revealed that CoS was the most conductive and could accelerate electron transfer. The CoS presented tremella-like and excellent catalytic activities towards hydrogen peroxide and glucose. The sensor based on CoS performed amperometric sensing of hydrogen peroxide in a linear range between 5.00 μM and 14.82 mM. Meanwhile, sensing of glucose with double-linear range, one is between 5.00 μM and 1.10 mM, the other is between 1.20 mM and 10.20 mM. These due to the fact that more and more intermediate species absorb onto electrode surface with increasing the concentration of glucose, which limit the following glucose oxidation. Furthermore, the hydrogen peroxide and glucose sensors based on tremella-like CoS also exhibited excellent selectivity, stability, and reproducibility. Thus, the sensor showed potential utilities in hydrogen peroxide and glucose detection. - Highlights: • Tremella-like CoS was prepared by an environmentally friendly hydrothermal method. • The CoS exhibited excellent catalytic activity towards hydrogen peroxide and glucose. • The sensors based on CoS can be applied to detect real samples.

Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

Directory of Open Access Journals (Sweden)

Vickers SP

2014-07-01

Full Text Available Steven P Vickers,1 Sharon C Cheetham,1 Katie R Headland,1 Keith Dickinson,1 Rolf Grempler,2 Eric Mayoux,2 Michael Mark,2 Thomas Klein2 1RenaSci, BioCity Nottingham, Nottingham, UK; 2Boehringer Ingelheim Pharma, Biberach an der Riss, Germany Abstract: The present study assessed the potential of the sodium glucose-linked transporter (SGLT-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. Keywords

Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

Energy Technology Data Exchange (ETDEWEB)

Tomioka, Shigemasa, E-mail: tomioka@dent.tokushima-u.ac.jp [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Kaneko, Miyuki [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Satomura, Kazuhito [First Department of Oral and Maxillofacial Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Mikyu, Tomiko; Nakajo, Nobuyoshi [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan)

2009-10-09

We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2-{sup 3}H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 {mu}M) significantly increased V{sub max} but not K{sub m} of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

International Nuclear Information System (INIS)

Tomioka, Shigemasa; Kaneko, Miyuki; Satomura, Kazuhito; Mikyu, Tomiko; Nakajo, Nobuyoshi

2009-01-01

We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2- 3 H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 μM) significantly increased V max but not K m of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

Is contraction-stimulated glucose transport feedforward regulated by Ca²⁺?

DEFF Research Database (Denmark)

Jensen, Thomas Elbenhardt; Angin, Yeliz; Sylow, Lykke

2014-01-01

cell types. The literature is contrasted against our recent findings suggesting that SR Ca(2+) release is neither essential nor adequate to stimulate glucose transport in muscle. Instead, feedback signals through AMPK and mechanical stress are likely to account for most of contraction......In many cell types, Ca(2+) signals to increase the movement and surface membrane insertion of vesicles. In skeletal muscle, Ca(2+) is predominantly released from the sarcoplasmic reticulum (SR) to initiate contraction. Sarcoplasmic reticulum Ca(2+) release is widely believed to be a direct......-stimulated glucose transport. A revised working model is proposed, in which muscle glucose transport during contraction is not directly regulated by SR Ca(2+) release but rather responds exclusively to feedback signals activated secondary to cross-bridge cycling and tension development....

Glucose uptake and growth of glucose-limited chemostat cultures of Aspergillus niger and a disruptant lacking MstA, a high-affinity glucose transporter

DEFF Research Database (Denmark)

Jørgensen, Thomas R; vanKuyk, Patricia A; Poulsen, Bjarne R

2007-01-01

This is a study of high-affinity glucose uptake in Aspergillus niger and the effect of disruption of a high-affinity monosaccharide-transporter gene, mstA. The substrate saturation constant (K(s)) of a reference strain was about 15 microM in glucose-limited chemostat culture. Disruption of mst......-affinity uptake system of A. niger. The mstA disruptant and a reference strain were cultivated in glucose-limited chemostat cultures at low, intermediate and high dilution rate (D=0.07 h(-1), 0.14 h(-1) and 0.20 h(-1)). Mycelium harvested from steady-state cultures was subjected to glucose uptake assays...

Glucose metabolism transporters and epilepsy: only GLUT1 has an established role.

Science.gov (United States)

Hildebrand, Michael S; Damiano, John A; Mullen, Saul A; Bellows, Susannah T; Oliver, Karen L; Dahl, Hans-Henrik M; Scheffer, Ingrid E; Berkovic, Samuel F

2014-02-01

The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects

Directory of Open Access Journals (Sweden)

Atsuo Tahara

2016-03-01

Full Text Available The sodium-glucose cotransporter (SGLT 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes.

Effects of the Addition of Glucose, Sodium Bicarbonate, and Vitamin E to the Drinking Water of Pre-Slaughter Broiler Chickens on Carcass Yield, Gastric Emptying and Meat Quality

Directory of Open Access Journals (Sweden)

TG Petrolli

2016-03-01

Full Text Available ABSTRACT An experiment was conducted of the poultry facilities of La Salle Agricultural College in Xanxerê, SC, Brazil, to evaluate the effect of the administration of sodium bicarbonate, glucose and vitamin E to the drinking water during pre-slaughter feed withdrawal on carcass yield, organ relative weights (heart, liver, proventriculus, and gizzard, gizzard emptying, and meat quality of broiler chickens. The applied treatments were: water as control; 50g/L of glucose; 50g/L de glucose + 200mg/L of vitamin E; 75g/L of glucose; 75g/L + 200mg/L of vitamin E; 0.45% of sodium bicarbonate; 0.45% of sodium bicarbonate + 200mg/L of vitamin E; 0.55% of sodium bicarbonate; 0.55% of sodium bicarbonate + 200mg/L of vitamin E; 200mg/L de vitamin E. On the last day before slaughter, during the water diet period,500 birds were distributed in a completely randomized experimental design with ten treatments and ten replicates of five birds each. No difference in broiler carcass yield and organ relative weights was found. There were no significant changes in gizzard contents, in ultimate meat, cooking loss, shear force value, or in the meat color parameters L* (lightness, a* (redness and b* (yellowness. It was concluded is that the addition of glucose, sodium bicarbonate, and vitamin E to the drinking water during pre-slaughter feed withdrawal period has no influence on carcass yield or on relative organ weight, neither on the emptying of the gizzard contents and the meat quality of broiler chickens.

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

Science.gov (United States)

Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

2004-01-01

Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Pnootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Pnootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

N-Methyl-D aspartate receptor-mediated effect on glucose transporter-3 levels of high glucose exposed-SH-SY5Y dopaminergic neurons.

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Engin, Ayse Basak; Engin, Evren Doruk; Karakus, Resul; Aral, Arzu; Gulbahar, Ozlem; Engin, Atilla

2017-11-01

High glucose and insulin lead to neuronal insulin resistance. Glucose transport into the neurons is achieved by regulatory induction of surface glucose transporter-3 (GLUT3) instead of the insulin. N-methyl-D aspartate (NMDA) receptor activity increases GLUT3 expression. This study explored whether an endogenous NMDA receptor antagonist, kynurenic acid (KynA) affects the neuronal cell viability at high glucose concentrations. SH-SY5Y neuroblastoma cells were exposed to 150-250 mg/dL glucose and 40 μU/mL insulin. In KynA and N-nitro-l-arginine methyl ester (L-NAME) supplemented cultures, oxidative stress, mitochondrial metabolic activity (MTT), nitric oxide as nitrite+nitrate (NOx) and GLUT3 were determined at the end of 24 and 48-h incubation periods. Viable cells were counted by trypan blue dye. High glucose-exposed SH-SY5Y cells showed two-times more GLUT3 expression at second 24-h period. While GLUT3-stimulated glucose transport and oxidative stress was increased, total mitochondrial metabolic activity was significantly reduced. Insulin supplementation to high glucose decreased NOx synthesis and GLUT3 levels, in contrast oxidative stress increased three-fold. KynA significantly reduced oxidative stress, and increased MTT by regulating NOx production and GLUT3 expression. KynA is a noteworthy compound, as an endogenous, specific NMDA receptor antagonist; it significantly reduces oxidative stress, while increasing cell viability at high glucose and insulin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Herbivory-induced glucose transporter gene expression in the brown planthopper, Nilaparvata lugens.

Science.gov (United States)

Kikuta, Shingo; Nakamura, Yuki; Hattori, Makoto; Sato, Ryoichi; Kikawada, Takahiro; Noda, Hiroaki

2015-09-01

Nilaparvata lugens, the brown planthopper (BPH) feeds on rice phloem sap, containing high amounts of sucrose as a carbon source. Nutrients such as sugars in the digestive tract are incorporated into the body cavity via transporters with substrate selectivity. Eighteen sugar transporter genes of BPH (Nlst) were reported and three transporters have been functionally characterized. However, individual characteristics of NlST members associated with sugar transport remain poorly understood. Comparative gene expression analyses using oligo-microarray and quantitative RT-PCR revealed that the sugar transporter gene Nlst16 was markedly up-regulated during BPH feeding. Expression of Nlst16 was induced 2 h after BPH feeding on rice plants. Nlst16, mainly expressed in the midgut, appears to be involved in carbohydrate incorporation from the gut cavity into the hemolymph. Nlst1 (NlHT1), the most highly expressed sugar transporter gene in the midgut was not up-regulated during BPH feeding. The biochemical function of NlST16 was shown as facilitative glucose transport along gradients. Glucose uptake activity by NlST16 was higher than that of NlST1 in the Xenopus oocyte expression system. At least two NlST members are responsible for glucose uptake in the BPH midgut, suggesting that the midgut of BPH is equipped with various types of transporters having diversified manner for sugar uptake. Copyright © 2015 Elsevier Ltd. All rights reserved.

CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

Science.gov (United States)

Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

2016-10-04

Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin.

Science.gov (United States)

Bogdanffy, Matthew S; Stachlewitz, Robert F; van Tongeren, Susan; Knight, Brian; Sharp, Dale E; Ku, Warren; Hart, Susan Emeigh; Blanchard, Kerry

2014-01-01

Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose cotransporter 2, was developed for treatment of type 2 diabetes mellitus. Nonclinical safety of empagliflozin was studied in a battery of tests to support global market authorization. Safety pharmacology studies indicated no effect of empagliflozin on measures of respiratory or central nervous system function in rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively, empagliflozin exhibited a toxicity profile consistent with secondary supratherapeutic pharmacology related to glucose loss and included decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and urinary changes such as polyuria and glucosuria. Microscopic changes were consistently observed in kidney and included tubular nephropathy and interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy (mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in female mice or female rats. Renal adenoma and carcinoma were induced in male mice only at exposures 45 times the maximum clinical dose. These tumors were associated with a spectrum of nonneoplastic changes suggestive of a nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male rats, testicular interstitial cell tumors and hemangiomas of the mesenteric lymph node were observed; both tumors are common in rats and are unlikely to be relevant to humans. These studies demonstrate the nonclinical safety of empagliflozin. © The Author(s) 2014.

Endocrine regulation of ion transport in the avian lower intestine

DEFF Research Database (Denmark)

Laverty, Gary; Elbrønd, Vibeke Sødring; Árnason, Sighvatur S.

2006-01-01

The lower intestine (colon and coprodeum) of the domestic fowl maintains a very active, transporting epithelium, with a microvillus brush border, columnar epithelial cells, and a variety of transport systems. The colon of normal or high salt-acclimated hens expresses sodium-linked glucose and amino...

De novo expression of sodium-glucose cotransporter SGLT2 in Bowman's capsule coincides with replacement of parietal epithelial cell layer with proximal tubule-like epithelium.

Science.gov (United States)

Tabatabai, Niloofar M; North, Paula E; Regner, Kevin R; Kumar, Suresh N; Duris, Christine B; Blodgett, Amy B

2014-08-01

In kidney nephron, parietal epithelial cells line the Bowman's capsule and function as a permeability barrier for the glomerular filtrate. Bowman's capsule cells with proximal tubule epithelial morphology have been found. However, the effects of tubular metaplasia in Bowman's capsule on kidney function remain poorly understood. Sodium-glucose cotransporter 2 (SGLT2) plays a major role in reabsorption of glucose in the kidney and is expressed on brush border membrane (BBM) of epithelial cells in the early segment of the proximal tubule. We hypothesized that SGLT2 is expressed in tubularized Bowman's capsule and used our novel antibody to test this hypothesis. Immunohistochemical analysis was performed with our SGLT2 antibody on C57BL/6 mouse kidney prone to have tubularized Bowman's capsules. Cell membrane was examined with periodic acid-Schiff (PAS) stain. The results showed that SGLT2 was localized on BBM of the proximal tubules in young and adult mice. Bowman's capsules were lined mostly with normal brush border-less parietal epithelial cells in young mice, while they were almost completely covered with proximal tubule-like cells in adult mice. Regardless of age, SGLT2 was expressed on BBM of the tubularized Bowman's capsule but did not co-localize with nephrin in the glomerulus. SGLT2-expressing tubular cells expanded from the urinary pole toward the vascular pole of the Bowman's capsule. This study identified the localization of SGLT2 in the Bowman's capsule. Bowman's capsules with tubular metaplasia may acquire roles in reabsorption of filtered glucose and sodium.

Transformation of Sodium Bicarbonate and CO2 into Sodium Formate over NiPd Nanoparticle Catalyst

Science.gov (United States)

Wang, Mengnan; Zhang, Jiaguang; Yan, Ning

2013-09-01

The present research systematically investigated, for the first time, the transformation of sodium bicarbonate and CO2 into sodium formate over a series of Ni based metal nanoparticles (NPs). Ni NPs and eight NiM (M stands for a second metal) NPs were prepared by a facile wet chemical process and then their catalytic performance were evaluated in sodium bicarbonate hydrogenation. Bimetallic NiPd NPs with a composition of 7:3 were found to be superior for this reaction, which are more active than both pure Ni and Pd NPs. Hot filtration experiment suggested the NPs to be the truly catalytic active species and kinetic analysis indicated the reaction mechanism to be different than most homogeneous catalysts. The enhanced activity of the bimetallic nanoparticles may be attributed to their smaller size and improved stability.

L-lactic acid and sodium p-toluenesulfonate co-doped polypyrrole for high performance cathode in sodium ion battery

Science.gov (United States)

Liao, Qishu; Hou, Hongying; Liu, Xianxi; Yao, Yuan; Dai, Zhipeng; Yu, Chengyi; Li, Dongdong

2018-04-01

In this work, polypyrrole (PPy) was co-doped with L-lactic acid (LA) and sodium p-toluenesulfonate (TsONa) for high performance cathode in sodium ion battery (SIB) via facile one-step electropolymerization on Fe foil. The as-synthesized LA/TsONa co-doped PPy cathode was investigated in terms of scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), galvanostatic charge/discharge and cyclic voltammetry (CV). The results suggested that some oval-bud-like LA/TsONa co-doped PPy particles did form and tightly combine with the surface of Fe foil; furthermore, LA/TsONa co-doped PPy cathode also delivered higher electrochemical performances than TsONa mono-doped PPy cathode. For example, the initial specific discharge capacity was as high as about 124 mAh/g, and the reversible specific capacity still maintained at about 110 mAh/g even after 50 cycles, higher than those of TsONa mono-doped PPy cathode. The synergy effect of multi components of LA/TsONa co-doped PPy cathode should be responsible for high electrochemical performances.

Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus

Science.gov (United States)

Abdul-Ghani, Muhammad A.; Norton, Luke

2015-01-01

Hyperglycemia is the primary factor responsible for the microvascular, and to a lesser extent macrovascular, complications of diabetes. Despite this well-established relationship, approximately half of all type 2 diabetic patients in the US have a hemoglobin A1c (HbA1c) ≥7.0%. This is associated in part with the side effects, i.e., weight gain and hypoglycemia, of currently available antidiabetic agents and in part with the failure to utilize medications that reverse the basic pathophysiological defects present in patients with type 2 diabetes. The kidney has been shown to play a central role in the development of hyperglycemia by excessive production of glucose throughout the sleeping hours and enhanced reabsorption of filtered glucose by the renal tubules secondary to an increase in the threshold at which glucose spills into the urine. Recently, a new class of antidiabetic agents, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has been developed and approved for the treatment of patients with type 2 diabetes. In this review, we examine their mechanism of action, efficacy, safety, and place in the therapeutic armamentarium. Since the SGLT2 inhibitors have a unique mode of action that differs from all other oral and injectable antidiabetic agents, they can be used at all stages of the disease and in combination with all other antidiabetic medications. PMID:26354881

Metabolic Effects of Glucose-Fructose Co-Ingestion Compared to Glucose Alone during Exercise in Type 1 Diabetes

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Lia Bally

2017-02-01

Full Text Available This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU with glucose alone (GLU in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol underwent a 90 min iso-energetic continuous cycling session at 50% VO2max while ingesting combined glucose-fructose (GLUFRU or glucose alone (GLU to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13C-fructose and 13C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU (p = 0.46. Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg−1·min−1, p < 0.001 and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg−1·min−1 p < 0.001 in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg−1·min−1, p < 0.001. Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012 in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU (p > 0.05 for all. Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.

Electron transport phosphorylation in rumen butyrivibrios: unprecedented ATP yield for glucose fermentation to butyrate

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Timothy eHackmann

2015-06-01

Full Text Available From a genomic analysis of rumen butyrivibrios (Butyrivibrio and Pseudobutyrivibrio spp., we have re-evaluated the contribution of electron transport phosphorylation to ATP formation in this group. This group is unique in that most (76% genomes were predicted to possess genes for both Ech and Rnf transmembrane ion pumps. These pumps act in concert with the NifJ and Bcd-Etf to form a electrochemical potential (ΔμH+ and ΔμNa+, which drives ATP synthesis by electron transport phosphorylation. Of the 62 total butyrivibrio genomes currently available from the Hungate 1000 project, all 62 were predicted to possess NifJ, which reduces oxidized ferredoxin (Fdox during pyruvate conversion to acetyl-CoA. All 62 possessed all subunits of Bcd-Etf, which reduces Fdox and oxidizes reduced NAD (NADred during crotonyl-CoA reduction. Additionally, 61 genomes possessed all subunits of the Rnf, which generates ΔμH+ or ΔμNa+ from oxidation of reduced Fd and reduction of oxidized NAD (NADox. Further, 47 genomes possessed all 6 subunits of the Ech, which generates ΔμH+ from oxidation of reduced Fd (Fdred. For glucose fermentation to butyrate and H2, the electrochemical potential established should drive synthesis of ~1.5 ATP by the F0F1-ATP synthase (possessed by all 62 genomes. The total yield is ~4.5 ATP/glucose after accounting for 3 ATP formed by classic substrate-level phosphorylation, and it is one the highest yields for any glucose fermentation. The yield was the same when unsaturated fatty acid bonds, not H+, served as the electron acceptor (as during biohydrogenation. Possession of both Ech and Rnf had been previously documented in only a few sulfate-reducers, was rare in other rumen prokaryotic genomes in our analysis, and may confer an energetic advantage to rumen butyrivibrios. This unique energy conservation system might enhance the butyrivibrios’ ability to overcome growth inhibition by unsaturated fatty acids, as postulated herein.

Effects of sodium bicarbonate on the end-tidal CO[sub 2], PaCO[sub 2], HCO[sub 3][sup -], PH and cerebral blood flow

Energy Technology Data Exchange (ETDEWEB)

Komatani, Akio; Akutsu, Tooru; Yoshida, Michihiko; Yamaguchi, Koichi; Seo, Hiroshi (Yamagata Univ. (Japan). School of Medicine)

1992-09-01

To estimate the quantitative reactivity of cerebral blood flow (CBF), the effects of sodium bicarbonate on the end-tidal CO[sub 2], arterial partial pressure of CO[sub 2] (PaCO[sub 2]), HCO[sub 3][sup -], pH and CBF were examined. The CBF was measured by [sup 133]Xe inhalation method with ring type SPECT (HEADTOME). Activation study with sodium bicarbonate administration was performed after 30 minutes of resting study, and the reactivity of each parameters was investigated. The arterial HCO[sub 3][sup -] and pH increased with similar reactivity, but PaCO[sub 2], end-tidal CO[sub 2] and CBF in the non-injured hemisphere changed with irregular reactivity. The excellent correlation between PaCO[sub 2] and end-tidal CO[sub 2] was vanished by the administration of sodium bicarbonate. The reactivity of CBF did not correlate with reactivity of PaCO[sub 2] and end-tidal CO[sub 2], but correlated with arterial HCO[sub 3][sup -] and pH. Thus the measurement of arterial HCO[sub 3][sup -] and pH may be indispensable to estimate the CBF reactivity with the administration of sodium bicarbonate. (author).

Evolutionary ancestry and novel functions of the mammalian glucose transporter (GLUT) family.

Science.gov (United States)

Wilson-O'Brien, Amy L; Patron, Nicola; Rogers, Suzanne

2010-05-21

In general, sugar porters function by proton-coupled symport or facilitative transport modes. Symporters, coupled to electrochemical energy, transport nutrients against a substrate gradient. Facilitative carriers transport sugars along a concentration gradient, thus transport is dependent upon extracellular nutrient levels. Across bacteria, fungi, unicellular non-vertebrates and plants, proton-coupled hexose symport is a crucial process supplying energy under conditions of nutrient flux. In mammals it has been assumed that evolution of whole body regulatory mechanisms would eliminate this need. To determine whether any isoforms bearing this function might be conserved in mammals, we investigated the relationship between the transporters of animals and the proton-coupled hexose symporters found in other species. We took a comparative genomic approach and have performed the first comprehensive and statistically supported phylogenetic analysis of all mammalian glucose transporter (GLUT) isoforms. Our data reveals the mammalian GLUT proteins segregate into five distinct classes. This evolutionary ancestry gives insight to structure, function and transport mechanisms within the groups. Combined with biological assays, we present novel evidence that, in response to changing nutrient availability and environmental pH, proton-coupled, active glucose symport function is maintained in mammalian cells. The analyses show the ancestry, evolutionary conservation and biological importance of the GLUT classes. These findings significantly extend our understanding of the evolution of mammalian glucose transport systems. They also reveal that mammals may have conserved an adaptive response to nutrient demand that would have important physiological implications to cell survival and growth.

Insulin-sensitive phospholipid signaling systems and glucose transport. Update II.

Science.gov (United States)

Farese, R V

2001-04-01

Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidylcholine with subsequent increases in phosphatidic acid (PA) and diacylglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.

IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells

International Nuclear Information System (INIS)

Sinha, M.K.; Buchanan, C.; Raineri-Maldonado, C.; Khazanie, P.; Atkinson, S.; DiMarchi, R.; Caro, J.F.

1990-01-01

Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: (1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; (2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; (3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and (4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin

Crystal structure of a bacterial homologue of glucose transporters GLUT1-4.

Science.gov (United States)

Sun, Linfeng; Zeng, Xin; Yan, Chuangye; Sun, Xiuyun; Gong, Xinqi; Rao, Yu; Yan, Nieng

2012-10-18

Glucose transporters are essential for metabolism of glucose in cells of diverse organisms from microbes to humans, exemplified by the disease-related human proteins GLUT1, 2, 3 and 4. Despite rigorous efforts, the structural information for GLUT1-4 or their homologues remains largely unknown. Here we report three related crystal structures of XylE, an Escherichia coli homologue of GLUT1-4, in complex with d-xylose, d-glucose and 6-bromo-6-deoxy-D-glucose, at resolutions of 2.8, 2.9 and 2.6 Å, respectively. The structure consists of a typical major facilitator superfamily fold of 12 transmembrane segments and a unique intracellular four-helix domain. XylE was captured in an outward-facing, partly occluded conformation. Most of the important amino acids responsible for recognition of D-xylose or d-glucose are invariant in GLUT1-4, suggesting functional and mechanistic conservations. Structure-based modelling of GLUT1-4 allows mapping and interpretation of disease-related mutations. The structural and biochemical information reported here constitutes an important framework for mechanistic understanding of glucose transporters and sugar porters in general.

Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus.

Science.gov (United States)

Stanirowski, Paweł Jan; Szukiewicz, Dariusz; Pazura-Turowska, Monika; Sawicki, Włodzimierz; Cendrowski, Krzysztof

2018-04-01

Gestational diabetes mellitus and pregestational diabetes mellitus constitute carbohydrate metabolism disorders, which, if not diagnosed and adequately treated, lead to serious and often life-threatening pregnancy complications. According to a recently formulated hypothesis, some diabetes-related complications, such as fetal macrosomia, may be the result of disturbances in the transplacental transport of nutrients-in particular, excessive maternal-fetal glucose transfer. Throughout pregnancy, glucose flux across the placenta is mediated by the group of facilitative glucose transporters (GLUT), the expression of which in different placental compartments is the precondition for effective glucose uptake from maternal blood and its subsequent transfer to the fetal circulation. In diabetes-complicated pregnancies, the location, expression and activity of glucose transporters are modified to an extent that results in alterations in the maternal-fetal glucose exchange, potentially leading to an excessive supply of energy substrates to the fetus. This paper reviews the literature on the expression and activity of glucose transporter proteins-GLUT-1, GLUT-3, GLUT-4, GLUT-8, GLUT-9 and GLUT-12-in the human placenta, with a special focus on diabetes-complicated pregnancy. The characteristics of transporters in conditions of maternal normoglycemia and modifications occurring in the diabetic placenta are summarized, and the factors responsible for the regulation of the expression of selected isoforms are described. Finally, the impact of alterations in the placental expression of the aforementioned members of the GLUT family on intrauterine fetal development in pregnancies complicated by diabetes mellitus is discussed. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Comparison of sodium borohydride hydrolysis kinetics on Co-based nanocomposite catalysts

International Nuclear Information System (INIS)

Hristov, Georgi; Chorbadzhiyska, Elitsa; Mitov, Mario; Rashkov, Rashko; Hubenova, Yolina

2011-01-01

In this study, we compared the results, obtained with several Co-based nanocomposites (CoMnB, CoNiMnB and CoNiMoW) produced by electrodeposition on Ni-foam, as catalysts for the sodium borohydride hydrolysis reaction. Based on the comparative analyses, we propose CoNiMnB electrodeposits as most suitable catalysts for development of Hydrogen-on-Demand (HOD) system, while CoNiMoW ones as potential anodes for Direct Borohydride Fuel Cells (DBFCs). Keywords: Hydrogen-on-Demand (HOD), Nanocomposites, Hydrolysis, Catalyst, Kinetic

Transformation of Sodium Bicarbonate and CO2 into Sodium Formate over NiPd Nanoparticle Catalyst

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Mengnan eWang

2013-09-01

Full Text Available The present research systematically investigated, for the first time, the transformation of sodium bicarbonate and CO2 into sodium formate over a series of Ni based metal nanoparticles (NPs. Ni NPs and eight NiM (M stands for a second metal NPs were prepared by a facile wet chemical process and then their catalytic performance were evaluated in sodium bicarbonate hydrogenation. Bimetallic NiPd NPs with a composition of 7:3 were found to be superior for this reaction, which are more active than both pure Ni and Pd NPs. Hot filtration experiment suggested the NPs to be the truly catalytic active species and kinetic analysis indicated the reaction mechanism to be different than most homogeneous catalysts. The enhanced activity of the bimetallic nanoparticles may be attributed to their smaller size and improved stability.

Glucose metabolism in diabetic blood vessels

International Nuclear Information System (INIS)

Brown, B.J.; Crass, M.F. III

1986-01-01

Since glycolysis appears to be coupled to active ion transport in vascular smooth muscle, alterations in glucose metabolism may contribute to cellular dysfunction and angiopathy in diabetes. Uptake and utilization of glucose were studied in perfused blood vessels in which pulsatile flow and perfusion pressure were similar to those measured directly in vivo. Thoracic aortae isolated from 8-wk alloxan diabetic (D) and nondiabetic control rabbits were cannulated, tethered, and perfused with oxygenated buffer containing 7 or 25 mM glucose and tracer amounts of glucose-U -14 C. Norepinephrine (NE) (10 -6 M) and/or insulin (I) (150 μU/ml) and albumin (0.2%) were added. NE-induced tension development increased glucose uptake 39% and 14 CO 2 and lactate production 2.3-fold. With 7 mM glucose, marked decreases in glucose uptake (74%), 14 CO 2 (68%), lactate (30%), total tissue glycogen (75%), and tissue phospholipids (70%) were observed in D. Addition of I or elevation of exogenous glucose to 25 mM normalized glucose uptake, but had differential effects on the pattern of substrate utilization. Thus, in D, there was a marked depression of vascular glucose metabolism that was partially reversed by addition of low concentrations of insulin or D levels of glucose

Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid

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Hongbin Tu

2015-11-01

Full Text Available Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA, a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.

Effect of diet on insulin binding and glucose transport in rat sarcolemmal vesicles

International Nuclear Information System (INIS)

Grimditch, G.K.; Barnard, R.J.; Sternlicht, E.; Whitson, R.H.; Kaplan, S.A.

1987-01-01

The purpose of this study was to compare the effects of a high-fat, high-sucrose diet (HFS) and a low-fat, high-complex carbohydrate diet (LFC) on glucose tolerance, insulin binding, and glucose transport in rat skeletal muscle. During the intravenous glucose tolerance test, peak glucose values at 5 min were significantly higher in the HFS group; 0-, 20-, and 60-min values were similar. Insulin values were significantly higher in the HFS group at all time points (except 60 min), indicating whole-body insulin resistance. Skeletal muscle was responsible, in part, for this insulin resistance, because specific D-glucose transport in isolated sarcolemmal (SL) vesicles under basal conditions was similar between LFC and HFS rats, despite the higher plasma insulin levels. Scatchard analyses of insulin binding curves to sarcolemmal vesicles revealed that the K/sub a/ of the high-affinity binding sites was significantly reduced by the HFS diet; no other binding changes were noted. Specific D-glucose transport in SL vesicles after maximum insulin stimulation (1 U/kg) was significantly depressed in the HFS group, indicating that HFS feeding also caused a postbinding defect. These results indicate that the insulin resistance in skeletal muscle associated with a HFS diet is due to both a decrease in the K/sub a/ of the high-affinity insulin receptors and a postbinding defect

49 CFR 173.189 - Batteries containing sodium or cells containing sodium.

Science.gov (United States)

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Batteries containing sodium or cells containing sodium. 173.189 Section 173.189 Transportation Other Regulations Relating to Transportation PIPELINE AND... Than Class 1 and Class 7 § 173.189 Batteries containing sodium or cells containing sodium. (a...

Response of HT115, a highly invasive human colorectal adenocarcinoma cell line, to sodium butyrate treatment and glucose deprivation

Czech Academy of Sciences Publication Activity Database

Štokrová, Jitka; Sovová, Vlasta; Šloncová, Eva; Kučerová, Dana; Tuháčková, Zdena; Korb, Jan

2005-01-01

Roč. 26, č. 3 (2005), s. 793-799 ISSN 1019-6439 R&D Projects: GA AV ČR(CZ) KSK5020115 Keywords : HT115 cells * sodium butyrate * glucose deprivation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.681, year: 2005

Evolutionary ancestry and novel functions of the mammalian glucose transporter (GLUT family

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Patron Nicola

2010-05-01

Full Text Available Abstract Background In general, sugar porters function by proton-coupled symport or facilitative transport modes. Symporters, coupled to electrochemical energy, transport nutrients against a substrate gradient. Facilitative carriers transport sugars along a concentration gradient, thus transport is dependent upon extracellular nutrient levels. Across bacteria, fungi, unicellular non-vertebrates and plants, proton-coupled hexose symport is a crucial process supplying energy under conditions of nutrient flux. In mammals it has been assumed that evolution of whole body regulatory mechanisms would eliminate this need. To determine whether any isoforms bearing this function might be conserved in mammals, we investigated the relationship between the transporters of animals and the proton-coupled hexose symporters found in other species. Results We took a comparative genomic approach and have performed the first comprehensive and statistically supported phylogenetic analysis of all mammalian glucose transporter (GLUT isoforms. Our data reveals the mammalian GLUT proteins segregate into five distinct classes. This evolutionary ancestry gives insight to structure, function and transport mechanisms within the groups. Combined with biological assays, we present novel evidence that, in response to changing nutrient availability and environmental pH, proton-coupled, active glucose symport function is maintained in mammalian cells. Conclusions The analyses show the ancestry, evolutionary conservation and biological importance of the GLUT classes. These findings significantly extend our understanding of the evolution of mammalian glucose transport systems. They also reveal that mammals may have conserved an adaptive response to nutrient demand that would have important physiological implications to cell survival and growth.

Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes

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Kim Y

2012-08-01

Full Text Available Yoojin Kim, Ambika R BabuDivision of Endocrinology, John Stroger Jr Hospital of Cook County and Rush University, Chicago, IL, USABackground: The kidney plays an important role in glucose metabolism, and has been considered a target for therapeutic intervention. The sodium-glucose cotransporter type 2 (SGLT2 mediates most of the glucose reabsorption from the proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a unique mechanism to lower elevated blood glucose levels in diabetes. The purpose of this review is to explore the physiology of SGLT2 and discuss several SGLT2 inhibitors which have clinical data in patients with type 2 diabetes.Methods: We performed a PubMed search using the terms "SGLT2" and "SGLT2 inhibitor" through April 10, 2012. Published articles, press releases, and abstracts presented at national and international meetings were considered.Results: SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes. They are generally well tolerated. However, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors on diabetic complications and cardiovascular safety are crucial to determine the risk-benefit ratio. A recent decision by the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including

Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

Science.gov (United States)

Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

2018-02-15

The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

Genome, secretome and glucose transport highlight unique features of the protein production host Pichia pastoris

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Mattanovich Diethard

2009-06-01

Full Text Available Abstract Background Pichia pastoris is widely used as a production platform for heterologous proteins and model organism for organelle proliferation. Without a published genome sequence available, strain and process development relied mainly on analogies to other, well studied yeasts like Saccharomyces cerevisiae. Results To investigate specific features of growth and protein secretion, we have sequenced the 9.4 Mb genome of the type strain DSMZ 70382 and analyzed the secretome and the sugar transporters. The computationally predicted secretome consists of 88 ORFs. When grown on glucose, only 20 proteins were actually secreted at detectable levels. These data highlight one major feature of P. pastoris, namely the low contamination of heterologous proteins with host cell protein, when applying glucose based expression systems. Putative sugar transporters were identified and compared to those of related yeast species. The genome comprises 2 homologs to S. cerevisiae low affinity transporters and 2 to high affinity transporters of other Crabtree negative yeasts. Contrary to other yeasts, P. pastoris possesses 4 H+/glycerol transporters. Conclusion This work highlights significant advantages of using the P. pastoris system with glucose based expression and fermentation strategies. As only few proteins and no proteases are actually secreted on glucose, it becomes evident that cell lysis is the relevant cause of proteolytic degradation of secreted proteins. The endowment with hexose transporters, dominantly of the high affinity type, limits glucose uptake rates and thus overflow metabolism as observed in S. cerevisiae. The presence of 4 genes for glycerol transporters explains the high specific growth rates on this substrate and underlines the suitability of a glycerol/glucose based fermentation strategy. Furthermore, we present an open access web based genome browser http://www.pichiagenome.org.

Acoustic signal processing for the detection of sodium boiling or sodium-water reaction in LMFRs. Final report of a co-ordinated research programme 1990-1995

International Nuclear Information System (INIS)

1997-05-01

This report is a summary of the work performed under a co-ordinated research programme entitled Acoustic Signal Processing for the Detection of Sodium Boiling or Sodium-Water Reaction in Liquid Metal Cooled Fast Reactors. The programme was organized by the IAEA and carried out from 1990 to 1995. It was the continuation of an earlier research co-ordination programme entitled Signal Processing Techniques for Sodium Boiling Noise Detection, which was carried out from 1984 to 1989. Refs, figs, tabs

Control of radioactive material transport in sodium-cooled reactors

International Nuclear Information System (INIS)

Brehm, W.F.

1980-03-01

The Radioactivity Control Technology (RCT) program was established by the Department of Energy to develop and demonstrate methods to control radionuclide transport to ex-core regions of sodium-cooled reactors. This radioactive material is contained within the reactor heat transport system with any release to the environment well below limits established by regulations. However, maintenance, repair, decontamination, and disposal operations potentially expose plant workers to radiation fields arising from radionuclides transported to primary system components. This paper deals with radioactive material generated and transported during steady-state operation, which remains after 24 Na decay. Potential release of radioactivity during postulated accident conditions is not discussed. The control methods for radionuclide transport, with emphasis on new information obtained since the last Environmental Control Symposium, are described. Development of control methods is an achievable goal

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

Science.gov (United States)

Akman, Cigdem I; Engelstad, Kristin; Hinton, Veronica J; Ullner, Paivi; Koenigsberger, Dorcas; Leary, Linda; Wang, Dong; De Vivo, Darryl C

2010-01-01

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

SOCON: a computer model for analyzing the behavior of sodium-concrete reactions

International Nuclear Information System (INIS)

Nguyen, D.G.; Muhlestein, L.D.

1985-03-01

Guided by experimental evidence available to date, ranging from basic laboratory studies to large scale tests, a mechanistic computer model (the SOCON model) has been developed to analyze the behavior of SOdium-CONcrete reactions. The model accounts for the thermal, chemical and mechanical phenomena which interact to determine the consequences of the reactions. Reaction limiting mechanisms could be any process which reduces water release and sodium transport to fresh concrete; the buildup of the inert reaction product layer would increase the resistance to sodium transport; water dry-out would decrease the bubble agitation transport mechanism. However, stress-induced failure of concrete, such as spalling, crushing and cracking, and a massive release of gaseous products (hydrogen, water vapor and CO 2 ) would increase the transport of sodium to the reaction zone. The results of SOCON calculations are in excellent agreement with measurements obtained from large-scale sodium-limestone concrete reaction tests of duration up to 100 hours conducted at the Hanford Engineering Development Laboratory. 8 refs., 7 figs

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic)

DEFF Research Database (Denmark)

Birkeland, Kåre I.; Jørgensen, Marit E.; Carstensen, Bendix

2017-01-01

, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40...... with the results of clinical trials in patients at high cardiovascular risk. Funding AstraZeneca....

Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

Science.gov (United States)

Chichger, Havovi; Cleasby, Mark E; Srai, Surjit K; Unwin, Robert J; Debnam, Edward S; Marks, Joanne

2016-06-01

What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC

Sodium bicarbonate cotransporter NBCe2 gene variants increase sodium and bicarbonate transport in human renal proximal tubule cells.

Science.gov (United States)

Gildea, John J; Xu, Peng; Kemp, Brandon A; Carlson, Julia M; Tran, Hanh T; Bigler Wang, Dora; Langouët-Astrié, Christophe J; McGrath, Helen E; Carey, Robert M; Jose, Pedro A; Felder, Robin A

2018-01-01

Salt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension. However, little is known about how NBCe2 contributes to salt sensitivity, although NBCe2 regulates renal tubular sodium bicarbonate transport. We hypothesized that SLC4A5 rs10177833 and rs7571842 increase NBCe2 expression and human renal proximal tubule cell (hRPTC) sodium transport and may be a cause of salt sensitivity of blood pressure. To characterize the hRPTC ion transport of wild-type (WT) and homozygous variants (HV) of SLC4A5. The expressions of NBCe2 mRNA and protein were not different between hRPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, luminal to basolateral sodium transport, NHE3 protein, and Cl-/HCO3- exchanger activity in hRPTCs were higher in HV than WT SLC4A5. Increasing intracellular sodium enhanced the apical location of NBCe2 in HV hRPTCs (4.24±0.35% to 11.06±1.72% (P<0.05, N = 3, 2-way ANOVA, Holm-Sidak test)) as determined by Total Internal Reflection Fluorescence Microscopy (TIRFM). In hRPTCs isolated from kidney tissue, increasing intracellular sodium enhanced bicarbonate-dependent pH recovery rate and increased NBCe2 mRNA and protein expressions to a greater extent in HV than WT SLC4A5 (+38.00±6.23% vs HV normal salt (P<0.01, N = 4, 2-way ANOVA, Holm-Sidak test)). In hRPTCs isolated from freshly voided urine, bicarbonate-dependent pH recovery was also faster in those from salt-sensitive and carriers of HV SLC4A5 than from salt-resistant and carriers of WT SLC4A5. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was normalized by SLC4A5- but not SLC4A4-shRNA. The binding of purified hepatocyte

 The role of glucose transporter 1 (GLUT1 in the diagnosis and therapy of tumors

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Paweł Jóźwiak

2012-03-01

Full Text Available  Malignant cells are known to enhance glucose metabolism, to increase glucose uptake and to inhibit the process of oxidative phosphorylation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells that allow them to compensate the inefficient extraction of energy from glucose in order to continue their uncontrolled growth and proliferation. Upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins named GLUT. Overexpression of GLUTs, especially the hypoxia-responsive GLUT1, has been frequently observed in various human carcinomas. Many studies have reported a correlation between GLUT1 expression level and the grade of tumor aggressiveness, which suggests that GLUT1 expression may be of prognostic significance. Therefore, GLUT1 is a key rate-limiting factor in the transport and glucose metabolism in cancer cells. This paper presents the current state of knowledge on GLUT1 regulation as well as its utility in the diagnosis and therapy of cancers.

Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus : Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications

NARCIS (Netherlands)

Heerspink, Hiddo J. L.; Perkins, Bruce A.; Fitchett, David H.; Husain, Mansoor; Cherney, David Z. I.

2016-01-01

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and

Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1.

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Min-Sun Park

Full Text Available Glucose transporters (GLUTs provide a pathway for glucose transport across membranes. Human GLUTs are implicated in devastating diseases such as heart disease, hyper- and hypo-glycemia, type 2 diabetes and cancer. The human GLUT1 has been recently crystalized in the inward-facing open conformation. However, there is no other structural information for other conformations. The X-ray structures of E. coli Xylose permease (XylE, a glucose transporter homolog, are available in multiple conformations with and without the substrates D-xylose and D-glucose. XylE has high sequence homology to human GLUT1 and key residues in the sugar-binding pocket are conserved. Here we construct a homology model for human GLUT1 based on the available XylE crystal structure in the partially occluded outward-facing conformation. A long unbiased all atom molecular dynamics simulation starting from the model can capture a new fully opened outward-facing conformation. Our investigation of molecular interactions at the interface between the transmembrane (TM domains and the intracellular helices (ICH domain in the outward- and inward-facing conformation supports that the ICH domain likely stabilizes the outward-facing conformation in GLUT1. Furthermore, inducing a conformational transition, our simulations manifest a global asymmetric rocker switch motion and detailed molecular interactions between the substrate and residues through the water-filled selective pore along a pathway from the extracellular to the intracellular side. The results presented here are consistent with previously published biochemical, mutagenesis and functional studies. Together, this study shed light on the structure and functional relationships of GLUT1 in multiple conformational states.

Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca2+ release

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Thomas E. Jensen

2014-10-01

Full Text Available Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca2+ as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca2+ release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca2+ centric paradigm.

Competition between pentoses and glucose during uptake and catabolism in recombinant Saccharomyces cerevisiae

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Subtil Thorsten

2012-03-01

Full Text Available Abstract Background In mixed sugar fermentations with recombinant Saccharomyces cerevisiae strains able to ferment D-xylose and L-arabinose the pentose sugars are normally only utilized after depletion of D-glucose. This has been attributed to competitive inhibition of pentose uptake by D-glucose as pentose sugars are taken up into yeast cells by individual members of the yeast hexose transporter family. We wanted to investigate whether D-glucose inhibits pentose utilization only by blocking its uptake or also by interfering with its further metabolism. Results To distinguish between inhibitory effects of D-glucose on pentose uptake and pentose catabolism, maltose was used as an alternative carbon source in maltose-pentose co-consumption experiments. Maltose is taken up by a specific maltose transport system and hydrolyzed only intracellularly into two D-glucose molecules. Pentose consumption decreased by about 20 - 30% during the simultaneous utilization of maltose indicating that hexose catabolism can impede pentose utilization. To test whether intracellular D-glucose might impair pentose utilization, hexo-/glucokinase deletion mutants were constructed. Those mutants are known to accumulate intracellular D-glucose when incubated with maltose. However, pentose utilization was not effected in the presence of maltose. Addition of increasing concentrations of D-glucose to the hexo-/glucokinase mutants finally completely blocked D-xylose as well as L-arabinose consumption, indicating a pronounced inhibitory effect of D-glucose on pentose uptake. Nevertheless, constitutive overexpression of pentose-transporting hexose transporters like Hxt7 and Gal2 could improve pentose consumption in the presence of D-glucose. Conclusion Our results confirm that D-glucose impairs the simultaneous utilization of pentoses mainly due to inhibition of pentose uptake. Whereas intracellular D-glucose does not seem to have an inhibitory effect on pentose utilization

Identification of rice cornichon as a possible cargo receptor for the Golgi-localized sodium transporter OsHKT1;3

Science.gov (United States)

Rosas-Santiago, Paul; Lagunas-Gómez, Daniel; Barkla, Bronwyn J.; Vera-Estrella, Rosario; Lalonde, Sylvie; Jones, Alexander; Frommer, Wolf B.; Zimmermannova, Olga; Sychrová, Hana; Pantoja, Omar

2015-01-01

Membrane proteins are synthesized and folded in the endoplasmic reticulum (ER), and continue their path to their site of residence along the secretory pathway. The COPII system has been identified as a key player for selecting and directing the fate of membrane and secretory cargo proteins. Selection of cargo proteins within the COPII vesicles is achieved by cargo receptors. The cornichon cargo receptor belongs to a conserved protein family found in eukaryotes that has been demonstrated to participate in the selection of integral membrane proteins as cargo for their correct targeting. Here it is demonstrated at the cellular level that rice cornichon OsCNIH1 interacts with OsHKT1;3 and, in yeast cells, enables the expression of the sodium transporter to the Golgi apparatus. Physical and functional HKT–cornichon interactions are confirmed by the mating-based split ubiquitin system, bimolecular fluorescence complementation, and Xenopus oocyte and yeast expression systems. The interaction between the two proteins occurs in the ER of plant cells and their co-expression in oocytes leads to the sequestration of the transporter in the ER. In the yeast cornichon mutant erv14, OsHKT1;3 is mistargeted, preventing the toxic effects of sodium transport in the cell observed in wild-type cells or in the erv14 mutant that co-expressed OsHKT1;3 with either OsCNIH1 or Erv14p. Identification and characterization of rice cornichon as a possible cargo receptor opens up the opportunity to improve our knowledge on membrane protein targeting in plant cells. PMID:25750424

Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

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Murrin L Charles

2011-03-01

Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

Glucose transporter-1 deficiency syndrome : the expanding clinical and genetic spectrum of a treatable disorder

NARCIS (Netherlands)

Leen, Wilhelmina G.; Klepper, Joerg; Verbeek, Marcel M.; Leferink, Maike; Hofste, Tom; van Engelen, Baziel G.; Wevers, Ron A.; Arthur, Todd; Bahi-Buisson, Nadia; Ballhausen, Diana; Bekhof, Jolita; van Bogaert, Patrick; Carrilho, Ines; Chabrol, Brigitte; Champion, Michael P.; Coldwell, James; Clayton, Peter; Donner, Elizabeth; Evangeliou, Athanasios; Ebinger, Friedrich; Farrell, Kevin; Forsyth, Rob J.; de Goede, Christian G. E. L.; Gross, Stephanie; Grunewald, Stephanie; Holthausen, Hans; Jayawant, Sandeep; Lachlan, Katherine; Laugel, Vincent; Leppig, Kathy; Lim, Ming J.; Mancini, Grazia; Della Marina, Adela; Martorell, Loreto; McMenamin, Joe; Meuwissen, Marije E. C.; Mundy, Helen; Nilsson, Nils O.; Panzer, Axel; Poll-The, Bwee T.; Rauscher, Christian; Rouselle, Christophe M. R.; Sandvig, Inger; Scheffner, Thomas; Sheridan, Eamonn; Simpson, Neil; Sykora, Parol; Tomlinson, Richard; Trounce, John; Webb, David; Weschke, Bernhard; Scheffer, Hans; Willemsen, Michel A.

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder

NARCIS (Netherlands)

W.G. Leen (Wilhelmina); J. Klepper (Joerg); M.M. Verbeek (Marcel); M. Leferink (Maike); T. Hofste (Tom); B.G.M. van Engelen (Baziel); R.A. Wevers (Ron); T. Arthur (Todd); N. Bahi-Buisson (Nadia); D. Ballhausen (Diana); J. Bekhof (Jolita); P. van Bogaert (Patrick); I. Carrilho (Inês); B. Chabrol (Brigitte); M.P. Champion (Michael); J. Coldwell (James); P. Clayton (Peter); E. Donner (Elizabeth); A. Evangeliou (Athanasios); F. Ebinger (Friedrich); K. Farrell (Kevin); R.J. Forsyth (Rob); C.G.E.L. de Goede (Christian); S. Gross (Stephanie); S. Grünewald (Sonja); H. Holthausen (Hans); S. Jayawant (Sandeep); K. Lachlan (Katherine); V. Laugel (Vincent); K. Leppig (Kathy); M.J. Lim (Ming); G.M.S. Mancini (Grazia); A.D. Marina; L. Martorell (Loreto); J. McMenamin (Joe); M.E.C. Meuwissen (Marije); H. Mundy (Helen); N.O. Nilsson (Nils); A. Panzer (Axel); B.T. Poll-The; C. Rauscher (Christian); C.M.R. Rouselle (Christophe); I. Sandvig (Inger); T. Scheffner (Thomas); E. Sheridan (Eamonn); N. Simpson (Neil); P. Sykora (Parol); R. Tomlinson (Richard); J. Trounce (John); D.W.M. Webb (David); B. Weschke (Bernhard); H. Scheffer (Hans); M.A. Willemsen (Michél)

2010-01-01

textabstractGlucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

NARCIS (Netherlands)

Leen, Wilhelmina G.; Klepper, Joerg; Verbeek, Marcel M.; Leferink, Maike; Hofste, Tom; van Engelen, Baziel G.; Wevers, Ron A.; Arthur, Todd; Bahi-Buisson, Nadia; Ballhausen, Diana; Bekhof, Jolita; van Bogaert, Patrick; Carrilho, Inês; Chabrol, Brigitte; Champion, Michael P.; Coldwell, James; Clayton, Peter; Donner, Elizabeth; Evangeliou, Athanasios; Ebinger, Friedrich; Farrell, Kevin; Forsyth, Rob J.; de Goede, Christian G. E. L.; Gross, Stephanie; Grunewald, Stephanie; Holthausen, Hans; Jayawant, Sandeep; Lachlan, Katherine; Laugel, Vincent; Leppig, Kathy; Lim, Ming J.; Mancini, Grazia; Marina, Adela Della; Martorell, Loreto; McMenamin, Joe; Meuwissen, Marije E. C.; Mundy, Helen; Nilsson, Nils O.; Panzer, Axel; Poll-The, Bwee T.; Rauscher, Christian; Rouselle, Christophe M. R.; Sandvig, Inger; Scheffner, Thomas; Sheridan, Eamonn; Simpson, Neil; Sykora, Parol; Tomlinson, Richard; Trounce, John; Webb, David; Weschke, Bernhard; Scheffer, Hans; Willemsen, Michél A.

2010-01-01

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

NARCIS (Netherlands)

Leen, W.G.; Klepper, J.; Verbeek, M.M.; Leferink, M.; Hofste, T.; Engelen, B.G.M. van; Wevers, R.A.; Arthur, T.; Bahi-Buisson, N.; Ballhausen, D.; Bekhof, J.; Bogaert, P. van; Carrilho, I.; Chabrol, B.; Champion, M.P.; Coldwell, J.; Clayton, P.; Donner, E.; Evangeliou, A.; Ebinger, F.; Farrell, K.; Forsyth, R.J.; Goede, C.G. de; Gross, S.; Grunewald, S.; Holthausen, H.; Jayawant, S.; Lachlan, K.; Laugel, V.; Leppig, K.; Lim, M.J.; Mancini, G.; Marina, A.D.; Martorell, L.; McMenamin, J.; Meuwissen, M.E.; Mundy, H.; Nilsson, N.O.; Panzer, A.; Poll-The, B.T.; Rauscher, C.; Rouselle, C.M.; Sandvig, I.; Scheffner, T.; Sheridan, E.; Simpson, N.; Sykora, P.; Tomlinson, R.; Trounce, J.; Webb, D.; Weschke, B.; Scheffer, H.; Willemsen, M.A.A.P.

2010-01-01

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

Preliminary conceptual design of the secondary sodium circuit-eliminated JSFR (Japan Sodium Fast Reactor) adopting a supercritical CO2 turbine system (2). Turbine system and plant size

International Nuclear Information System (INIS)

Kisohara, Naoyuki; Sakamoto, Yoshihiko; Kotake, Shoji

2014-09-01

Research and development of the supercritical CO 2 (S-CO 2 ) cycle turbine system is underway in various countries for further improvement of the safety and economy of sodium-cooled fast reactors. The Component Design and Balance-Of-Plant (CD and BOP) of the Generation IV International Nuclear Forum (Gen-IV) has addressed this study, and their analytical and experimental results have been discussed between the relevant countries. JAEA, who is a member of the CD and BOP, has performed a design study of an S-CO 2 gas turbine system applied to the Japan Sodium-cooled Fast Reactor (JSFR). In this study, the S-CO 2 cycle turbine system was directly connected to the primary sodium system of the JSFR to eliminate the secondary sodium circuit, aiming for further economical improvement. This is because there is no risk of sodium-water reaction in the S-CO 2 cycle turbine system of SFRs. This report describes the system configuration, heat/mass balance, and main components of the S-CO 2 turbine system, based on the JSFR specifications. The layout of components and piping in the reactor and turbine buildings were examined and the dimensions of the buildings were estimated. The study has revealed that the reactor and turbine buildings could be reduced by 7% and 40%, respectively, in comparison with those in the existing JSFR design with the secondary sodium circuit employing the steam turbine. The cycle thermal was also calculated as 41.9-42.3%, which is nearly the same as that of the JSFR with the water/steam system. (author)

Improvement of the physicochemical properties of Co-amorphous naproxen-indomethacin by naproxen-sodium

DEFF Research Database (Denmark)

Beyer, Andreas; Grohganz, Holger; Löbmann, Korbinian

2017-01-01

Improvement of the physicochemical properties of amorphous active pharmaceutical ingredients (APIs) applying the concept of co-amorphisation is a promising alternative to the use of polymer glass solutions. In co-amorphous systems, the physical stability and the dissolution rate of the involved c...... or full exchange of naproxen by its sodium salt was performed, which may present a general optimization method to improve co-amorphous systems....... In the present study, it was thus tested if the physicochemical properties of co-amorphous naproxen-indomethacin could be optimized by incorporation of the naproxen sodium into the system. Three different co-amorphous systems in nine different molar ratios were prepared by quench-cooling: naproxen...... components may be improved in comparison to the respective single amorphous phases. However, for the co-amorphous naproxen-indomethacin model system it has been reported that recrystallization could not be prevented for more than 112days regardless of the applied preparation method and blend ratio...

Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

DEFF Research Database (Denmark)

Kårhus, Martin L; Brønden, Andreas; Sonne, David P

2017-01-01

Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

Rewiring the Glucose Transportation and Central Metabolic Pathways for Overproduction of N-Acetylglucosamine in Bacillus subtilis.

Science.gov (United States)

Gu, Yang; Deng, Jieying; Liu, Yanfeng; Li, Jianghua; Shin, Hyun-Dong; Du, Guocheng; Chen, Jian; Liu, Long

2017-10-01

N-acetylglucosamine (GlcNAc) is an important amino sugar extensively used in the healthcare field. In a previous study, the recombinant Bacillus subtilis strain BSGN6-P xylA -glmS-pP43NMK-GNA1 (BN0-GNA1) had been constructed for microbial production of GlcNAc by pathway design and modular optimization. Here, the production of GlcNAc is further improved by rewiring both the glucose transportation and central metabolic pathways. First, the phosphotransferase system (PTS) is blocked by deletion of three genes, yyzE (encoding the PTS system transporter subunit IIA YyzE), ypqE (encoding the PTS system transporter subunit IIA YpqE), and ptsG (encoding the PTS system glucose-specific EIICBA component), resulting in 47.6% increase in the GlcNAc titer (from 6.5 ± 0.25 to 9.6 ± 0.16 g L -1 ) in shake flasks. Then, reinforcement of the expression of the glcP and glcK genes and optimization of glucose facilitator proteins are performed to promote glucose import and phosphorylation. Next, the competitive pathways for GlcNAc synthesis, namely glycolysis, peptidoglycan synthesis pathway, pentose phosphate pathway, and tricarboxylic acid cycle, are repressed by initiation codon-optimization strategies, and the GlcNAc titer in shake flasks is improved from 10.8 ± 0.25 to 13.2 ± 0.31 g L -1 . Finally, the GlcNAc titer is further increased to 42.1 ± 1.1 g L -1 in a 3-L fed-batch bioreactor, which is 1.72-fold that of the original strain, BN0-GNA1. This study shows considerably enhanced GlcNAc production, and the metabolic engineering strategy described here will be useful for engineering other prokaryotic microorganisms for the production of GlcNAc and related molecules. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inhibitin: a specific inhibitor of sodium/sodium exchange in erythrocytes.

OpenAIRE

Morgan, K; Brown, R C; Spurlock, G; Southgate, K; Mir, M A

1986-01-01

An inhibitor of ouabain-insensitive sodium/sodium exchange in erythrocytes has been isolated from leukemic promyelocytes. To explore the specific effects of this inhibitor, named inhibitin, sodium transport experiments were carried out in human erythrocytes. Inhibitin reduced ouabain-insensitive bidirectional sodium transport. It did not change net sodium fluxes, had no significant effect on rubidium influx, and did not inhibit sodium-potassium-ATPase activity. The inhibitory effect of inhibi...

A Hexose Transporter Homologue Controls Glucose Repression in the Methylotrophic Yeast Hansenula polymorpha

NARCIS (Netherlands)

Stasyk, Oleh V.; Stasyk, Olena G.; Komduur, Janet; Veenhuis, Marten; Cregg, James M.; Sibirny, Andrei A.

2004-01-01

Peroxisome biogenesis and synthesis of peroxisomal enzymes in the methylotrophic yeast Hansenula polymorpha are under the strict control of glucose repression. We identified an H. polymorpha glucose catabolite repression gene (HpGCR1) that encodes a hexose transporter homologue. Deficiency in GCR1

Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) : A randomized, placebo-controlled trial

NARCIS (Netherlands)

Neal, Bruce; Perkovic, Vlado; Matthews, David R.; Mahaffey, Kenneth W.; Fulcher, Greg; Meininger, Gary; Erondu, Ngozi; Desai, Mehul; Shaw, Wayne; Vercruysse, Frank; Yee, Jacqueline; Deng, Hsiaowei; de Zeeuw, Dick

Aims: The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal

Expression and Purification of Rat Glucose Transporter 1 in Pichia pastoris.

Science.gov (United States)

Venskutonytė, Raminta; Elbing, Karin; Lindkvist-Petersson, Karin

2018-01-01

Large amounts of pure and homogenous protein are a prerequisite for several biochemical and biophysical analyses, and in particular if aiming at resolving the three-dimensional protein structure. Here we describe the production of the rat glucose transporter 1 (GLUT1), a membrane protein facilitating the transport of glucose in cells. The protein is recombinantly expressed in the yeast Pichia pastoris. It is easily maintained and large-scale protein production in shaker flasks, as commonly performed in academic research laboratories, results in relatively high yields of membrane protein. The purification protocol describes all steps needed to obtain a pure and homogenous GLUT1 protein solution, including cell growth, membrane isolation, and chromatographic purification methods.

Sodium-glucose cotransporter (SGLT)-2-inhibitorer til patienter med type 2-diabetes

DEFF Research Database (Denmark)

Røder, Michael Einar; Storgaard, Heidi; Rungby, Jørgen

2016-01-01

The sodium-glucose cotransporter 2 inhibitor (SGLT-2i)-class is efficacious as monotherapy and as add-on therapy with an expected lowering of the glycated haemoglobin (HbA1c) concentration of approximately 7 mmol/mol. Side effects relate to the mode of action, genital infections are the main...... problem. Extremely rare cases of ketoacidosis are reported, mostly in patients with Type 1 diabetes. One SGLT-2i, empagliflozin, has been shown to reduce cardiovascular mortality and progression of kidney disease in patients with Type 2 diabetes and cardiovascular disease. Outcome trials for other SGLT-2i...... are pending. SGLT-2i are now in guidelines as a possible second-line therapy or in case of metformin intolerance....

Hierarchical Co(OH)_2 nanostructures/glassy carbon electrode derived from Co(BTC) metal–organic frameworks for glucose sensing

International Nuclear Information System (INIS)

He, Juan; Lu, Xingping; Yu, Jie; Wang, Li; Song, Yonghai

2016-01-01

A novel Co(OH)_2/glassy carbon electrode (GCE) has been fabricated via metal–organic framework (MOF)-directed method. In the strategy, the Co(BTC, 1,3,5-benzentricarboxylic acid) MOFs/GCE was firstly prepared by alternately immersing GCE in Co"2"+ and BTC solution based on a layer-by-layer method. And then, the Co(OH)_2 with hierarchical flake nanostructure/GCE was constructed by immersing Co(BTC) MOFs/GCE into 0.1 M NaOH solution at room temperature. Such strategy improves the distribution of hierarchical Co(OH)_2 nanostructures on electrode surface greatly, enhances the stability of nanomaterials on the electrode surface, and increases the use efficiency of the Co(OH)_2 nanostructures. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray powder diffraction, energy dispersive spectroscopy, Fourier transform infrared spectroscopy, and Raman spectra were used to characterize the Co(BTC) MOFs/GCE and Co(OH)_2/GCE. Based on the hierarchical Co(OH)_2 nanostructures/GCE, a novel and sensitive nonenzymatic glucose sensor was developed. The good performance of the resulted sensor toward the detection of glucose was ascribed to hierarchical flake nanostructures, good mechanical stability, excellent distribution, and large specific surface area of Co(OH)_2 nanostructures. The proposed preparation method is simple, efficient, and cheap .Graphical Abstract.

Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices.

Science.gov (United States)

Jakoby, Patrick; Schmidt, Elke; Ruminot, Iván; Gutiérrez, Robin; Barros, L Felipe; Deitmer, Joachim W

2014-01-01

Glucose is the most important energy substrate for the brain, and its cellular distribution is a subject of great current interest. We have employed fluorescent glucose probes, the 2-deoxy-D-glucose derivates 6- and 2-([N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose) (2-NBDG), to measure transport and metabolism of glucose in acute slices of mouse hippocampus and cerebellum. In the hippocampus, 6-NBDG, which is not metabolized and hence indicates glucose transport, was taken up faster in astrocyte-rich layers (Stratum radiatum [S.r.], Stratum oriens [S.o.]) than in pyramidal cells. Metabolizable 2-NBDG showed larger signals in S.r. and S.o. than in Stratum pyramidale, suggesting faster glucose utilization rate in the astrocyte versus the neuronal compartment. Similarly, we found higher uptake and temperature-sensitive metabolism of 2-NBDG in Bergmann glia when compared with adjacent Purkinje neurons of cerebellar slices. A comparison between 6-NBDG transport and glucose transport in cultured cells using a fluorescence resonance energy transfer nanosensor showed that relative to glucose, 6-NBDG is transported better by neurons than by astrocytes. These results indicate that the preferential transport and metabolism of glucose by glial cells versus neurons proposed for the hippocampus and cerebellum by ourselves (in vitro) and for the barrel cortex by Chuquet et al. (in vivo) is more pronounced than anticipated.

Screening For Inhibitors Of Essential Leishmania Glucose Transporters

Science.gov (United States)

2011-07-01

parasite life cycle and, unlike he amastigote form that lives inside mammalian macrophages, s viable provided that an alternative energy source such as pro...glucose transporters havebeenvalidated asnewdrug targets for proto- zoan parasites including Plasmodium falciparum, Leishmania mexicana and Trypanosoma...such as Leishmania species, Trypanosoma rucei, and Plasmodium falciparum, the causative agents of leish- aniasis, African sleeping sickness, and malaria

LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.

Science.gov (United States)

Powell, David R; Smith, Melinda; Greer, Jennifer; Harris, Angela; Zhao, Sharon; DaCosta, Christopher; Mseeh, Faika; Shadoan, Melanie K; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi-Ming

2013-05-01

LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

Diabetic Ketoacidosis in a Patient with Type 2 Diabetes After Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Treatment

DEFF Research Database (Denmark)

Storgaard, Heidi; Bagger, Jonatan I; Knop, Filip K

2016-01-01

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have...... been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT2i dapagliflozin. He was admitted with DKA 5 days after the initiation of treatment with the SGLT2i dapagliflozin...... 72 hr with insulin as the only glucose-lowering therapy. After 1 month, dapagliflozin was reintroduced as add-on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone...

The Structure of a Sugar Transporter of the Glucose EIIC Superfamily Provides Insight into the Elevator Mechanism of Membrane Transport.

Science.gov (United States)

McCoy, Jason G; Ren, Zhenning; Stanevich, Vitali; Lee, Jumin; Mitra, Sharmistha; Levin, Elena J; Poget, Sebastien; Quick, Matthias; Im, Wonpil; Zhou, Ming

2016-06-07

The phosphoenolpyruvate:carbohydrate phosphotransferase systems are found in bacteria, where they play central roles in sugar uptake and regulation of cellular uptake processes. Little is known about how the membrane-embedded components (EIICs) selectively mediate the passage of carbohydrates across the membrane. Here we report the functional characterization and 2.55-Å resolution structure of a maltose transporter, bcMalT, belonging to the glucose superfamily of EIIC transporters. bcMalT crystallized in an outward-facing occluded conformation, in contrast to the structure of another glucose superfamily EIIC, bcChbC, which crystallized in an inward-facing occluded conformation. The structures differ in the position of a structurally conserved substrate-binding domain that is suggested to play a central role in sugar transport. In addition, molecular dynamics simulations suggest a potential pathway for substrate entry from the periplasm into the bcMalT substrate-binding site. These results provide a mechanistic framework for understanding substrate recognition and translocation for the glucose superfamily EIIC transporters. Copyright © 2016 Elsevier Ltd. All rights reserved.

Glucose transporter expression differs between bovine monocyte and macrophage subsets and is influenced by milk production.

Science.gov (United States)

Eger, M; Hussen, J; Koy, M; Dänicke, S; Schuberth, H-J; Breves, G

2016-03-01

The peripartal period of dairy cows is characterized by negative energy balance and higher incidences of infectious diseases such as mastitis or metritis. With the onset of lactation, milk production is prioritized and large amounts of glucose are transported into the mammary gland. Decreased overall energy availability might impair the function of monocytes acting as key innate immune cells, which give rise to macrophages and dendritic cells and link innate and adaptive immunity. Information on glucose requirements of bovine immune cells is rare. Therefore, this study aims to evaluate glucose transporter expression of the 3 bovine monocyte subsets (classical, intermediate, and nonclassical monocytes) and monocyte-derived macrophages and to identify influences of the peripartal period. Blood samples were either collected from nonpregnant healthy cows or from 16 peripartal German Holstein cows at d -14, +7, and +21 relative to parturition. Quantitative real-time PCR was applied to determine mRNA expression of glucose transporters (GLUT) 1, GLUT3, and GLUT4 in monocyte subsets and monocyte-derived macrophages. The low GLUT1 and GLUT3 expression in nonclassical monocytes was unaltered during differentiation into macrophages, whereas in classical and intermediate monocytes GLUT expression was downregulated. Alternatively activated M2 macrophages consumed more glucose compared with classically activated M1 macrophages. The GLUT4 mRNA was only detectable in unstimulated macrophages. Neither monocytes nor macrophages were insulin responsive. In the peripartum period, monocyte GLUT1 and GLUT3 expression and the GLUT3/GLUT1 ratio were negatively correlated with lactose production. The high-affinity GLUT3 transporter appears to be the predominant glucose transporter on bovine monocytes and macrophages, especially in the peripartal period when blood glucose levels decline. Glucose transporter expression in monocytes is downregulated as a function of lactose production, which

Characterization of Gene Candidates for Vacuolar Sodium Transport from Hordeum Vulgare

KAUST Repository

Scheu, Arne Hagen August

2017-05-01

Soil salinity is a major abiotic stress for land plants, and multiple mechanisms of salt tolerance have evolved. Tissue tolerance is one of these mechanisms, which involves the sequestration of sodium into the vacuole to retain low cytosolic sodium concentrations. This enables the plant to maintain cellular functions, and ultimately maintain growth and yield. However, the molecular components involved in tissue tolerance remain elusive. Several candidate genes for vacuolar sodium sequestration have recently been identified by proteome analysis of vacuolar membranes purified from the salt-tolerant cereal Hordeum vulgare (barley). In this study, I aimed to characterize these candidates in more detail. I successfully cloned coding sequences for the majority of candidate genes with primers designed based on the barley reference genome sequence. During the course of this study a newer genome sequence with improved annotations was published, to which I also compared my observations. To study the candidate genes, I used the heterologous expression system Saccharomyces cerevisiae (yeast). I used several salt sensitive yeast strains (deficient in intrinsic sodium transporters) to test whether the candidate genes would affect their salt tolerance by mediating the sequestration of sodium into the yeast vacuole. I observed a reduction in growth upon expression for several of the gene candidate under salt-stress conditions. However, confocal microscopy suggests that most gene products are subject to degradation, and did not localize to the vacuolar membrane (tonoplast). Therefore, growth effects cannot be linked to protein function without further evidence. Various potential causes are discussed, including inaccuracies in the genome resource used as reference for primer design and issues inherent to the model system. Finally, I make suggestions on how to proceed to further characterize the candidate genes and hopefully identify novel sodium transporters from barley.

Insights from the Fungus Fusarium oxysporum Point to High Affinity Glucose Transporters as Targets for Enhancing Ethanol Production from Lignocellulose

Science.gov (United States)

Ali, Shahin S.; Nugent, Brian; Mullins, Ewen; Doohan, Fiona M.

2013-01-01

Ethanol is the most-widely used biofuel in the world today. Lignocellulosic plant biomass derived from agricultural residue can be converted to ethanol via microbial bioprocessing. Fungi such as Fusarium oxysporum can simultaneously saccharify straw to sugars and ferment sugars to ethanol. But there are many bottlenecks that need to be overcome to increase the efficacy of microbial production of ethanol from straw, not least enhancement of the rate of fermentation of both hexose and pentose sugars. This research tested the hypothesis that the rate of sugar uptake by F. oxysporum would enhance the ethanol yields from lignocellulosic straw and that high affinity glucose transporters can enhance ethanol yields from this substrate. We characterized a novel hexose transporter (Hxt) from this fungus. The F. oxysporum Hxt represents a novel transporter with homology to yeast glucose signaling/transporter proteins Rgt2 and Snf3, but it lacks their C-terminal domain which is necessary for glucose signalling. Its expression level decreased with increasing glucose concentration in the medium and in a glucose uptake study the Km(glucose) was 0.9 mM, which indicated that the protein is a high affinity glucose transporter. Post-translational gene silencing or over expression of the Hxt in F. oxysporum directly affected the glucose and xylose transport capacity and ethanol yielded by F. oxysporum from straw, glucose and xylose. Thus we conclude that this Hxt has the capacity to transport both C5 and C6 sugars and to enhance ethanol yields from lignocellulosic material. This study has confirmed that high affinity glucose transporters are ideal candidates for improving ethanol yields from lignocellulose because their activity and level of expression is high in low glucose concentrations, which is very common during the process of consolidated processing. PMID:23382943

Insights from the fungus Fusarium oxysporum point to high affinity glucose transporters as targets for enhancing ethanol production from lignocellulose.

Directory of Open Access Journals (Sweden)

Shahin S Ali

Full Text Available Ethanol is the most-widely used biofuel in the world today. Lignocellulosic plant biomass derived from agricultural residue can be converted to ethanol via microbial bioprocessing. Fungi such as Fusarium oxysporum can simultaneously saccharify straw to sugars and ferment sugars to ethanol. But there are many bottlenecks that need to be overcome to increase the efficacy of microbial production of ethanol from straw, not least enhancement of the rate of fermentation of both hexose and pentose sugars. This research tested the hypothesis that the rate of sugar uptake by F. oxysporum would enhance the ethanol yields from lignocellulosic straw and that high affinity glucose transporters can enhance ethanol yields from this substrate. We characterized a novel hexose transporter (Hxt from this fungus. The F. oxysporum Hxt represents a novel transporter with homology to yeast glucose signaling/transporter proteins Rgt2 and Snf3, but it lacks their C-terminal domain which is necessary for glucose signalling. Its expression level decreased with increasing glucose concentration in the medium and in a glucose uptake study the Km((glucose was 0.9 mM, which indicated that the protein is a high affinity glucose transporter. Post-translational gene silencing or over expression of the Hxt in F. oxysporum directly affected the glucose and xylose transport capacity and ethanol yielded by F. oxysporum from straw, glucose and xylose. Thus we conclude that this Hxt has the capacity to transport both C5 and C6 sugars and to enhance ethanol yields from lignocellulosic material. This study has confirmed that high affinity glucose transporters are ideal candidates for improving ethanol yields from lignocellulose because their activity and level of expression is high in low glucose concentrations, which is very common during the process of consolidated processing.

The effects of combined glucose-electrolyte and sodium bicarbonate ingestion on prolonged intermittent exercise performance.

Science.gov (United States)

Price, Mike James; Cripps, David

2012-01-01

This study examined the effects of combined glucose and sodium bicarbonate ingestion prior to intermittent exercise. Ninemales (mean ± s age 25.4 ± 6.6 years, body mass 78.8 ± 12.0 kg, maximal oxygen uptake (VO2 max)) 47.0 ± 7 ml · kg · min(-1)) undertook 4 × 45 min intermittent cycling trials including 15 × 10 s sprints one hour after ingesting placebo (PLA), glucose (CHO), sodium bicarbonate (NaHCO3) or a combined CHO and NaHCO3 solution (COMB). Post ingestion blood pH (7.45 ± 0.03, 7.46 ± 0.03, 7.32 ± 0.05, 7.32 ± 0.01) and bicarbonate (30.3 ± 2.1, 30.7 ± 1.8, 24.2 ± 1.2, 24.0 ± 1.8 mmol · l(-1)) were greater for NaHCO3 and COMB when compared to PLA and CHO, remaining elevated throughout exercise (main effect for trial; P < 0.05). Blood lactate concentration was greatest throughout exercise for NaHCO3 and COMB (main effect for trial; P < 0.05). Blood glucose concentration was greatest 15 min post-ingestion for CHO followed by COMB, NaHCO3 and PLA (7.13 ± 0.60, 5.58 ± 0.75, 4.51 ± 0.56, 4.46 ± 0.59 mmol · l(-1), respectively; P < 0.05). Gastrointestinal distress was lower during COMB compared to NaHCO3 at 15 min post-ingestion (P < 0.05). No differences were observed for sprint performance between trials (P = 1.00). The results of this study suggest that a combined CHO and NaHCO3 beverage reduced gastrointestinal distress and CHO availability but did not improve performance. Although there was no effect on performance an investigation of the effects in more highly trained individuals may be warranted.

Analysis of the Sodium Recirculation Theory of Solute Coupled Water Transport in Small Intestine

DEFF Research Database (Denmark)

Larsen, E. H.; Sørensen, Jens Nørkær; Sørensen, J. B.

2002-01-01

Our previous mathematical model of solute-coupled water transport through the intestinal epithelium is extended for dealing with electrolytes rather than electroneutral solutes. A 3Na+-2K+ pump in the lateral membranes provides the energy-requiring step for driving transjunctional and translateral......, computations predict that the concentration differences between lis and bathing solutions are small for all three ions. Nevertheless, the diffusion fluxes of the ions out of lis significantly exceed their mass transports. It is concluded that isotonic transport requires recirculation of all three ions....... The computed sodium recirculation flux that is required for isotonic transport corresponds to that estimated in experiments on toad small intestine. This result is shown to be robust and independent of whether the apical entrance mechanism for the sodium ion is a channel, a SGLT1 transporter driving inward...

Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

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Michela Riz

2015-12-01

Full Text Available Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1, peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT and ATP-sensitive K+-channels (K(ATP-channels to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale

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Yassin SA

2017-03-01

Full Text Available Sayf A Yassin,1 Vanita R Aroda2 1MedStar Union Memorial Hospital, Baltimore, 2MedStar Health Research Institute, Hyattsville, MD, USA Abstract: Type 2 diabetes mellitus (T2DM is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM. Keywords: sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, type 2 diabetes mellitus, combination therapy

Effect of vanadate on glucose transporter (GLUT4) intrinsic activity in skeletal muscle plasma membrane giant vesicles

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Kristiansen, S; Youn, J; Richter, Erik

1996-01-01

of vanadate (NaVO3) on glucose transporter (GLUT4) intrinsic activity (V(max) = intrinsic activity x [GLUT4 protein]) was studied in muscle plasma membrane giant vesicles. Giant vesicles (average diameter 7.6 microns) were produced by collagenase treatment of rat skeletal muscle. The vesicles were incubated......) 55% and 60%, respectively, compared with control. The plasma membrane GLUT4 protein content was not changed in response to vanadate. It is concluded that vanadate decreased glucose transport per GLUT4 (intrinsic activity). This finding suggests that regulation of glucose transport in skeletal muscle...

Water transport by the Na+/glucose cotransporter under isotonic conditions

DEFF Research Database (Denmark)

Zeuthen, T; Meinild, A K; Klaerke, D A

1997-01-01

Solute cotransport in the Na+/glucose cotransporter is directly coupled to significant water fluxes. The water fluxes are energized by the downhill fluxes of the other substrates by a mechanism within the protein itself. In the present paper we investigate the Na+/glucose cotransporter expressed ...... of water molecules and the number of Na+ ions transported, equivalent to 390 water molecules per glucose molecule. Unstirred layer effects are ruled out on the basis of experiments on native oocytes incubated with the ionophores gramicidin D or nystatin.......Solute cotransport in the Na+/glucose cotransporter is directly coupled to significant water fluxes. The water fluxes are energized by the downhill fluxes of the other substrates by a mechanism within the protein itself. In the present paper we investigate the Na+/glucose cotransporter expressed...... in Xenopus oocytes. We present a method which allows short-term exposures to sugar under voltage clamp conditions. We demonstrate that water is cotransported with the solutes despite no osmotic differences between the external and intracellular solutions. There is a fixed ratio of 195:1 between the number...

Natriuretic Hormones, Endogenous Ouabain, and Related Sodium Transport Inhibitors

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John eHamlyn

2014-12-01

Full Text Available The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NH. In addition to the atrial peptides (APs, the circulation contains unidentified physiologically-relevant NHs. One NH is controlled by the central nervous system (CNS and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide. Both NHs have short (<35 minutes circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress nitric oxide in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain-like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority.

Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34 motor neuron-like cells via AMPK pathway activation.

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Daniel, Bareket; Green, Omer; Viskind, Olga; Gruzman, Arie

2013-09-01

Riluzole is the only approved ALS drug. Riluzole influences several cellular pathways, but its exact mechanism of action remains unclear. Our goal was to study the drug's influence on the glucose transport rate in two ALS relevant cell types, neurons and myotubes. Stably transfected wild-type or mutant G93A human SOD1 NSC-34 motor neuron-like cells and rat L6 myotubes were exposed to riluzole. The rate of glucose uptake, translocation of glucose transporters to the cell's plasma membrane and the main glucose transport regulatory proteins' phosphorylation levels were measured. We found that riluzole increases the glucose transport rate and up-regulates the translocation of glucose transporters to plasma membrane in both types of cells. Riluzole leads to AMPK phosphorylation and to the phosphorylation of its downstream target, AS-160. In conclusion, increasing the glucose transport rate in ALS affected cells might be one of the mechanisms of riluzole's therapeutic effect. These findings can be used to rationally design and synthesize novel anti-ALS drugs that modulate glucose transport in neurons and skeletal muscles.

The alternating access mechanism of transport as observed in the sodium-hydantoin transporter Mhp1

International Nuclear Information System (INIS)

Weyand, Simone; Shimamura, Tatsuro; Beckstein, Oliver; Sansom, Mark S. P.; Iwata, So; Henderson, Peter J. F.; Cameron, Alexander D.

2011-01-01

Crystal structures of a membrane protein transporter in three different conformational states provide insights into the transport mechanism. Secondary active transporters move molecules across cell membranes by coupling this process to the energetically favourable downhill movement of ions or protons along an electrochemical gradient. They function by the alternating access model of transport in which, through conformational changes, the substrate binding site alternately faces either side of the membrane. Owing to the difficulties in obtaining the crystal structure of a single transporter in different conformational states, relatively little structural information is known to explain how this process occurs. Here, the structure of the sodium-benzylhydantoin transporter, Mhp1, from Microbacterium liquefaciens, has been determined in three conformational states; from this a mechanism is proposed for switching from the outward-facing open conformation through an occluded structure to the inward-facing open state

Brain glucose transport and phosphorylation under acute insulin-induced hypoglycemia in mice: an 18F-FDG PET study.

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Alf, Malte F; Duarte, João M N; Schibli, Roger; Gruetter, Rolf; Krämer, Stefanie D

2013-12-01

We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. Quantitative (18)F-FDG PET combined with the acquisition of real-time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue-compartment model for (18)F-FDG, and the results were evaluated with Michaelis-Menten saturation kinetics. Glucose clearance from plasma to brain (K1,glc) and the phosphorylation rate constant increased with decreasing plasma glucose (Gp), in particular at a Gp of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a Gp of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a Gp of less than 2-3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function.

Hemodynamic and renal implications of sodium-glucose cotransporter- 2 inhibitors in type 2 diabetes mellitus.

Science.gov (United States)

Tejedor Jorge, Alberto

2016-11-01

In DM2, there is increased expression of the proximal glucose transporter SGLT2. The increased glucose reabsorption from the urine to the proximal tubule and subsequently to the bloodstream, has three direct effects on the prognosis of patients with DM2: a) it increases the daily glucose load by raising the renal threshold for glucose, thus augmenting requirements for oral antidiabetics and insulin. This progressive increase occurs throughout the course of the disease and in parallel with the increase in renal mass (renal hypertrophy); b) because of the greater glucose reabsorption, glycosuria is lower than the level corresponding to glycaemia, decreasing the stimulus on the tubuloglomerular feedback system of the distal nephron. As a result, the glomerular vasodilation caused by hyperglycaemia is not arrested, maintaining glomerular hyperfiltration, and c) the excess glucose transported to the proximal tubular cells modifies their redox status, increasing local production of glycosylating products and activating local production of proinflammatory and profibrotic proliferative mediators. These mediators are responsible for the direct free radical damage to proximal tubular cells, for increased SGLT2 expression, increased production of collagen IV and extracellular matrix, and activation of monocyte/macrophages able to cause endothelial injury. The use of SGLT2 inhibitors not only reduces the reabsorption of glucose from the glomerular filtrate back into the circulationthus improving metabolic control in diabetesbut also restores tubuloglomerular feedback by increasing glycosuria and distal urinary flow. However, the most notable effect is due to inhibition of glucose entry to the proximal tubular cells. Glycosuria is toxic to the kidney: it harms glucosetransporting cells, that is, the proximal cells, which contain SGLT2. In animal models, SGLT2 inhibition reduces local production of oxygen-free radicals, the formation of mesangial matrix and collagen IV

Influence of the dialyzer membrane material on sodium transport in hemodialysis.

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Lopot, F; Kotyk, P; Bláha, J; Válek, A

1995-11-01

Traditionally Gibbs-Donnan coefficients based on the mean charge of plasma proteins are used as the only correction factor in equations describing sodium transport across the dialyzer membrane. This ignores the possible impact of the membrane material. Correction coefficients (CC) of the whole dialyzer were measured during in vivo dialysis as a quotient of dialysate to plasma sodium in an equilibrated state for different membrane materials used in commercially available dialyzers. Their mean value and correlation with total plasma protein content (TPP) were evaluated. CC for the six materials evaluated differed both in the intercept and slope of the regression line CC versus TPP: Cuprophan 1: CC = 1.0253 - 0.00017 x TPP; Hemophan 1: CC = 1.119 - 0.00175 x TPP; Hemophan 2: CC = 1.095 - 0.00111 x TPP; PMMA: CC = 1.0353 - 0.00044 x TPP; SCE:CC = 1.114 - 0.00145 x TPP; and Cuprophan 1:CC = 1.0562 - 0.00065 x TPP. The observed differences are attributed to the different charge densities of the membrane materials and suggest that for a precise description of sodium transport, the role of the membrane material needs to be considered.

Identification of rice cornichon as a possible cargo receptor for the Golgi-localized sodium transporter OsHKT1;3.

Science.gov (United States)

Rosas-Santiago, Paul; Lagunas-Gómez, Daniel; Barkla, Bronwyn J; Vera-Estrella, Rosario; Lalonde, Sylvie; Jones, Alexander; Frommer, Wolf B; Zimmermannova, Olga; Sychrová, Hana; Pantoja, Omar

2015-05-01

Membrane proteins are synthesized and folded in the endoplasmic reticulum (ER), and continue their path to their site of residence along the secretory pathway. The COPII system has been identified as a key player for selecting and directing the fate of membrane and secretory cargo proteins. Selection of cargo proteins within the COPII vesicles is achieved by cargo receptors. The cornichon cargo receptor belongs to a conserved protein family found in eukaryotes that has been demonstrated to participate in the selection of integral membrane proteins as cargo for their correct targeting. Here it is demonstrated at the cellular level that rice cornichon OsCNIH1 interacts with OsHKT1;3 and, in yeast cells, enables the expression of the sodium transporter to the Golgi apparatus. Physical and functional HKT-cornichon interactions are confirmed by the mating-based split ubiquitin system, bimolecular fluorescence complementation, and Xenopus oocyte and yeast expression systems. The interaction between the two proteins occurs in the ER of plant cells and their co-expression in oocytes leads to the sequestration of the transporter in the ER. In the yeast cornichon mutant erv14, OsHKT1;3 is mistargeted, preventing the toxic effects of sodium transport in the cell observed in wild-type cells or in the erv14 mutant that co-expressed OsHKT1;3 with either OsCNIH1 or Erv14p. Identification and characterization of rice cornichon as a possible cargo receptor opens up the opportunity to improve our knowledge on membrane protein targeting in plant cells. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Kinetics of metabolism of glucose, propionate and CO2 in steers as affected by injecting phlorizin and feeding propionate

International Nuclear Information System (INIS)

Veenhuizen, J.J.; Russell, R.W.; Young, J.W.

1988-01-01

Effects of injecting phlorizin subcutaneously and/or feeding propionate on metabolism of glucose, propionate and CO2 were determined for four steers used in a 4 x 4 Latin square design. Isotope dilution techniques were used to determine a four-pool kinetic solution for the flux of carbon among plasma glucose, rumen propionate, blood CO2 and rumen CO2. Injecting 1 g of phlorizin twice daily for 19 d resulted in 7.1 mol glucose C/d being excreted in urine. The basal glucose production of 13.4 mol C/d was increased to 17.9 mol C/d with phlorizin. There was no change in glucose oxidation or propionate production. The percentage of plasma glucose derived from propionate was unaffected by phlorizin, but 54 +/- 0.4% of total propionate was converted to plasma glucose during phlorizin treatment versus 40 +/- 0.6% during the basal treatment. When propionate was fed (18.3 mol C/d) glucose production increased to 21.2 mol C/d from the basal value of 13.4 mol C/d, and propionate oxidation to CO2 increased to 14.9 mol C/d from the basal value of 4.1 mol C/d. Glucose derived from propionate was 43 +/- 5% for the basal treatment and 67 +/- 3% during propionate feeding. The percentage of propionate converted to plasma glucose and blood and rumen CO2 was not affected by feeding propionate. An increased need for glucose, because of glucose excretion during phlorizin treatment, caused an increased utilization of propionate for gluconeogenesis, but an increased availability of propionate caused an increase in glucose production without affecting the relative distribution of carbon from propionate

In silico analysis and experimental validation of azelastine hydrochloride (N4) targeting sodium taurocholate co-transporting polypeptide (NTCP) in HBV therapy.

Science.gov (United States)

Fu, L-L; Liu, J; Chen, Y; Wang, F-T; Wen, X; Liu, H-Q; Wang, M-Y; Ouyang, L; Huang, J; Bao, J-K; Wei, Y-Q

2014-08-01

The aim of this study was to explore sodium taurocholate co-transporting polypeptide (NTCP) exerting its function with hepatitis B virus (HBV) and its targeted candidate compounds, in HBV therapy. Identification of NTCP as a novel HBV target for screening candidate small molecules, was used by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro virological examination, q-PCR, western blotting and cytotoxicity studies were used for validating efficacy of the candidate compound. We used the phylogenetic analysis of NTCP and constructed its protein-protein network. Also, we screened compounds from Drugbank and ZINC, among which five were validated for their authentication in HepG 2.2.15 cells. Then, we selected compound N4 (azelastine hydrochloride) as the most potent of them. This showed good inhibitory activity against HBsAg (IC50 = 7.5 μm) and HBeAg (IC50 = 3.7 μm), as well as high SI value (SI = 4.68). Further MD simulation results supported good interaction between compound N4 and NTCP. In silico analysis and experimental validation together demonstrated that compound N4 can target NTCP in HepG2.2.15 cells, which may shed light on exploring it as a potential anti-HBV drug. © 2014 John Wiley & Sons Ltd.

Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin

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Sandra Bowles

2017-03-01

Full Text Available Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer tested at 1–150 µM had an apparent rate of permeability (Papp typical of poorly absorbed compounds (1.73 × 10−6 cm/s. Major glucose transporters, sodium glucose linked transporter 1 (SGLT1 and glucose transporter 2 (GLUT2, and efflux protein (P-glycoprotein, PgP (1.84 × 10−6 cm/s; efflux ratio: 1.1 were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM, which decreased the Papp value to 2.9 × 10−7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.

Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin.

Science.gov (United States)

Bowles, Sandra; Joubert, Elizabeth; de Beer, Dalene; Louw, Johan; Brunschwig, Christel; Njoroge, Mathew; Lawrence, Nina; Wiesner, Lubbe; Chibale, Kelly; Muller, Christo

2017-03-30

Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (P app ) typical of poorly absorbed compounds (1.73 × 10 -6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10 -6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the P app of aspalathin was not affected by the presence of specific inhibitors. The P app of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the P app value to 2.9 × 10 -7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.

Assessment of ground transportation stress in juvenile Kemp's ridley sea turtles (Lepidochelys kempii).

Science.gov (United States)

Hunt, Kathleen E; Innis, Charles J; Kennedy, Adam E; McNally, Kerry L; Davis, Deborah G; Burgess, Elizabeth A; Merigo, Constance

2016-01-01

Sea turtle rehabilitation centres frequently transport sea turtles for long distances to move animals between centres or to release them at beaches, yet there is little information on the possible effects of transportation-related stress ('transport stress') on sea turtles. To assess whether transport stress is a clinically relevant concern for endangered Kemp's ridley sea turtles (Lepidochelys kempii), we obtained pre-transport and post-transport plasma samples from 26 juvenile Kemp's ridley sea turtles that were transported for 13 h (n = 15 turtles) or 26 h (n = 11 turtles) by truck for release at beaches. To control for effects of handling, food restriction and time of day, the same turtles were also studied on 'control days' 2 weeks prior to transport, i.e. with two samples taken to mimic pre-transport and post-transport timing, but without transportation. Blood samples were analysed for nine clinical health measures (pH, pCO2, pO2, HCO3, sodium, potassium, ionized calcium, lactate and haematocrit) and four 'stress-associated' parameters (corticosterone, glucose, white blood cell count and heterophil-to-lymphocyte ratio). Vital signs (heart rate, respiratory rate and cloacal temperature) were also monitored. Corticosterone and glucose showed pronounced elevations due specifically to transportation; for corticosterone, this elevation was significant only for the longer transport duration, whereas glucose increased significantly after both transport durations. However, clinical health measures and vital signs showed minimal or no changes in response to any sampling event (with or without transport), and all turtles appeared to be in good clinical health after both transport durations. Thus, transportation elicits a mild, but detectable, adrenal stress response that is more pronounced during longer durations of transport; nonetheless, Kemp's ridley sea turtles can tolerate ground transportation of up to 26 h in good health. These results are likely

Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium–glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents

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Takahiro Oguma

2016-12-01

Full Text Available We investigated whether structurally different sodium–glucose cotransporter (SGLT 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4 inhibitors, could enhance glucagon-like peptide-1 (GLP-1 secretion during oral glucose tolerance tests (OGTTs in rodents. Three different SGLT inhibitors—1-(β-d-Glucopyranosyl-4-chloro-3-[5-(6-fluoro-2-pyridyl-2-thienylmethyl]benzene (GTB, TA-1887, and canagliflozin—were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1 elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus.

Wortmannin inhibits both insulin- and contraction-stimulated glucose uptake and transport in rat skeletal muscle

DEFF Research Database (Denmark)

Wojtaszewski, Jørgen; Hansen, B F; Ursø, Birgitte

1996-01-01

The role of phosphatidylinositol (PI) 3-kinase for insulin- and contraction-stimulated muscle glucose transport was investigated in rat skeletal muscle perfused with a cell-free perfusate. The insulin receptor substrate-1-associated PI 3-kinase activity was increased sixfold upon insulin...... stimulation but was unaffected by contractions. In addition, the insulin-stimulated PI 3-kinase activity and muscle glucose uptake and transport in individual muscles were dose-dependently inhibited by wortmannin with one-half maximal inhibition values of approximately 10 nM and total inhibition at 1 micro......M. This concentration of wortmannin also decreased the contraction-stimulated glucose transport and uptake by approximately 30-70% without confounding effects on contractility or on muscle ATP and phosphocreatine concentrations. At higher concentrations (3 and 10 microM), wortmannin completely blocked the contraction...

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

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Ogawa, Eiichi [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Hosokawa, Masaya [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Faculty of Human Sciences, Tezukayama Gakuin University, Osaka (Japan); Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Tsukiyama, Katsushi; Yamada, Yuichiro [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Department of Internal Medicine, Division of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita (Japan); Seino, Yutaka [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Kansai Electric Power Hospital, Osaka (Japan); Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); CREST of Japan Science and Technology Cooperation (JST), Kyoto (Japan)

2011-01-07

Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

International Nuclear Information System (INIS)

Ogawa, Eiichi; Hosokawa, Masaya; Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito; Tsukiyama, Katsushi; Yamada, Yuichiro; Seino, Yutaka; Inagaki, Nobuya

2011-01-01

Research highlights: → Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. → Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. → The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic β cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [ 14 C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [ 14 C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather

Blood Glucose Determination

DEFF Research Database (Denmark)

Lippi, Giuseppe; Nybo, Mads; Cadamuro, Janne

2018-01-01

The measurement of fasting plasma glucose may be biased by a time-dependent decrease of glucose in blood tubes, mainly attributable to blood cell metabolism when glycolysis is not rapidly inhibited or blood cells cannot be rapidly separated from plasma. Although glycolysis inhibitors such as sodium...

Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca2+ release

DEFF Research Database (Denmark)

Jensen, Thomas Elbenhardt; Sylow, Lykke; Rose, Adam John

2014-01-01

signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca(2+) release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress......-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport...

Development and application of a fluorescent glucose uptake assay for the high-throughput screening of non-glycoside SGLT2 inhibitors.

Science.gov (United States)

Wu, Szu-Huei; Yao, Chun-Hsu; Hsieh, Chieh-Jui; Liu, Yu-Wei; Chao, Yu-Sheng; Song, Jen-Shin; Lee, Jinq-Chyi

2015-07-10

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are of current interest as a treatment for type 2 diabetes. Efforts have been made to discover phlorizin-related glycosides with good SGLT2 inhibitory activity. To increase structural diversity and better understand the role of non-glycoside SGLT2 inhibitors on glycemic control, we initiated a research program to identify non-glycoside hits from high-throughput screening. Here, we report the development of a novel, fluorogenic probe-based glucose uptake system based on a Cu(I)-catalyzed [3+2] cycloaddition. The safer processes and cheaper substances made the developed assay our first priority for large-scale primary screening as compared to the well-known [(14)C]-labeled α-methyl-D-glucopyranoside ([(14)C]-AMG) radioactive assay. This effort culminated in the identification of a benzimidazole, non-glycoside SGLT2 hit with an EC50 value of 0.62 μM by high-throughput screening of 41,000 compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

Transport of the Glucosamine-Derived Browning Product Fructosazine (Polyhydroxyalkylpyrazine) Across the Human Intestinal Caco-2 Cell Monolayer: Role of the Hexose Transporters.

Science.gov (United States)

Bhattacherjee, Abhishek; Hrynets, Yuliya; Betti, Mirko

2017-06-14

The transport mechanism of fructosazine, a glucosamine self-condensation product, was investigated using a Caco-2 cell model. Fructosazine transport was assessed by measuring the bidirectional permeability coefficient across Caco-2 cells. The mechanism of transport was evaluated using phlorizin, an inhibitor of sodium-dependent glucose cotransporters (SGLT) 1 and 2, phloretin and quercetin, inhibitors of glucose transporters (GLUT) 1 and 2, transcytosis inhibitor wortmannin, and gap junction disruptor cytochalasin D. The role of hexose transporters was further studied using downregulated or overexpressed cell lines. The apparent permeability (P a,b ) of fructosazine was 1.30 ± 0.02 × 10 -6 cm/s. No significant (p > 0.05) effect was observed in fructosazine transport by adding wortmannin and cytochalasin D. The presence of phlorizin, phloretin, and quercetin decreased fructosazine transport. The downregulated GLUT cells line was unable to transport fructosazine. In human intestinal epithelial Caco-2 cells, GLUT1 or GLUT2 and SGLT are mainly responsible for fructosazine transport.

Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle

OpenAIRE

Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu; Jung, Michelle M.; Rathod, Amee; Middelbeek, R. Jan-Willem; Lessard, Sarah J.; Treebak, Jonas T.; Tsuchihara, Katsuya; Esumi, Hiroyasu; Richter, Erik A.; Wojtaszewski, Jørgen F. P.; Hirshman, Michael F.; Goodyear, Laurie J.

2010-01-01

The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKα2 activity showing no effect on contraction-stimulated...

Sodium sieving in children

NARCIS (Netherlands)

Rusthoven, Esther; Krediet, Raymond T.; Willems, Hans L.; Monnens, Leo A.; Schröder, Cornelis H.

2005-01-01

Sodium sieving is a consequence of dissociation between the amount of water and sodium transported over the peritoneal membrane. This dissociation occurs in the presence of aquaporin-mediated water transport. Sieving of sodium can be used as a rough measure for aquaporin-mediated water transport.

Simultaneous measurement of glucose blood–brain transport constants and metabolic rate in rat brain using in-vivo 1H MRS

Science.gov (United States)

Du, Fei; Zhang, Yi; Zhu, Xiao-Hong; Chen, Wei

2012-01-01

Cerebral glucose consumption and glucose transport across the blood–brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMRglc) and glucose transport constants (KT: half-saturation constant; Tmax: maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMRglc, KT, and Tmax via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo 1H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMRglc, Tmax, and KT were determined to be 0.44±0.17 μmol/g per minute, 1.35±0.47 μmol/g per minute, and 13.4±6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMRglc and Tmax are more reliable than that of KT. The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. PMID:22714049

Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells.

Science.gov (United States)

Al-Ahmad, Abraham J

2017-10-01

Glucose constitutes a major source of energy of mammalian brains. Glucose uptake at the blood-brain barrier (BBB) occurs through a facilitated glucose transport, through glucose transporter 1 (GLUT1), although other isoforms have been described at the BBB. Mutations in GLUT1 are associated with the GLUT1 deficiency syndrome, yet none of the current in vitro models of the human BBB maybe suited for modeling such a disorder. In this study, we investigated the expression of glucose transporters and glucose diffusion across brain microvascular endothelial cells (BMECs) derived from healthy patient-derived induced pluripotent stem cells (iPSCs). We investigated the expression of different glucose transporters at the BBB using immunocytochemistry and flow cytometry and measured glucose uptake and diffusion across BMEC monolayers obtained from two iPSC lines and from hCMEC/D3 cells. BMEC monolayers showed expression of several glucose transporters, in particular GLUT1, GLUT3, and GLUT4. Diffusion of glucose across the monolayers was mediated via a saturable transcellular mechanism and partially inhibited by pharmacological inhibitors. Taken together, our study suggests the presence of several glucose transporters isoforms at the human BBB and demonstrates the feasibility of modeling glucose across the BBB using patient-derived stem cells. Copyright © 2017 the American Physiological Society.

Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients

Directory of Open Access Journals (Sweden)

Eugenio Cersosimo

2014-03-01

Full Text Available The importance of the kidney in glucose homeostasis has been recognized for many years. Recent observations indicating a greater role of renal glucose metabolism in various physiologic and pathologic conditions have rekindled the interest in renal glucose handling as a potential target for the treatment of diabetes. The enormous capacity of the proximal tubular cells to reabsorb the filtered glucose load entirely, utilizing the sodium-glucose co-transporter system (primarily SGLT-2, became the focus of attention. Original studies conducted in experimental animals with the nonspecific SGLT inhibitor phlorizin showed that hyperglycemia after pancreatectomy decreased as a result of forced glycosuria. Subsequently, several compounds with more selective SGLT-2 inhibition properties (“second-generation” were developed. Some agents made it into pre-clinical and clinical trials and a few have already been approved for commercial use in the treatment of type 2 diabetes. In general, a 6-month period of therapy with SGLT-2 inhibitors is followed by a mean urinary glucose excretion rate of ~80 g/day accompanied by a decline in fasting and postprandial glucose with average decreases in HgA1C ~1.0%. Concomitant body weight loss and a mild but consistent drop in blood pressure also have been reported. In contrast, transient polyuria, thirst with dehydration and occasional hypotension have been described early in the treatment. In addition, a significant increase in the occurrence of uro-genital infections, particularly in women has been documented with the use of SGLT-2 inhibitors. Conclusion: Although long-term cardiovascular, renal and bone/mineral effects are unknown SGLT-2 inhibitors, if used with caution and in the proper patient provide a unique insulin-independent therapeutic option in the management of obese type 2 diabetes patients.

Immobilization of Styrene-acrylamide Co-polymer on Either Silica Particles or Inner Surface of Silica Capillary for the Separation of D-Glucose Anomers

International Nuclear Information System (INIS)

Ali, Faiz; Kim, Yune Sung; Cheong, Won Jo

2014-01-01

Styrene-acrylamide co-polymer was immobilized on porous partially sub-2 μm silica monolith particles and inner surface of fused silica capillary (50 μm ID and 28 cm length) to result in μLC and CEC stationary phases, respectively, for separation of anomeric D-glucose derivatives. Reversed addition-fragmentation transfer (RAFT) polymerization was incorporated to induce surface polymerization. Acrylamide was employed to incorporate amide-functionality in the stationary phase. The resultant μLC and CEC stationary phases were able to separate isomers of D-glucose derivatives with high selectivity and efficiency. The mobile phase of 75/ 25 (v/v) acetonitrile (ACN)/water with 0.1% TFA, was used for HPLC with a packed column (1 mm ID, 300 mm length). The effects of pH and ACN composition on anomeric separation of D-glucose in CEC have been examined. A mobile phase of 85/15 (v/v) ACN/30 mM sodium acetate pH 6.7 was found the optimized mobile phase for CEC. The CEC stationary phase also gave good separation of other saccharides such as maltotriose and Dextran 1500 (MW∼1500) with good separation efficiency (number of theoretical plates ∼300,000/m)

Immobilization of Styrene-acrylamide Co-polymer on Either Silica Particles or Inner Surface of Silica Capillary for the Separation of D-Glucose Anomers

Energy Technology Data Exchange (ETDEWEB)

Ali, Faiz; Kim, Yune Sung; Cheong, Won Jo [Inha Univ., Incheon (Korea, Republic of)

2014-02-15

Styrene-acrylamide co-polymer was immobilized on porous partially sub-2 μm silica monolith particles and inner surface of fused silica capillary (50 μm ID and 28 cm length) to result in μLC and CEC stationary phases, respectively, for separation of anomeric D-glucose derivatives. Reversed addition-fragmentation transfer (RAFT) polymerization was incorporated to induce surface polymerization. Acrylamide was employed to incorporate amide-functionality in the stationary phase. The resultant μLC and CEC stationary phases were able to separate isomers of D-glucose derivatives with high selectivity and efficiency. The mobile phase of 75/ 25 (v/v) acetonitrile (ACN)/water with 0.1% TFA, was used for HPLC with a packed column (1 mm ID, 300 mm length). The effects of pH and ACN composition on anomeric separation of D-glucose in CEC have been examined. A mobile phase of 85/15 (v/v) ACN/30 mM sodium acetate pH 6.7 was found the optimized mobile phase for CEC. The CEC stationary phase also gave good separation of other saccharides such as maltotriose and Dextran 1500 (MW∼1500) with good separation efficiency (number of theoretical plates ∼300,000/m)

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with Type 2 diabetes

DEFF Research Database (Denmark)

Røder, Michael Einar; Storgaard, Heidi; Rungby, Jørgen

2016-01-01

The sodium-glucose cotransporter 2 inhibitor (SGLT-2i)-class is efficacious as monotherapy and as add-on therapy with an expected lowering of the glycated haemoglobin (HbA1c) concentration of approximately 7 mmol/mol. Side effects relate to the mode of action, genital infections are the main...... problem. Extremely rare cases of ketoacidosis are reported, mostly in patients with Type 1 diabetes. One SGLT-2i, empagliflozin, has been shown to reduce cardiovascular mortality and progression of kidney disease in patients with Type 2 diabetes and cardiovascular disease. Outcome trials for other SGLT-2i...... are pending. SGLT-2i are now in guidelines as a possible second-line therapy or in case of metformin intolerance....

Assessment of ground transportation stress in juvenile Kemp’s ridley sea turtles (Lepidochelys kempii)

Science.gov (United States)

Hunt, Kathleen E.; Innis, Charles J.; Kennedy, Adam E.; McNally, Kerry L.; Davis, Deborah G.; Burgess, Elizabeth A.; Merigo, Constance

2016-01-01

Sea turtle rehabilitation centres frequently transport sea turtles for long distances to move animals between centres or to release them at beaches, yet there is little information on the possible effects of transportation-related stress (‘transport stress’) on sea turtles. To assess whether transport stress is a clinically relevant concern for endangered Kemp’s ridley sea turtles (Lepidochelys kempii), we obtained pre-transport and post-transport plasma samples from 26 juvenile Kemp’s ridley sea turtles that were transported for 13 h (n = 15 turtles) or 26 h (n = 11 turtles) by truck for release at beaches. To control for effects of handling, food restriction and time of day, the same turtles were also studied on ‘control days’ 2 weeks prior to transport, i.e. with two samples taken to mimic pre-transport and post-transport timing, but without transportation. Blood samples were analysed for nine clinical health measures (pH, pCO2, pO2, HCO3, sodium, potassium, ionized calcium, lactate and haematocrit) and four ‘stress-associated’ parameters (corticosterone, glucose, white blood cell count and heterophil-to-lymphocyte ratio). Vital signs (heart rate, respiratory rate and cloacal temperature) were also monitored. Corticosterone and glucose showed pronounced elevations due specifically to transportation; for corticosterone, this elevation was significant only for the longer transport duration, whereas glucose increased significantly after both transport durations. However, clinical health measures and vital signs showed minimal or no changes in response to any sampling event (with or without transport), and all turtles appeared to be in good clinical health after both transport durations. Thus, transportation elicits a mild, but detectable, adrenal stress response that is more pronounced during longer durations of transport; nonetheless, Kemp’s ridley sea turtles can tolerate ground transportation of up to 26 h in good health. These

Co-consumption of sugars or ethanol and glucose in a Saccharomyces cerevisiae strain deleted in the HXK2 gene.

Science.gov (United States)

Raamsdonk, L M; Diderich, J A; Kuiper, A; van Gaalen, M; Kruckeberg, A L; Berden, J A; Van Dam, K; Kruckberg, A L

2001-08-01

In previous studies it was shown that deletion of the HXK2 gene in Saccharomyces cerevisiae yields a strain that hardly produces ethanol and grows almost exclusively oxidatively in the presence of abundant glucose. This paper reports on physiological studies on the hxk2 deletion strain on mixtures of glucose/sucrose, glucose/galactose, glucose/maltose and glucose/ethanol in aerobic batch cultures. The hxk2 deletion strain co-consumed galactose and sucrose, together with glucose. In addition, co-consumption of glucose and ethanol was observed during the early exponential growth phase. In S.cerevisiae, co-consumption of ethanol and glucose (in the presence of abundant glucose) has never been reported before. The specific respiration rate of the hxk2 deletion strain growing on the glucose/ethanol mixture was 900 micromol.min(-1).(g protein)(-1), which is four to five times higher than that of the hxk2 deletion strain growing oxidatively on glucose, three times higher than its parent growing on ethanol (when respiration is fully derepressed) and is almost 10 times higher than its parent growing on glucose (when respiration is repressed). This indicates that the hxk2 deletion strain has a strongly enhanced oxidative capacity when grown on a mixture of glucose and ethanol. Copyright 2001 John Wiley & Sons, Ltd.

Interactions between co-expressed Arabidopsis sucrose transporters in the split-ubiquitin system

Directory of Open Access Journals (Sweden)

Lalonde Sylvie

2003-03-01

Full Text Available Abstract Background The Arabidopsis genome contains nine sucrose transporter paralogs falling into three clades: SUT1-like, SUT2 and SUT4. The carriers differ in their kinetic properties. Many transport proteins are known to exist as oligomers. The yeast-based split ubiquitin system can be used to analyze the ability of membrane proteins to interact. Results Promoter-GUS fusions were used to analyze the cellular expression of the three transporter genes in transgenic Arabidopsis plants. All three fusion genes are co-expressed in companion cells. Protein-protein interactions between Arabidopsis sucrose transporters were tested using the split ubiquitin system. Three paralogous sucrose transporters are capable of interacting as either homo- or heteromers. The interactions are specific, since a potassium channel and a glucose transporter did not show interaction with sucrose transporters. Also the biosynthetic and metabolizing enzymes, sucrose phosphate phosphatase and sucrose synthase, which were found to be at least in part bound to the plasma membrane, did not specifically interact with sucrose transporters. Conclusions The split-ubiquitin system provides a powerful tool to detect potential interactions between plant membrane proteins by heterologous expression in yeast, and can be used to screen for interactions with membrane proteins as baits. Like other membrane proteins, the Arabidopsis sucrose transporters are able to form oligomers. The biochemical approaches are required to confirm the in planta interaction.

Effect of selective blockade of oxygen consumption, glucose transport, and Ca2+ influx on thyroxine action in human mononuclear cells

DEFF Research Database (Denmark)

Kvetny, J; Matzen, L E

1990-01-01

The effect of selective blockade of cellular glucose transporters, Ca2+ influx, and mitochondrial oxygen consumption on thyroxine (T4)-stimulated oxygen consumption and glucose uptake was examined in human mononuclear blood cells. Blockade of glucose transporters by cytochalasin B (1 x 10(-5) mol....../L) and of Ca2+ influx by alprenolol (1 x 10(-5) mol/L) and verapamil (4 x 10(-4) mol/L) inhibited T4-activated glucose uptaken and reduced T4-stimulated oxygen consumption by 20%. Uncoupling of mitochondrial oxygen consumption by azide (1 x 10(-3) mol/L) inhibited T4-stimulated oxygen consumption, but had...... no effect on glucose uptake. We conclude that T4-stimulated glucose uptake in human mononuclear blood cells is dependent on intact glucose transporters and Ca2+ influx, but not on mitochondrial oxygen consumption. However, oxygen consumption is, in part, dependent on intact glucose uptake....

Hippocampal infusions of glucose reverse memory deficits produced by co-infusions of a GABA receptor agonist.

Science.gov (United States)

Krebs-Kraft, Desiree L; Parent, Marise B

2008-02-01

Although septal infusions of glucose typically have positive effects on memory, we have shown repeatedly that this treatment exacerbates memory deficits produced by co-infusions of gamma-aminobutyric acid (GABA) receptor agonists. The present experiments tested whether this negative interaction between glucose and GABA in the medial septum would be observed in the hippocampus, a brain region where glucose typically has positive effects on memory. Specifically, we determined whether hippocampal infusions of glucose would reverse or exacerbate memory deficits produced by hippocampal co-infusions of the GABA receptor agonist muscimol. Fifteen minutes prior to either assessing spontaneous alternation (SA) or continuous multiple trial inhibitory avoidance (CMIA) training, male Sprague-Dawley-derived rats were given bilateral hippocampal infusions of vehicle (phosphate-buffered saline [PBS], 1 microl/2 min), glucose (33 or 50 nmol), muscimol (0.3 or 0.4 microg, SA or 3 microg, CMIA) or muscimol and glucose combined in one solution. The results indicated that hippocampal infusions of muscimol alone decreased SA scores and CMIA retention latencies. More importantly, hippocampal infusions of glucose, at doses that had no effect when infused alone, attenuated (33 nmol) or reversed (50 nmol) the muscimol-induced memory deficits. Thus, although co-infusions of glucose with muscimol into the medial septum impair memory, the present findings show that an opposite effect is observed in the hippocampus. Collectively, these findings suggest that the memory-impairing interaction between glucose and GABA in the medial septum is not a general property of the brain, but rather is brain region-dependent.

Hierarchical Co(OH){sub 2} nanostructures/glassy carbon electrode derived from Co(BTC) metal–organic frameworks for glucose sensing

Energy Technology Data Exchange (ETDEWEB)

He, Juan; Lu, Xingping; Yu, Jie; Wang, Li; Song, Yonghai, E-mail: yhsonggroup@hotmail.com [Jiangxi Normal University, Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering (China)

2016-07-15

A novel Co(OH){sub 2}/glassy carbon electrode (GCE) has been fabricated via metal–organic framework (MOF)-directed method. In the strategy, the Co(BTC, 1,3,5-benzentricarboxylic acid) MOFs/GCE was firstly prepared by alternately immersing GCE in Co{sup 2+} and BTC solution based on a layer-by-layer method. And then, the Co(OH){sub 2} with hierarchical flake nanostructure/GCE was constructed by immersing Co(BTC) MOFs/GCE into 0.1 M NaOH solution at room temperature. Such strategy improves the distribution of hierarchical Co(OH){sub 2} nanostructures on electrode surface greatly, enhances the stability of nanomaterials on the electrode surface, and increases the use efficiency of the Co(OH){sub 2} nanostructures. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray powder diffraction, energy dispersive spectroscopy, Fourier transform infrared spectroscopy, and Raman spectra were used to characterize the Co(BTC) MOFs/GCE and Co(OH){sub 2}/GCE. Based on the hierarchical Co(OH){sub 2} nanostructures/GCE, a novel and sensitive nonenzymatic glucose sensor was developed. The good performance of the resulted sensor toward the detection of glucose was ascribed to hierarchical flake nanostructures, good mechanical stability, excellent distribution, and large specific surface area of Co(OH){sub 2} nanostructures. The proposed preparation method is simple, efficient, and cheap .Graphical Abstract.

Hydrothermal Synthesis of Co-Ru Alloy Particle Catalysts for Hydrogen Generation from Sodium Borohydride

Directory of Open Access Journals (Sweden)

Marija Kurtinaitienė

2013-01-01

Full Text Available We report the synthesis of μm and sub-μm-sized Co, Ru, and Co-Ru alloy species by hydrothermal approach in the aqueous alkaline solutions (pH ≥ 13 containing CoCl2 and/or RuCl3, sodium citrate, and hydrazine hydrate and a study of their catalytic properties for hydrogen generation by hydrolysis of sodium borohydride solution. This way provides a simple platform for fabrication of the ball-shaped Co-Ru alloy catalysts containing up to 12 wt% Ru. Note that bimetallic Co-Ru alloy bowls containing even 7 at.% Ru have demonstrated catalytic properties that are comparable with the ones of pure Ru particles fabricated by the same method. This result is of great importance in view of the preparation of cost-efficient catalysts for hydrogen generation from borohydrides. The morphology and composition of fabricated catalyst particles have been characterized using scanning electron microscopy, energy dispersive X-ray diffraction, and inductively coupled plasma optical emission spectrometry.

Optimization of pipeline transport for CO2 sequestration

International Nuclear Information System (INIS)

Zhang, Z.X.; Wang, G.X.; Massarotto, P.; Rudolph, V.

2006-01-01

Coal fired power generation will continue to provide energy to the world for the foreseeable future. However, this energy use is a significant contributor to increased atmospheric CO 2 concentration and, hence, global warming. Capture and disposal of CO 2 has received increased R and D attention in the last decade as the technology promises to be the most cost effective for large scale reductions in CO 2 emissions. This paper addresses CO 2 transport via pipeline from capture site to disposal site, in terms of system optimization, energy efficiency and overall economics. Technically, CO 2 can be transported through pipelines in the form of a gas, a supercritical fluid or in the subcooled liquid state. Operationally, most CO 2 pipelines used for enhanced oil recovery transport CO 2 as a supercritical fluid. In this paper, supercritical fluid and subcooled liquid transport are examined and compared, including their impacts on energy efficiency and cost. Using a commercially available process simulator, ASPEN PLUS 10.1, the results show that subcooled liquid transport maximizes the energy efficiency and minimizes the cost of CO 2 transport over long distances under both isothermal and adiabatic conditions. Pipeline transport of subcooled liquid CO 2 can be ideally used in areas of cold climate or by burying and insulating the pipeline. In very warm climates, periodic refrigeration to cool the CO 2 below its critical point of 31.1 o C, may prove economical. Simulations have been used to determine the maximum safe pipeline distances to subsequent booster stations as a function of inlet pressure, environmental temperature and ground level heat flux conditions

Lack of SLC2A1 (glucose transporter 1) mutations in 30 Italian patients with alternating hemiplegia of childhood.

Science.gov (United States)

De Grandis, Elisa; Stagnaro, Michela; Biancheri, Roberta; Giannotta, Melania; Gobbi, Giuseppe; Traverso, Monica; Veneselli, Edvige; Zara, Federico

2013-07-01

Alternating hemiplegia of childhood is a rare, predominantly sporadic disorder. Diagnosis is clinical, and little is known about genetics. Glucose transporter 1 deficiency syndrome shares with alternating hemiplegia of childhood paroxysmal and nonparoxysmal symptoms. The aim of the study was to investigate glucose transporter 1 mutations in 30 Italian patients. Genetic material was analyzed by DNA amplification and glucose transporter 1 region sequencing. Mutational analysis findings of the SLC2A1 gene were negative in all patients. The pattern of movement disorders was reviewed. Interictal dystonia and multiple paroxysmal events were typical of alternating hemiplegia of childhood. In conclusion, alternating hemiplegia of childhood is a heterogeneous clinical condition, and although glucose transporter 1 deficiency can represent an undiagnosed cause of this disorder, mutational analysis is not routinely recommended. Alternatively, a careful clinical analysis and the 3-O-methyl-D-glucose uptake test can allow prompt identification of a subgroup of patients with alternating hemiplegia of childhood treatable with a ketogenic diet.

Effects of insulin and epinephrine on Na+-K+ and glucose transport in soleus muscle

International Nuclear Information System (INIS)

Clausen, T.; Flatman, J.A.

1987-01-01

To identify possible cause-effect relationships between changes in active Na + -K + transport, resting membrane potential, and glucose transport, the effects of insulin and epinephrine were compared in rat soleus muscle. Epinephrine, which produced twice as large a hyperpolarization as insulin, induced only a modest increase in 14 C-labeled sugar transport. Ouabain, at a concentration (10 -3 M) sufficient to block active Na + -K + transport and the hyperpolarization induced by the two hormones, did not interfere with sugar transport stimulation. After Na + loading in K + -free buffer, the return to K + -containing standard buffer caused marked stimulation of active 22 Na + - 42 K + transport, twice the hyperpolarization produced by insulin but no change in sugar transport. The insulin-induced activation of the 22 Na + - 42 K + pump leads to decreased intracellular 22 Na + concentration and hyperpolarization, but none of these events can account for the concomitant activation of the glucose transport system. The stimulating effect of insulin on active Na + -K + transport was not suppressed by amiloride, indicating that in intact skeletal muscle it is not elicited by a primary increase in Na + influx via the Na + /H + -exchange system

Influence of glucose and urea on 125I transport across an anion exchange paper membrane

International Nuclear Information System (INIS)

Inoue, Hiroyoshi

2001-01-01

In order to study the influence of glucose and urea on the 125 I transport across an anion exchange paper membrane, the transmembrane potential, the fluxes, and the concentrations of 125 I, glucose and urea within the membrane were measured in the Na 125 I concentration-cell system containing glucose or urea. Glucose and urea increased the membrane/solution distribution of the iodide ion, but scarcely affected the diffusion process of iodide ion within the membrane

Characterization of Gene Candidates for Vacuolar Sodium Transport from Hordeum Vulgare

KAUST Repository

Scheu, Arne Hagen August

2017-01-01

Various potential causes are discussed, including inaccuracies in the genome resource used as reference for primer design and issues inherent to the model system. Finally, I make suggestions on how to proceed to further characterize the candidate genes and hopefully identify novel sodium transporters from barley.

Preliminary Plugging tests in Narrow Sodium Channels by Sodium and Carbon Dioxide reaction

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-05-15

This report is on the investigation of the physical/chemical phenomena that a slow loss of CO{sub 2} inventory into sodium after the sodium-CO{sub 2} boundary failure in PCHEs in realistic operating conditions. The first phenomenon is potential channel plugging inside the narrow PCHE channel. Unlike a conventional shell and- tube type HXs, failures in a PCHE are expected to be small cracks. If the faulted channel is blocked, it may have a positive function for plant safety because the pressure boundary would automatically recover due to this self-plugging. The other one is damage propagation on pressure boundary, which is referred to as potential wastage with combined corrosion/erosion effect. Physical/chemical phenomena that a slow loss of CO{sub 2} inventory into sodium after the sodium-CO{sub 2} boundary failure in printed circuit heat exchangers (PCHEs) were investigated. Our preliminary experimental results of plugging show that sodium flow immediately stopped as CO{sub 2} was injected through the nozzle at 300-400 .deg. C in 3 mm sodium channels, whereas sodium flow stopped about 60 min after CO{sub 2} injection in 5 mm sodium channels.

Co-overexpressing a plasma membrane and a vacuolar membrane sodium/proton antiporter significantly improves salt tolerance in transgenic Arabidopsis plants.

Science.gov (United States)

The Arabidopsis gene AtNHX1 encodes a vacuolar membrane bound sodium/proton (Sodium/Hydrogen) antiporter that transports sodium into the vacuole and exports hydrogen into the cytoplasm. The Arabidopsis gene SOS1 encodes a plasma membrane bound sodium/hydrogen antiporter that exports sodium to the ex...

Altered regulation of renal sodium transporters in salt-sensitive hypertensive rats induced by uninephrectomy.

Science.gov (United States)

Jung, Ji Yong; Lee, Jay Wook; Kim, Sejoong; Jung, Eun Sook; Jang, Hye Ryoun; Han, Jin Suk; Joo, Kwon Wook

2009-12-01

Uninephrectomy (uNx) in young rats causes salt-sensitive hypertension (SSH). Alterations of sodium handling in residual nephrons may play a role in the pathogenesis. Therefore, we evaluated the adaptive alterations of renal sodium transporters according to salt intake in uNx-SSH rats. uNx or sham operations were performed in male Sprague-Dawley rats, and normal-salt diet was fed for 4 weeks. Four experimental groups were used: sham-operated rats raised on a high-salt diet for 2 weeks (CHH) or on a low-salt diet for 1 week after 1 week's high-salt diet (CHL) and uNx rats fed on the same diet (NHH, NHL) as the sham-operated rats were fed. Expression of major renal sodium transporters were determined by semiquantitative immunoblotting. Systolic blood pressure was increased in NHH and NHL groups, compared with CHH and CHL, respectively. Protein abundances of Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and Na(+)/Cl(-) cotransporter (NCC) in the CHH group were lower than the CHL group. Expression of epithelial sodium channel (ENaC)-γ increased in the CHH group. In contrast, expressions of NKCC2 and NCC in the NHH group didn't show any significant alterations, compared to the NHL group. Expressions of ENaC-α and ENaC-β in the NHH group were higher than the CHH group. Adaptive alterations of NKCC2 and NCC to changes of salt intake were different in the uNx group, and changes in ENaC-α and ENaC-β were also different. These altered regulations of sodium transporters may be involved in the pathogenesis of SSH in the uNx rat model.

Metabolic Transition of Milk Lactose Synthesis and Up-regulation by AKT1 in Sows from Late Pregnancy to Lactation.

Science.gov (United States)

Chen, Fang; Chen, Baoliang; Guan, Wutai; Chen, Jun; Lv, Yantao; Qiao, Hanzhen; Wang, Chaoxian; Zhang, Yinzhi

2017-03-01

Lactose plays a crucial role in controlling milk volume by inducing water toward into the mammary secretory vesicles from the mammary epithelial cell cytoplasm, thereby maintaining osmolality. In current study, we determined the expression of several lactose synthesis related genes, including glucose transporters (glucose transporter 1, glucose transporter 8, sodium-glucose cotransporter 1, sodium-glucose cotransporter 3, and sodium-glucose cotransporter 5), lactose synthases (α-lactalbumin and β1,4-galactosyltransferase), and hexokinases (hexokinase-1 and hexokinase-2) in sow mammary gland tissue at day 17 before delivery, on the 1st day of lactation and at peak lactation. The data showed that glucose transporter 1 was the dominant glucose transporter within sow mammary gland and that expression of each glucose transporter 1, sodium-glucose cotransporter 1, hexokinase-1, hexokinase-2, α-lactalbumin, and β1,4-galactosyltransferase were increased (p lactose synthesis was significantly elevated with the increase of milk production and AKT1 could positively regulate lactose synthesis.

Sodium removal from CSRDM lower part by water vapour - CO2 process

International Nuclear Information System (INIS)

Sundar Raj, S.I.; Sreedhar, B.K.; Gurumoorthy, K.; Rajan, K.K.; Kalyanasundaram, P.; Rajan, M.; Vaidyanathan, G.

2006-01-01

Sodium is the primary and secondary coolant in fast reactors. Primary and secondary circuits components like Control and Safety Rod Drive Mechanism (CSRDM), pumps, heat exchangers etc. handle liquid sodium. Sodium has good affinity to oxygen and reacts vigorously with water. Hence sodium cleaning is the first and important activity in the maintenance of the components. In reactor components this cleaning process also helps in removing a major part of radioactive contaminants after which they are subjected to chemical decontamination. There are several methods available for removing sodium from components. Out of these, the water vapour-CO 2 process is selected for large components such as pumps, heat exchangers etc. while steam cleaning is used for the core sub assemblies. The cleaning processes are to be closely monitored to ensure safety because the release of hydrogen is to be kept below 4 % during the process. This paper discusses the in house facility and the experience in the successful use of the process in the cleaning of CSRDM. (author)

Blood glucose level reconstruction as a function of transcapillary glucose transport.

Science.gov (United States)

Koutny, Tomas

2014-10-01

A diabetic patient occasionally undergoes a detailed monitoring of their glucose levels. Over the course of a few days, a monitoring system provides a detailed track of their interstitial fluid glucose levels measured in their subcutaneous tissue. A discrepancy in the blood and interstitial fluid glucose levels is unimportant because the blood glucose levels are not measured continuously. Approximately five blood glucose level samples are taken per day, and the interstitial fluid glucose level is usually measured every 5min. An increased frequency of blood glucose level sampling would cause discomfort for the patient; thus, there is a need for methods to estimate blood glucose levels from the glucose levels measured in subcutaneous tissue. The Steil-Rebrin model is widely used to describe the relationship between blood and interstitial fluid glucose dynamics. However, we measured glucose level patterns for which the Steil-Rebrin model does not hold. Therefore, we based our research on a different model that relates present blood and interstitial fluid glucose levels to future interstitial fluid glucose levels. Using this model, we derived an improved model for calculating blood glucose levels. In the experiments conducted, this model outperformed the Steil-Rebrin model while introducing no additional requirements for glucose sample collection. In subcutaneous tissue, 26.71% of the calculated blood glucose levels had absolute values of relative differences from smoothed measured blood glucose levels less than or equal to 5% using the Steil-Rebrin model. However, the same difference interval was encountered in 63.01% of the calculated blood glucose levels using the proposed model. In addition, 79.45% of the levels calculated with the Steil-Rebrin model compared with 95.21% of the levels calculated with the proposed model had 20% difference intervals. Copyright © 2014 Elsevier Ltd. All rights reserved.

The second sodium site in the dopamine transporter controls cation permeability and is regulated by chloride

DEFF Research Database (Denmark)

Borre, Lars; Andreassen, Thorvald F; Shi, Lei

2014-01-01

The dopamine transporter (DAT) belongs to the family of neurotransmitter:sodium symporters (NSSs) and controls dopamine (DA) homeostasis by mediating Na(+)- and Cl(-)-dependent reuptake of DA. Here we used two-electrode voltage clamp measurements in Xenopus oocytes together with targeted mutagene......The dopamine transporter (DAT) belongs to the family of neurotransmitter:sodium symporters (NSSs) and controls dopamine (DA) homeostasis by mediating Na(+)- and Cl(-)-dependent reuptake of DA. Here we used two-electrode voltage clamp measurements in Xenopus oocytes together with targeted...

Economic evaluation of CO2 pipeline transport in China

International Nuclear Information System (INIS)

Zhang Dongjie; Wang Zhe; Sun Jining; Zhang Lili; Li Zheng

2012-01-01

Highlights: ► We build a static hydrodynamic model of CO 2 pipeline for CCS application. ► We study the impact on pressure drop of pipeline by viscosity, density and elevation. ► We point out that density has a bigger impact on pressure drop than viscosity. ► We suggest dense phase transport is preferred than supercritical state. ► We present cost-optimal pipeline diameters for different flowrates and distances. - Abstract: Carbon capture and sequestration (CCS) is an important option for CO 2 mitigation and an optimized CO 2 pipeline transport system is necessary for large scale CCS implementation. In the present work, a hydrodynamic model for CO 2 pipeline transport was built up and the hydrodynamic performances of CO 2 pipeline as well as the impacts of multiple factors on pressure drop behavior along the pipeline were studied. Based on the model, an economic model was established to optimize the CO 2 pipeline transport system economically and to evaluate the unit transport cost of CO 2 pipeline in China. The hydrodynamic model results show that pipe diameter, soil temperature, and pipeline elevation change have significant influence on the pressure drop behavior of CO 2 in the pipeline. The design of pipeline system, including pipeline diameter and number of boosters etc., was optimized to achieve a lowest unit CO 2 transport cost. In regarding to the unit cost, when the transport flow rate and distance are between 1–5 MtCO 2 /year and 100–500 km, respectively, the unit CO 2 transport cost mainly lies between 0.1–0.6 RMB/(tCO 2 km) and electricity consumption cost of the pipeline inlet compressor was found to take more than 60% of the total cost. The present work provides reference for CO 2 transport pipeline design and for feasibility evaluation of potential CCS projects in China.

Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

Science.gov (United States)

Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

2010-03-01

Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

Carbon transport in sodium systems

International Nuclear Information System (INIS)

Martin Espigares, M.; Lapena, J.; La Torre, M. de

1983-01-01

Carbon activities in dynamic non isothermal sodium system are determined using an equilibratium method. Foils of Fe-18 w% Cr-8 W% Ni alloy with low carbon content (in the as received condition) are exposed to dynamic liquid sodium in the temperature range between 450 0 C and 700 0 C. The analysis was used to evaluate the carburization-decarburization behaviour of type 304 stainless steel exposed to sodium. (author)

Investigation of Plugging of Narrow Sodium Channels by Sodium and Carbon Dioxide Interaction

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong; Kim, Tae-joon [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2014-10-15

The supercritical CO{sub 2} Brayton cycle system is known to be a promising power conversion system for improving the efficiency and preventing the sodium water reaction (SWR) of the current SFR concept using a Rankine steam cycle. PCHEs are known to have potential for reducing the volume occupied by the sodium-to-CO{sub 2} exchangers as well as the heat exchanger mass relative to traditional shell-and-tube heat exchangers. Here, we report a study on a plugging test by the interaction of sodium and CO{sub 2} to investigate design parameters of sodium channels in the realistic operating conditions. We investigated a plugging test by an interaction of sodium and CO{sub 2} with different cross sectional areas of the sodium channels. It was found that the flow rate of sodium decreased earlier and faster with a narrower cross sectional area compared to a wider one. Our experimental results are expected to be used for determining the sodium channel areas of PCHEs.

Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway

International Nuclear Information System (INIS)

Tang, Xiaojiang; Zhu, Jinqiu; Zhong, Zhiyong; Luo, Minhui; Li, Guangxian; Gong, Zhihong; Zhang, Chenzi; Fei, Fan; Ruan, Xiaolin; Zhou, Jinlin; Liu, Gaofeng; Li, Guoding; Olson, James; Ren, Xuefeng

2016-01-01

Chronic exposure to cadmium compounds (Cd 2+ ) is one of the major public health problems facing humans in the 21st century. Cd 2+ in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd 2+ from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000 mg/kg or 5000 mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd 2+ deposited in the kidneys of Cd 2+ -laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd 2+ level was reduced from 12.9 μg/g to 1.3 μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd 2+ from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd 2+ exposure.

Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway

Energy Technology Data Exchange (ETDEWEB)

Tang, Xiaojiang, E-mail: river-t@126.com [Guangdong Medical Laboratory Animal Center (China); Zhu, Jinqiu [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Zhong, Zhiyong; Luo, Minhui; Li, Guangxian [Guangdong Medical Laboratory Animal Center (China); Gong, Zhihong [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Zhang, Chenzi; Fei, Fan [Guangdong Medical Laboratory Animal Center (China); Ruan, Xiaolin [Guangdong Poison Control Center (China); Zhou, Jinlin [Golden Health (Foshan) Technology Co., Ltd (China); Liu, Gaofeng [School of Chemistry and Chemical Engineering, Sun Yat-Sen University (China); Li, Guoding [Guangdong Medical Laboratory Animal Center (China); Olson, James [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY (United States); Ren, Xuefeng, E-mail: xuefengr@buffalo.edu [Guangdong Medical Laboratory Animal Center (China); Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY (United States)

2016-08-15

Chronic exposure to cadmium compounds (Cd{sup 2+}) is one of the major public health problems facing humans in the 21st century. Cd{sup 2+} in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd{sup 2+} from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000 mg/kg or 5000 mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd{sup 2+} deposited in the kidneys of Cd{sup 2+}-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd{sup 2+} level was reduced from 12.9 μg/g to 1.3 μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd{sup 2+} from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd{sup 2+} exposure.

Measurement of glucose area under the curve using minimally invasive interstitial fluid extraction technology: evaluation of glucose monitoring concepts without blood sampling.

Science.gov (United States)

Sato, Toshiyuki; Okada, Seiki; Hagino, Kei; Asakura, Yoshihiro; Kikkawa, Yasuo; Kojima, Junko; Watanabe, Toshihiro; Maekawa, Yasunori; Isobe, Kazuki; Koike, Reona; Nakajima, Hiromu; Asano, Kaoru

2011-12-01

Monitoring postprandial hyperglycemia is crucial in treating diabetes, although its dynamics make accurate monitoring difficult. We developed a new technology for monitoring postprandial hyperglycemia using interstitial fluid (ISF) extraction technology without blood sampling. The glucose area under the curve (AUC) using this system was measured as accumulated ISF glucose (IG) with simultaneous calibration with sodium ions. The objective of this study was to evaluate this technological concept in healthy individuals. Minimally invasive ISF extraction technology (MIET) comprises two steps: pretreatment with microneedles and ISF accumulation over a specific time by contact with a solvent. The correlation between glucose and sodium ion levels using MIET was evaluated in 12 subjects with stable blood glucose (BG) levels during fasting. BG and IG time courses were evaluated in three subjects to confirm their relationship while BG was fluctuating. Furthermore, the accuracy of glucose AUC measurements by MIET was evaluated several hours after a meal in 30 subjects. A high correlation was observed between glucose and sodium ion levels when BG levels were stable (R=0.87), indicating that sodium ion is a good internal standard for calibration. The variation in IG and BG with MIET was similar, indicating that IG is an adequate substitute for BG. Finally, we showed a strong correlation (R=0.92) between IG-AUC and BG-AUC after a meal. These findings validate the adequacy of glucose AUC measurements using MIET. Monitoring glucose using MIET without blood sampling may be beneficial to patients with diabetes.

Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory.

Science.gov (United States)

Pearson-Leary, Jiah; McNay, Ewan C

2016-11-23

The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues. The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long

Transport of sodium through the cover gas of a sodium cooled fast reactor

International Nuclear Information System (INIS)

Clement, C.F.; Hawtin, P.

1977-01-01

Idealised models are presented for sodium vapour transport through argon or helium and the subsequent roof condensation. For both gases the dominant heat transfer mechanism from the pool is radiation but the mass transport process is convection for argon and diffusion for helium. For argon a theory based on work of Hills and Szekely is presented which predicts a heat transfer rate independent of the actual amount of condensation occurring in the cavity, and which suggests a mass transfer rate close to that calculated in the absence of condensation. Experimental determination of the temperature and velocity flow characteristics are desirable to examine and improve on the suspect basic assumption of the theory that the velocity flow pattern is unaffected by condensation. For helium diffusion theory predicts a mass transfer rate an order of magnitude smaller than for argon, but only a slightly smaller overall heat transfer rate because of the dominance of radiation. (author)

Solubilization and separation of the human erythrocyte D-glucose transporter covalently and noncovalently photoaffinity-labeled with [3H]cytochalasin B

International Nuclear Information System (INIS)

Kurokawa, T.; Tillotson, L.G.; Chen, C.C.; Isselbacher, K.J.

1986-01-01

The D-glucose transporter in the human erythrocyte membranes was photoaffinity-labeled with [ 3 H]cytochalasin B and solubilized with n-octyl β-D-glucopyranoside (octyl glucoside). [ 3 H]Cytochalasin B-bound proteins were further isolated by using Sephadex G-50 chromatography. The amount of [ 3 H]cytochalasin B associated with the membrane proteins was approximately 10% of the total radioactivity in the octyl glucoside extract. The solubilized photoaffinity-labeled D-glucose transporter was isolated and found to consist of two major peaks by DEAE-Sephacel chromatography. The radioactivity of peak II was considerably greater than that of peak I. The incorporation of [ 3 H]cytochalasin B into both peaks was blocked by the presence of D-glucose during photolysis. These results indicate the [ 3 H]cytochalasin B was covalently bound to the D-glucose transporter only in peak II and that peak II could be generated by the photoaffinity labeling of peak I. However, the D-glucose transport activity was associated only with peak I. These findings suggest that the anionic domain of the D-glucose transporter becomes exposed because of the conformational changes of the protein as a result of covalent binding with [ 3 H]cytochalasin B by photoaffinity labeling

Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

Science.gov (United States)

Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

2007-10-01

Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

Photoaffinity labeling of the human erythrocyte monosaccharide transporter with an aryl azide derivative of D-glucose

International Nuclear Information System (INIS)

Shanahan, M.F.; Wadzinski, B.E.; Lowndes, J.M.; Ruoho, A.E.

1985-01-01

A photoreactive, radioiodinated derivative of glucose, N-(4-iodoazidosalicyl)-6-amido-6-deoxyglucopyranose (IASA-glc), has been synthesized and used as a photoaffinity label for the human erythrocyte monosaccharide transporter. Photoinactivation and photoinsertion are both light-dependent and result in a marked decrease in the absorption spectra of the compound. When [ 125 I]IASA-glc was photolyzed with erythrocyte ghost membranes, photoinsertion of radiolabel was observed in three major regions, spectrin, band 3, and a protein of 58,000 daltons located in the zone 4.5 region. Of the three regions which were photolabeled, only labeling of polypeptides in the zone 4.5 region was partially blocked by D-glucose. In the non-iodinated form, N-(4-azidosalicyl)-6-amido-6-deoxy-glucopyranose inhibited the labeling of the transporter by [ 125 I]IASA-glc more effectively than D-glucose. The ability to synthesize this [ 125 I]containing photoprobe for the monosaccharide transporter at carrier-free levels offers several new advantages for investigating the structure of this transport protein in the erythrocyte

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

International Nuclear Information System (INIS)

Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine; Halimi, Serge; Demongeot, Jacques

2007-01-01

Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using 125 I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

Science.gov (United States)

Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

2007-01-01

Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state and it has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats with 125I-6-Deoxy-6-Iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood were assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady-state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p<0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) and whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. PMID:17171359

Effect of in vivo injection of cholera and pertussis toxin on glucose transport in rat skeletal muscle

DEFF Research Database (Denmark)

Ploug, Thorkil; Han, X; Petersen, L N

1997-01-01

Cholera toxin (CTX) and pertussis toxin (PTX) were examined for their ability to inhibit glucose transport in perfused skeletal muscle. Twenty-five hours after an intravenous injection of CTX, basal transport was decreased approximately 30%, and insulin- and contraction-stimulated transport...... in GLUT-1 protein content was found. In contrast, GLUT-4 mRNA was unchanged, but transcripts for GLUT-1 were increased > or = 150% in all three muscles from CTX-treated rats. The findings suggest that CTX via increased cAMP impairs basal as well as insulin- and contraction-stimulated muscle glucose...

Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.

Science.gov (United States)

Tanegashima, Kosuke; Sato-Miyata, Yukiko; Funakoshi, Masabumi; Nishito, Yasumasa; Aigaki, Toshiro; Hara, Takahiko

2017-01-01

We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon β-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9-mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that β-OHB is a HDAC inhibitor and show that β-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Substrate binding to SGLT1 investigated by single molecule force spectroscopy

International Nuclear Information System (INIS)

Neundlinger, I. J.

2010-01-01

D-glucose serves as one of the most important fuels in various organism due to its fundamental role in ATP-, protein and lipid synthesis. Thus, sustaining glucose homeostasis is a crucial issue of life as disorders can cause severe malfunctions such as glucose-galactose-malabsorbtion (GGM). Sodium-glucose co-transporter, SGLTs, especially the high affinity transporter SGLT1, play a crucial role in accumulation of glucose in the cell as they facilitate transport of the sugar into the cytoplasma across the cell membrane by a Na+-electrochemical potential. Even recently, members of the SGLT transporter family have become a therapeutic target for the treatment of hyperglycemia in type 2 diabetes. Hence, it is of particular importance to gain insights on the dynamic behavior of SGLTs during substrate binding and transport across the cell membrane on the single molecular level. In the present study, the Atomic Force Microscope (AFM) was employed to investigate the dynamic properties of the sodium-glucose co-transporter SGLT1 upon substrate binding under nearly physiological conditions. Hereto, new glucose derivatives were synthesized in order to probe the recognition efficiency of these molecules to SGLT1 embedded in the plasma membrane of living cells. A well established coupling protocol was used to covalently link (i) amino-modified D-glucose owning a conserved pyranose ring, (ii) 1-thio-β-D-glucose having a sulphur atom at C1 of the pyranose ring and (iii) the competitive inhibitor phlorizin to the AFM tip via poly(ethylene)glycol (PEG)-tether using different functional end groups and varying lengths. Binding characteristics, e.g. binding probability, interaction forces, influence of substances (glucose, phlorizin, sodium) and of molecule-linker compounds were obtained by performing single molecular recognition force spectroscopy (SMRFS) measurements. Moreover, temperature controlled radioactive binding/transport assays and SMRFS experiments yielded insights into

The early and late effects of digoxin treatment on the sodium transport, sodium content and Na+K+- ATPase or erythrocytes.

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Cumberbatch, M; Zareian, K; Davidson, C; Morgan, D B; Swaminathan, R

1981-01-01

1 Erythrocyte sodium content, sodium transport (ouabain sensitive sodium flux Eos, and ouabain sensitive efflux rate constant ERCos) sodium, potassium activated ouabain sensitive adenosine triphosphatase (Na+K+ATPase) and plasma digoxin were measured in patients during acute digitalisation and in patients who were on long-term digoxin treatment. 2 In the six patients who were studied during digitalisation, the ERCos and Na+K+ATPase activity decreased and erythrocyte sodium content increased during days 2-4 treatment, but there was no change in Eos. 3 In 39 patients on long term digoxin therapy (2-119 months) the erythrocyte sodium content was normal, but the erythrocyte Na+K+ATPase activity was higher than the control group. When the results from these 39 patients were divided according to the duration of treatment it was found that the erythrocyte sodium content was higher in patients treated for 2-4 months than in patients treated for longer periods and the erythrocyte Na+K+ATPase activity increased with duration of treatment. In eight patients (duration of treatment greater than 29 months) in whom ERCos and Eos were measured, ERCos and Eos were higher than the control group. 4 The results suggest that the effects of digoxin on erythrocytes which occur during acute digoxin treatment do not persist in the long term. 5 The possible explanation for the higher ERCos, Eos and Na+K+ATPase activity in patients treated with digoxin for more than 2 months is discussed. PMID:6268133

Glucose transporters GLUT4 and GLUT8 are upregulated after facial nerve axotomy in adult mice.

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Gómez, Olga; Ballester-Lurbe, Begoña; Mesonero, José E; Terrado, José

2011-10-01

Peripheral nerve axotomy in adult mice elicits a complex response that includes increased glucose uptake in regenerating nerve cells. This work analyses the expression of the neuronal glucose transporters GLUT3, GLUT4 and GLUT8 in the facial nucleus of adult mice during the first days after facial nerve axotomy. Our results show that whereas GLUT3 levels do not vary, GLUT4 and GLUT8 immunoreactivity increases in the cell body of the injured motoneurons after the lesion. A sharp increase in GLUT4 immunoreactivity was detected 3 days after the nerve injury and levels remained high on Day 8, but to a lesser extent. GLUT8 also increased the levels but later than GLUT4, as they only rose on Day 8 post-lesion. These results indicate that glucose transport is activated in regenerating motoneurons and that GLUT4 plays a main role in this function. These results also suggest that metabolic defects involving impairment of glucose transporters may be principal components of the neurotoxic mechanisms leading to motoneuron death. © 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.

The effectiveness of sodium hydroxide (NaOH) and sodium carbonate (Na2CO3) on the impurities removal of saturated salt solution

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Pujiastuti, C.; Ngatilah, Y.; Sumada, K.; Muljani, S.

2018-01-01

Increasing the quality of salt can be done through various methods such as washing (hydro-extraction), re-crystallization, ion exchange methods and others. In the process of salt quality improvement by re-crystallization method where salt product diluted with water to form saturated solution and re-crystallized through heating process. The quality of the salt produced is influenced by the quality of the dissolved salt and the crystallization mechanism applied. In this research is proposed a concept that before the saturated salt solution is recrystallized added a chemical for removal of the impurities such as magnesium ion (Mg), calcium (Ca), potassium (K) and sulfate (SO4) is contained in a saturated salt solution. The chemical reagents that used are sodium hydroxide (NaOH) 2 N and sodium carbonate (Na2CO3) 2 N. This research aims to study effectiveness of sodium hydroxide and sodium carbonate on the impurities removal of magnesium (Mg), calcium (Ca), potassium (K) and sulfate (SO4). The results showed that the addition of sodium hydroxide solution can be decreased the impurity ions of magnesium (Mg) 95.2%, calcium ion (Ca) 45%, while the addition of sodium carbonate solution can decreased magnesium ion (Mg) 66.67% and calcium ion (Ca) 77.5%, but both types of materials are not degradable sulfate ions (SO4). The sodium hydroxide solution more effective to decrease magnesium ion than sodium carbonate solution, and the sodium carbonate solution more effective to decrease calcium ion than sodium hydroxide solution.

Euglycemic Diabetic Ketoacidosis with Elevated Acetone in a Patient Taking a Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor.

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Andrews, Tory J; Cox, Robert D; Parker, Christina; Kolb, James

2017-02-01

Sodium-glucose cotransporter-2 (SGLT2) inhibitor medications are a class of antihyperglycemic agents that increase urinary glucose excretion by interfering with the reabsorption of glucose in the proximal renal tubules. In May of 2015, the U.S. Food and Drug Administration released a warning concerning a potential increased risk of ketoacidosis and ketosis in patients taking these medications. We present a case of a 57-year-old woman with type 2 diabetes mellitus taking a combination of canagliflozin and metformin who presented with progressive altered mental status over the previous 2 days. Her work-up demonstrated a metabolic acidosis with an anion gap of 38 and a venous serum pH of 7.08. The serum glucose was 168 mg/dL. The urinalysis showed glucose > 500 mg/dL and ketones of 80 mg/dL. Further evaluation demonstrated an elevated serum osmolality of 319 mOsm/kg and an acetone concentration of 93 mg/dL. She was treated with intravenous insulin and fluids, and the metabolic abnormalities and her altered mental status resolved within 36 h. This was the first episode of diabetic ketoacidosis (DKA) for this patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Diabetic patients on SGLT2 inhibitor medications are at risk for ketoacidosis. Due to the renal glucose-wasting properties of these drugs, they may present with ketoacidosis with only mild elevations in serum glucose, potentially complicating the diagnosis. Acetone is one of the three main ketone bodies formed during DKA and it may be present at considerable concentrations, contributing to the serum osmolality. Copyright © 2016 Elsevier Inc. All rights reserved.

Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.

Science.gov (United States)

Scheen, André J

2014-04-01

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

Optimizing the analysis strategy for the CANVAS Program : A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials

NARCIS (Netherlands)

Neal, Bruce; Perkovic, Vlado; Mahaffey, Kenneth W.; Fulcher, Greg; Erondu, Ngozi; Desai, Mehul; Shaw, Wayne; Law, Gordon; Walton, Marc K.; Rosenthal, Norm; de Zeeuw, Dick; Matthews, David R.

Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter

Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines

International Nuclear Information System (INIS)

Sasajima, Toshio; Miyagawa, Tadashi; Oku, Takamitsu; Gelovani, Juri G.; Finn, Ronald; Blasberg, Ronald

2004-01-01

Amino acid imaging is increasingly being used for assessment of brain tumor malignancy, extent of disease, and prognosis. This study explores the relationship between proliferative activity, amino acid transport, and glucose metabolism in three glioma cell lines (U87, Hs683, C6) at different phases of growth in culture. Growth phase was characterized by direct cell counting, proliferation index determined by flow cytometry, and [ 3 H]thymidine (TdR) accumulation, and was compared with the uptake of two non-metabolized amino acids ([ 14 C]aminocyclopentane carboxylic acid (ACPC) and [ 14 C]aminoisobutyric acid (AIB)), and [ 18 F]fluorodeoxyglucose (FDG). Highly significant relationships between cell number (density), proliferation index, and TdR accumulation rate were observed in all cell lines (r>0.99). Influx (K 1 ) of both ACPC and AIB was directly related to cell density, and inversely related to the proliferation index and TdR accumulation in all cell lines. The volume of distribution (V d ) for ACPC and AIB was lowest during rapid growth and highest during the near-plateau growth phase in all cell lines. FDG accumulation in Hs683 and C6 cells was unaffected by proliferation rate, growth phase, and cell density, whereas FDG accumulation was correlated with TdR accumulation, growth phase, and cell density in U87 cells. This study demonstrates that proliferation rate and glucose metabolism are not necessarily co-related in all glioma cell lines. The values of K 1 and V d for ACPC and AIB under different growth conditions suggest that these tumor cell lines can up-regulate amino acid transporters in their cell membranes when their growth conditions become adverse and less than optimal. (orig.)

Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice

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Atsuo Tahara

2016-07-01

Full Text Available Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.

Effect of Intravenous Small-Volume Hypertonic Sodium Bicarbonate, Sodium Chloride, and Glucose Solutions in Decreasing Plasma Potassium Concentration in Hyperkalemic Neonatal Calves with Diarrhea.

Science.gov (United States)

Trefz, F M; Constable, P D; Lorenz, I

2017-05-01

Hyperkalemia is a frequently observed electrolyte imbalance in dehydrated neonatal diarrheic calves that can result in skeletal muscle weakness and life-threatening cardiac conduction abnormalities and arrhythmias. Intravenous administration of a small-volume hypertonic NaHCO 3 solution is clinically more effective in decreasing the plasma potassium concentration (cK) in hyperkalemic diarrheic calves than hypertonic NaCl or glucose solutions. Twenty-two neonatal diarrheic calves with cK >5.8 mmol/L. Prospective randomized clinical trial. Calves randomly received either 8.4% NaHCO 3 (6.4 mL/kg BW; n = 7), 7.5% NaCl (5 mL/kg BW; n = 8), or 46.2% glucose (5 mL/kg BW; n = 7) IV over 5 minutes and were subsequently allowed to suckle 2 L of an electrolyte solution. Infusions with NaHCO 3 and NaCl provided an identical sodium load of 6.4 mmol/kg BW. Hypertonic NaHCO 3 infusions produced an immediate and sustained decrease in plasma cK. Hypertonic glucose infusions resulted in marked hyperglycemia and hyperinsulinemia, but cK remained unchanged for 20 minutes. Between 30 and 120 minutes after initiation of treatment, the most marked decrements in cK from baseline occurred in group NaHCO 3 , which were significantly (P < .05) larger during this period of time than in calves in group NaCl, but not group glucose. After 120 minutes, the mean decrease in cK from baseline was -26 ± 10%, -9 ± 8%, and -22 ± 6% in groups NaHCO 3 , NaCl, and glucose, respectively. Small-volume hypertonic NaHCO 3 infusions appear to have clinical advantages for the rapid resuscitation of hyperkalemic diarrheic calves, compared to hypertonic NaCl or glucose solutions. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Triiodothyronine Acutely Stimulates Glucose Transport into L6 Muscle Cells Without Increasing Surface GLUT4, GLUT1, or GLUT3

Science.gov (United States)

Teixeira, Silvania Silva; Tamrakar, Akhilesh K.; Goulart-Silva, Francemilson; Serrano-Nascimento, Caroline; Klip, Amira

2012-01-01

Background Thyroid hormones (THs) act genomically to stimulate glucose transport by elevating glucose transporter (Slc2a) expression and glucose utilization by cells. However, nongenomic effects of THs are now emerging. Here, we assess how triiodothyronine (T3) acutely affects glucose transport and the content of GLUT4, GLUT1, and GLUT3 at the surface of muscle cells, and possible interactions between T3 and insulin action. Methods Differentiated L6 myotubes transfected with myc-tagged Slc2a4 (L6-GLUT4myc) or Slc2a1 (L6-GLUT1myc) and wild-type L6 myotubes were studied in the following conditions: control, hypothyroid (Tx), Tx plus T3, Tx plus insulin, and Tx plus insulin and T3. Results Glucose uptake and GLUT4 content at the cell surface decreased in the Tx group relative to controls. T3 treatment for 30 minutes increased glucose transport into L6-GLUT4myc cells without altering surface GLUT4 content, which increased only thereafter. The total amount of GLUT4 protein remained unchanged among the groups studied. The surface GLUT1 content of L6-GLUT1myc cells also remained unaltered after T3 treatment; however, in these cells glucose transport was not stimulated by T3. In wild-type L6 cells, although T3 treatment increased the total amount of GLUT3, it did not change the surface GLUT3 content. Moreover, within 30 minutes, T3 stimulation of glucose uptake was additive to that of insulin in L6-GLUT4myc cells. As expected, insulin elevated surface GLUT4 content and glucose uptake. However, interestingly, surface GLUT4 content remained unchanged or even dropped with T3 plus insulin. Conclusions These data reveal that T3 rapidly increases glucose uptake in L6-GLUT4myc cells, which, at least for 30 minutes, did not depend on an increment in GLUT4 at the cell surface yet potentiates insulin action. We propose that this rapid T3 effect involves activation of GLUT4 transporters at the cell surface, but cannot discount the involvement of an unknown GLUT. PMID:22663547

Effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices

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Torres I.L.S.

2001-01-01

Full Text Available It has been suggested that glucocorticoids released during stress might impair neuronal function by decreasing glucose uptake by hippocampal neurons. Previous work has demonstrated that glucose uptake is reduced in hippocampal and cerebral cortex slices 24 h after exposure to acute stress, while no effect was observed after repeated stress. Here, we report the effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices and on plasma glucose and corticosterone levels. Male adult Wistar rats were exposed to restraint 1 h/day for 50 days in the chronic model. In the acute model there was a single exposure. Immediately or 24 h after stress, the animals were sacrificed and the hippocampus and cerebral cortex were dissected, sliced, and incubated with Krebs buffer, pH 7.4, containing 5 mM glucose and 0.2 µCi D-[U-14C] glucose. CO2 production from glucose was estimated. Trunk blood was also collected, and both corticosterone and glucose were measured. The results showed that corticosterone levels after exposure to acute restraint were increased, but the increase was smaller when the animals were submitted to repeated stress. Blood glucose levels increased after both acute and repeated stress. However, glucose utilization, measured as CO2 production in hippocampal and cerebral cortex slices, was the same in stressed and control groups under conditions of both acute and chronic stress. We conclude that, although stress may induce a decrease in glucose uptake, this effect is not sufficient to affect the energy metabolism of these cells.

Utilizing Co2+/Co3+ Redox Couple in P2-Layered Na0.66Co0.22Mn0.44Ti0.34O2 Cathode for Sodium-Ion Batteries.

Science.gov (United States)

Wang, Qin-Chao; Hu, Enyuan; Pan, Yang; Xiao, Na; Hong, Fan; Fu, Zheng-Wen; Wu, Xiao-Jing; Bak, Seong-Min; Yang, Xiao-Qing; Zhou, Yong-Ning

2017-11-01

Developing sodium-ion batteries for large-scale energy storage applications is facing big challenges of the lack of high-performance cathode materials. Here, a series of new cathode materials Na 0.66 Co x Mn 0.66- x Ti 0.34 O 2 for sodium-ion batteries are designed and synthesized aiming to reduce transition metal-ion ordering, charge ordering, as well as Na + and vacancy ordering. An interesting structure change of Na 0.66 Co x Mn 0.66- x Ti 0.34 O 2 from orthorhombic to hexagonal is revealed when Co content increases from x = 0 to 0.33. In particular, Na 0.66 Co 0.22 Mn 0.44 Ti 0.34 O 2 with a P2-type layered structure delivers a reversible capacity of 120 mAh g -1 at 0.1 C. When the current density increases to 10 C, a reversible capacity of 63.2 mAh g -1 can still be obtained, indicating a promising rate capability. The low valence Co 2+ substitution results in the formation of average Mn 3.7+ valence state in Na 0.66 Co 0.22 Mn 0.44 Ti 0.34 O 2 , effectively suppressing the Mn 3+ -induced Jahn-Teller distortion, and in turn stabilizing the layered structure. X-ray absorption spectroscopy results suggest that the charge compensation of Na 0.66 Co 0.22 Mn 0.44 Ti 0.34 O 2 during charge/discharge is contributed by Co 2.2+ /Co 3+ and Mn 3.3+ /Mn 4+ redox couples. This is the first time that the highly reversible Co 2+ /Co 3+ redox couple is observed in P2-layered cathodes for sodium-ion batteries. This finding may open new approaches to design advanced intercalation-type cathode materials.

Peritoneal fluid transport in CAPD patients with different transport rates of small solutes.

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Sobiecka, Danuta; Waniewski, Jacek; Weryński, Andrzej; Lindholm, Bengt

2004-01-01

Continuous ambulatory peritoneal dialysis (CAPD) patients with high peritoneal solute transport rate often have inadequate peritoneal fluid transport. It is not known whether this inadequate fluid transport is due solely to a too rapid fall of osmotic pressure, or if the decreased effectiveness of fluid transport is also a contributing factor. To analyze fluid transport parameters and the effectiveness of dialysis fluid osmotic pressure in the induction of fluid flow in CAPD patients with different small solute transport rates. 44 CAPD patients were placed in low (n = 6), low-average (n = 13), high-average (n = 19), and high (n = 6) transport groups according to a modified peritoneal equilibration test (PET). The study involved a 6-hour peritoneal dialysis dwell with 2 L 3.86% glucose dialysis fluid for each patient. Radioisotopically labeled serum albumin was added as a volume marker.The fluid transport parameters (osmotic conductance and fluid absorption rate) were estimated using three mathematical models of fluid transport: (1) Pyle model (model P), which describes ultrafiltration rate as an exponential function of time; (2) model OS, which is based on the linear relationship of ultrafiltration rate and overall osmolality gradient between dialysis fluid and blood; and (3) model G, which is based on the linear relationship between ultrafiltration rate and glucose concentration gradient between dialysis fluid and blood. Diffusive mass transport coefficients (K(BD)) for glucose, urea, creatinine, potassium, and sodium were estimated using the modified Babb-Randerson-Farrell model. The high transport group had significantly lower dialysate volume and glucose and osmolality gradients between dialysate and blood, but significantly higher K(BD) for small solutes compared with the other transport groups. Osmotic conductance, fluid absorption rate, and initial ultrafiltration rate did not differ among the transport groups for model OS and model P. Model G yielded

The effect of glucose concentration and sodium phenylbutyrate treatment on mitochondrial bioenergetics and ER stress in 3T3-L1 adipocytes.

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Tanis, Ross M; Piroli, Gerardo G; Day, Stani D; Frizzell, Norma

2015-01-01

While the 3T3-L1 adipocyte model is routinely used for the study of obesity and diabetes, the mitochondrial respiratory profile in normal versus high glucose has not been examined in detail. We matured adipocytes in normal (5mM) or high (30 mM) glucose and insulin and examined the mitochondrial bioenergetics. We also assessed the requirement for the Unfolded Protein Response (UPR) and ER stress under these conditions. Basal respiration was ~1.7-fold greater in adipocytes that had matured in 30 mM glucose; however, their ability to increase oxygen consumption in response to stress was impaired. Adipogenesis proceeded in both normal and high glucose with concomitant activation of the UPR, but only high glucose was associated with increased levels of ER stress and mitochondrial stress as observed by parallel increases in CHOP and protein succination. Treatment of adipocytes with sodium phenylbutyrate relieved mitochondrial stress through a reduction in mitochondrial respiration. Our data suggests that mitochondrial stress, protein succination and ER stress are uniquely linked in adipocytes matured in high glucose. Copyright © 2014 Elsevier B.V. All rights reserved.

Assessment of insulin resistance in fructose-fed rats with {sup 125}I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

Energy Technology Data Exchange (ETDEWEB)

Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine [INSERM, E340, 38000 Grenoble, (France); Univ Grenoble, 38000 Grenoble, (France); Halimi, Serge [CHRU Grenoble, Hopital Michallon, Service de Diabetologie, 38000 Grenoble, (France); Demongeot, Jacques [Univ Grenoble, 38000 Grenoble, (France); CNRS, UMR 5525, 38000 Grenoble, (France)

2007-05-15

Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using {sup 125}I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

Cloreto de sódio, benzocaína e óleo de cravo-da-índia na água de transporte de tilápia-do-nilo Sodium chloride, benzocaine and clove oil in tilapia transport water

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José Ricardo Oliveira

2009-07-01

tilapia (Oreochromis niloticus,chitraladalineage, was tested during 5 hours for transportation. A total of 1350 fingerlings were used ( weight 9.74 ± 0.04 g and length 6.79 ± 0.01 cm and 270 juveniles (average weight 29.6 ± 0.06 g and length 11.52 ± 0.01 cm. The fish were maintained without food for 24 hours in four 500L asbestos boxes with constant aeration. Subsequently, the fish were distributed in 54 5 L plastic bags and maintained in a solution of sodium chloride at a concentration of (0; 4; 8 g/L, benzocaine (0; 20; 40 mg/L and clove oil (0; 2; 5 mg/L. A randomized block experimental design was used with three replications, in multi-factorial arrangements, with three factors: substances, fish and different concentrations for each substance used. Dissolved oxygen, temperature, pH, salinity and ammonia were measured at the beginning of the experiment and the fish glucose at the end of the experiment. The largest glucose levels were detected in the juveniles maintained in water with clove oil and sodium chloride. Significant differences were not observed in the survival among types of fish and substances. However, the doses used of sodium chloride and benzocaine caused significant differences in the survival rate. There was low fingerling survival with 0 g/L of sodium chloride that differed from the doses 4 and 8 g/L. The clove oil presented similar results at all the different doses and all the substances on the glucose rates. Survival was satisfactory at the end of the experiment, with a general average of 97.26%, showing that the three substances can be used to transport fingerlings and juveniles during 5 hours. Sodium chloride is recommended because it was the most cost-effective.

The target-specific transporter and current status of diuretics as antihypertensive.

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Ali, Syed Salman; Sharma, Pramod Kumar; Garg, Vipin Kumar; Singh, Avnesh Kumar; Mondal, Sambhu Charan

2012-04-01

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the diuretic-sensitive sodium transporters at distal convoluted tubule has improved our understanding of the cellular mechanisms of action of each class of diuretics. Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure. Loop and thiazide diuretics are secreted from the proximal tubule via the organic anion transporter-1 and exert their diuretic action by binding to the Na(+)-K(+)-2Cl(-) co-transporter type 2 in the thick ascending limb and the Na(+)-Cl(-) co-transporter in the distal convoluted tubule, respectively. Recent studies in animal models suggest that abundance of these ion transporters is affected by long-term diuretic administration. The WHO/ISH guidelines point out that diuretics enhance the efficacy of antihypertensive drugs and will most often be a component of combination therapy. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

Science.gov (United States)

Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

1991-10-01

Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

Dissociation of in vitro sensitivities of glucose transport and antilipolysis to insulin in NIDDM

International Nuclear Information System (INIS)

Yki-Jaervinen, H.; Kubo, K.; Zawadzki, J.; Lillioja, S.; Young, A.; Abbott, W.; Foley, J.E.

1987-01-01

It is unclear from previous studies whether qualitative or only quantitative differences exist in insulin action in adipocytes obtained from obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) when compared with equally obese nondiabetic subjects. In addition, the role of changes in insulin binding as a cause of insulin resistance in NIDDM is still controversial. The authors compared the sensitivities of [ 14 C]-glucose transport and antilipolysis to insulin and measured [ 125 I]-insulin binding in abdominal adipocytes obtained from 45 obese nondiabetic, obese diabetic, and 15 nonobese female southwestern American Indians. Compared with the nonobese group, the sensitivities of glucose transport antilipolysis were reduced in both the obese nondiabetic and obese diabetic groups. Compared with the obese nondiabetic subjects, the ED 50 for stimulation of glucose transport was higher in the obese patients with NIDDM. In contrast, the ED 50 S for antilipolysis were similar in obese diabetic patients and obese nondiabetic subjects. No differences was found in insulin binding in patients with NIDDM when compared with the equally obese nondiabetic subjects. These data indicate 1) the mechanism of insulin resistance differs in NIDDM and obesity, and 2) the selective loss of insulin sensitivity in NIDDM precludes changes in insulin binding as a cause of insulin resistance in this disorder

Colorimetric detection and removal of radioactive Co ions using sodium alginate-based composite beads

International Nuclear Information System (INIS)

Kim, Daigeun; Jo, Ara; Yang, Hee-Man; Seo, Bum-Kyoung; Lee, Kune-Woo; Lee, Taek Seung

2017-01-01

Highlights: • Organic/inorganic hybridized alginate beads were newly synthesized via sol-gel chemistry. • Interaction between the azopyridine and metal ion is the main cause of Co ion detection. • The beads showed improved stability and least leakage of azopyridine during use. • Removal of Co ion was assessed by the ion-exchange of carboxylate groups in alginate. • The beads with dual functions of detection and removal of Co ion were successfully accomplished. - Abstract: We demonstrate a simple method for the visual determination and removal of Co ions using a bead-shaped, capturing probe based on hybridized sodium alginate. For Co ions, the designed protocol consisted of three main constituents: an azopyridine-based Co ion-probe for visual detection; sodium alginate as an adsorbent for the Co ion and a bead construct for removal and structure; silica as a linker for the probe and the alginate, leading to a robust structure. When the composite beads were exposed to Co ions, the yellow color of the beads turned to intensive violet and the color intensity was associated with the Co ion concentration. The color variation was quantified using red-green-blue (RGB) color values that were obtained with a scanner and evaluated with Photoshop. The technique achieved both visual recognition with obvious color change of the beads and efficient removal of the radioactive 60 Co ion. The sensing and removal of any radioactive isotope could be achieved with an appropriate sensing probe, to provide a simple and universal platform for remediation.

Colorimetric detection and removal of radioactive Co ions using sodium alginate-based composite beads

Energy Technology Data Exchange (ETDEWEB)

Kim, Daigeun; Jo, Ara [Organic and Optoelectronic Materials Laboratory, Department of Organic Materials Engineering, Chungnam National University, Daejeon 34134 (Korea, Republic of); Yang, Hee-Man; Seo, Bum-Kyoung; Lee, Kune-Woo [Decontamination and Decommissioning Research Division, Korea Atomic Energy Research Institute, Daejeon 34057 (Korea, Republic of); Lee, Taek Seung, E-mail: tslee@cnu.ac.kr [Organic and Optoelectronic Materials Laboratory, Department of Organic Materials Engineering, Chungnam National University, Daejeon 34134 (Korea, Republic of)

2017-03-15

Highlights: • Organic/inorganic hybridized alginate beads were newly synthesized via sol-gel chemistry. • Interaction between the azopyridine and metal ion is the main cause of Co ion detection. • The beads showed improved stability and least leakage of azopyridine during use. • Removal of Co ion was assessed by the ion-exchange of carboxylate groups in alginate. • The beads with dual functions of detection and removal of Co ion were successfully accomplished. - Abstract: We demonstrate a simple method for the visual determination and removal of Co ions using a bead-shaped, capturing probe based on hybridized sodium alginate. For Co ions, the designed protocol consisted of three main constituents: an azopyridine-based Co ion-probe for visual detection; sodium alginate as an adsorbent for the Co ion and a bead construct for removal and structure; silica as a linker for the probe and the alginate, leading to a robust structure. When the composite beads were exposed to Co ions, the yellow color of the beads turned to intensive violet and the color intensity was associated with the Co ion concentration. The color variation was quantified using red-green-blue (RGB) color values that were obtained with a scanner and evaluated with Photoshop. The technique achieved both visual recognition with obvious color change of the beads and efficient removal of the radioactive {sup 60}Co ion. The sensing and removal of any radioactive isotope could be achieved with an appropriate sensing probe, to provide a simple and universal platform for remediation.

[A comparison of post-surgical plasma glucose levels in patients on fluids with different glucose concentrations].

Science.gov (United States)

Martínez Carapeto, Isabel; López Castilla, José Domingo; Fresneda Gutiérrez, Reyes

2017-11-11

To compare plasma glucose levels and incidence of hyperglycaemia in the post-operative period after general surgery using fluids with different glucose. A randomised, open-label, non-blind, clinical trial was conducted on patients admitted to Paediatric Intensive Care Unit after elective surgery. The inclusion criteria were from 6 months to 14 years of age, with a weight greater than 6kg, onset glucose level >60mg/dL, and a signed informed consent, with no oral intake and maintenance intravenous fluid therapy using fluids with 3.3% or 5% glucose. Plasma glucose levels were measured before surgery, on admission, and 8, 24, and 48h, with the mean glucose levels and incidence of hyperglycaemia (glucose level >150mg/dL) in both groups being compared. A total of 60 patients received glucose/saline 1/3 (51mEq/L sodium and 33g/L glucose), and 70 glucose/saline 5/0.9% (154mEq/L sodium and 50g/L glucose). Mean glucose levels were higher in the group receiving glucose 5%, with no statistical difference. There was no significant difference in the incidence of hyperglycaemia; 8h: 26% in the 3.3% group vs. 21.3% in the 5% group (P=.63); 24h: 20% vs. 22.7% (P=.8); and 48h: 19% vs. 23.1% (P=.78). The use of fluids with 3.3% glucose in the post-operative period of general surgery maintains mean glucose levels in a similar range to that of patients receiving fluids with 5% glucose, with no difference in the incidence of hyperglycaemia. Copyright © 2017. Publicado por Elsevier España, S.L.U.

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

DEFF Research Database (Denmark)

Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa

2014-01-01

experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine......Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we......-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake...

Characterization of a novel sialic acid transporter of the sodium solute symporter (SSS) family and in vivo comparison with known bacterial sialic acid transporters.

Science.gov (United States)

Severi, Emmanuele; Hosie, Arthur H F; Hawkhead, Judith A; Thomas, Gavin H

2010-03-01

The function of sialic acids in the biology of bacterial pathogens is reflected by the diverse range of solute transporters that can recognize these sugar acids. Here, we use an Escherichia coliDeltananT strain to characterize the function of known and proposed bacterial sialic acid transporters. We discover that the STM1128 gene from Salmonella enterica serovar Typhimurium, which encodes a member of the sodium solute symporter family, is able to restore growth on sialic acid to the DeltananT strain and is able to transport [(14)C]-sialic acid. Using the DeltananT genetic background, we performed a direct in vivo comparison of the transport properties of the STM1128 protein with those of sialic acid transporters of the major facilitator superfamily and tripartite ATP-independent periplasmic families, E. coli NanT and Haemophilus influenzae SiaPQM, respectively. This revealed that both STM1128 and SiaPQM are sodium-dependent and, unlike SiaPQM, both STM1128 and NanT are reversible secondary carriers, demonstrating qualitative functional differences in the properties of sialic acid transporters used by bacteria that colonize humans.

Distributed Graphs for Solving Co-modal Transport Problems

OpenAIRE

Karama , Jeribi; Hinda , Mejri; Hayfa , Zgaya; Slim , Hammadi

2011-01-01

International audience; The paper presents a new approach based on a special distributed graphs in order to solve co-modal transport problems. The co-modal transport system consists on combining different transport modes effectively in terms of economic, environmental, service and financial efficiency, etc. However, the problem is that these systems must deal with different distributed information sources stored in different locations and provided by different public and private companies. In...

Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism

Energy Technology Data Exchange (ETDEWEB)

Moreira, Liliana, E-mail: lilianam87@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Araújo, Isabel, E-mail: isa.araujo013@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Costa, Tito, E-mail: tito.fmup16@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Correia-Branco, Ana, E-mail: ana.clmc.branco@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Faria, Ana, E-mail: anafaria@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Chemistry Investigation Centre (CIQ), Faculty of Sciences of University of Porto, Rua Campo Alegre, 4169-007 Porto (Portugal); Faculty of Nutrition and Food Sciences of University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto (Portugal); Martel, Fátima, E-mail: fmartel@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Keating, Elisa, E-mail: keating@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal)

2013-07-15

In this study we characterized {sup 3}H-2-deoxy-D-glucose ({sup 3}H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon {sup 3}H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells {sup 3}H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (V{sub max}) and affinity (K{sub m}), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that {sup 3}H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited {sup 3}H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. -- Highlights: • Glucose uptake by MCF7 and MDA-MB-231 cells is mainly mediated by GLUT1. • QUE and EGCG inhibit cellular glucose uptake thus abolishing the Warburg effect. • This process induces cytotoxicity and proliferation arrest in MCF7 cells. • The flavonoids’ effects are independent of estrogen receptor signalling.

Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism

International Nuclear Information System (INIS)

Moreira, Liliana; Araújo, Isabel; Costa, Tito; Correia-Branco, Ana; Faria, Ana; Martel, Fátima; Keating, Elisa

2013-01-01

In this study we characterized 3 H-2-deoxy-D-glucose ( 3 H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon 3 H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells 3 H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (V max ) and affinity (K m ), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that 3 H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited 3 H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. -- Highlights: • Glucose uptake by MCF7 and MDA-MB-231 cells is mainly mediated by GLUT1. • QUE and EGCG inhibit cellular glucose uptake thus abolishing the Warburg effect. • This process induces cytotoxicity and proliferation arrest in MCF7 cells. • The flavonoids’ effects are independent of estrogen receptor signalling

Electrolytic process to produce sodium hypochlorite using sodium ion conductive ceramic membranes

Science.gov (United States)

Balagopal, Shekar; Malhotra, Vinod; Pendleton, Justin; Reid, Kathy Jo

2012-09-18

An electrochemical process for the production of sodium hypochlorite is disclosed. The process may potentially be used to produce sodium hypochlorite from seawater or low purity un-softened or NaCl-based salt solutions. The process utilizes a sodium ion conductive ceramic membrane, such as membranes based on NASICON-type materials, in an electrolytic cell. In the process, water is reduced at a cathode to form hydroxyl ions and hydrogen gas. Chloride ions from a sodium chloride solution are oxidized in the anolyte compartment to produce chlorine gas which reacts with water to produce hypochlorous and hydrochloric acid. Sodium ions are transported from the anolyte compartment to the catholyte compartment across the sodium ion conductive ceramic membrane. Sodium hydroxide is transported from the catholyte compartment to the anolyte compartment to produce sodium hypochlorite within the anolyte compartment.

Evaluation of water transport behavior in sodium fire experiment-II

Energy Technology Data Exchange (ETDEWEB)

Nakagiri, Toshio [Japan Nuclear Cycle Development Inst., Oarai, Ibaraki (Japan). Oarai Engineering Center

2000-02-01

Evaluation of water transport behavior in Sodium Fire-II (Run-D4) was performed. Results of other experiments performed in Oarai-Engineering Center were considered in the evaluation, and the results of the evaluation were compared with the calculated results of ASSCOPS code. The main conclusions are described below. (1) It was estimated that aerosol hydrates were not formed in the test cell in the experiment, because of high gas temperatures (200degC - 300degC), but water vapor absorption by the formation of aerosol hydrates and water vapor condensation were occurred in humility measure line, because of low gas temperature (20degC - 40degC). Therefore, it was considered appropriate that measured water vapor concentration in the humidity measure line was different from the real concentration in the test cell. (2) Water vapor concentration in the test cell was assumed to be about 35,000 ppm during sodium leak, and reached to about 70,000 ppm because of water release from heated concrete (over 100degC) walls after 190 min from sodium leak started. The assumed value of about 35,000 ppm during sodium leak almost agree with assumed value from the quantity of aerosol in the humidity measure line, but no support for the value of about 70,000 ppm after 190 min could be found. Therefore, water release rate from heated concrete walls can change with their temperature history. (author)

Steviol Glycosides Modulate Glucose Transport in Different Cell Types

Science.gov (United States)

Rizzo, Benedetta; Zambonin, Laura; Leoncini, Emanuela; Vieceli Dalla Sega, Francesco; Prata, Cecilia; Fiorentini, Diana; Hrelia, Silvana

2013-01-01

Extracts from Stevia rebaudiana Bertoni, a plant native to Central and South America, have been used as a sweetener since ancient times. Currently, Stevia extracts are largely used as a noncaloric high-potency biosweetener alternative to sugar, due to the growing incidence of type 2 diabetes mellitus, obesity, and metabolic disorders worldwide. Despite the large number of studies on Stevia and steviol glycosides in vivo, little is reported concerning the cellular and molecular mechanisms underpinning the beneficial effects on human health. The effect of four commercial Stevia extracts on glucose transport activity was evaluated in HL-60 human leukaemia and in SH-SY5Y human neuroblastoma cells. The extracts were able to enhance glucose uptake in both cellular lines, as efficiently as insulin. Our data suggest that steviol glycosides could act by modulating GLUT translocation through the PI3K/Akt pathway since treatments with both insulin and Stevia extracts increased the phosphorylation of PI3K and Akt. Furthermore, Stevia extracts were able to revert the effect of the reduction of glucose uptake caused by methylglyoxal, an inhibitor of the insulin receptor/PI3K/Akt pathway. These results corroborate the hypothesis that Stevia extracts could mimic insulin effects modulating PI3K/Akt pathway. PMID:24327825

Analysis of metabolism of 6FDG: a PET glucose transport tracer

Energy Technology Data Exchange (ETDEWEB)

Muzic, Raymond F., E-mail: raymond.muzic@case.edu [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106 (United States); Chandramouli, Visvanathan [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Huang, Hsuan-Ming [Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106 (United States); Wu Chunying; Wang Yanming [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Ismail-Beigi, Faramarz [Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States)

2011-07-15

Introduction: We are developing {sup 18}F-labeled 6-fluoro-6-deoxy-D-glucose ([{sup 18}F]6FDG) as a tracer of glucose transport. As part of this process it is important to characterize and quantify putative metabolites. In contrast to the ubiquitous positron emission tomography (PET) tracer {sup 18}F-labeled 2-fluoro-2-deoxy-D-glucose ([{sup 18}F]2FDG) which is phosphorylated and trapped intracellularly, the substitution of fluorine for a hydroxyl group at carbon-6 in [{sup 18}F]6FDG should prevent its phosphorylation. Consequently, [{sup 18}F]6FDG has the potential to trace the transport step of glucose metabolism without the confounding effects of phosphorylation and subsequent steps of metabolism. Herein the focus is to determine whether, and the degree to which, [{sup 18}F]6FDG remains unchanged following intravenous injection. Methods: Biodistribution studies were performed using 6FDG labeled with {sup 18}F or with the longer-lived radionuclides {sup 3}H and {sup 14}C. Tissues were harvested at 1, 6, and 24 h following intravenous administration and radioactivity was extracted from the tissues and analyzed using a combination of ion exchange columns, high-performance liquid chromatography, and chemical reactivity. Results: At the 1 h time-point, the vast majority of radioactivity in the liver, brain, heart, skeletal muscle, and blood was identified as 6FDG. At the 6-h and 24-h time points, there was evidence of a minor amount of radioactive material that appeared to be 6-fluoro-6-deoxy-D-sorbitol and possibly 6-fluoro-6-deoxy-D-gluconic acid. Conclusion: On the time scale typical of PET imaging studies radioactive metabolites of [{sup 18}F]6FDG are negligible.

High-performance non-enzymatic catalysts based on 3D hierarchical hollow porous Co3O4 nanododecahedras in situ decorated on carbon nanotubes for glucose detection and biofuel cell application.

Science.gov (United States)

Wang, Shiyue; Zhang, Xiaohua; Huang, Junlin; Chen, Jinhua

2018-03-01

In this work, high-performance non-enzymatic catalysts based on 3D hierarchical hollow porous Co 3 O 4 nanododecahedras in situ decorated on carbon nanotubes (3D Co 3 O 4 -HPND/CNTs) were successfully prepared via direct carbonizing metal-organic framework-67 in situ grown on carbon nanotubes. The morphology, microstructure, and composite of 3D Co 3 O 4 -HPND/CNTs were characterized by scanning electron microscopy, transmission electron microscopy, micropore and chemisorption analyzer, and X-ray diffraction. The electrochemical characterizations indicated that 3D Co 3 O 4 -HPND/CNTs present considerably catalytic activity toward glucose oxidation and could be promising for constructing high-performance electrochemical non-enzymatic glucose sensors and glucose/O 2 biofuel cell. When used for non-enzymatic glucose detection, the 3D Co 3 O 4 -HPND/CNTs modified glassy carbon electrode (3D Co 3 O 4 -HPND/CNTs/GCE) exhibited excellent analytical performance with high sensitivity (22.21 mA mM -1  cm -2 ), low detection limit of 0.35 μM (S/N = 3), fast response (less than 5 s) and good stability. On the other hand, when the 3D Co 3 O 4 -HPND/CNTs/GCE worked as an anode of a biofuel cell, a maximum power density of 210 μW cm -2 at 0.15 V could be obtained, and the open circuit potential was 0.68 V. The attractive 3D hierarchical porous structural features, the large surface area, and the excellent conductivity based on the continuous and effective electron transport network in 3D Co 3 O 4 -HPND/CNTs endow 3D Co 3 O 4 -HPND/CNTs with the enhanced electrochemical performance and promising applications in electrochemical sensing, biofuel cell, and other energy storage and conversion devices such as supercapacitor. Graphical abstract High-performance non-enzymatic catalysts for enzymeless glucose sensing and biofuel cell based on 3D hierarchical hollow porous Co 3 O 4 nanododecahedras anchored on carbon nanotubes were successfully prepared via direct carbonizing

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

Science.gov (United States)

Choi, Chang-Ik

2016-08-27

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

Co-precipitation and solubility studies of cesium, potassium and sodium tetraphenylborate

International Nuclear Information System (INIS)

Peterson, R.A.

2000-01-01

This report contains the results from a study requested by High Level Waste on the co-precipitation and solubility of cesium, potassium, and sodium tetraphenylborate. Co-precipitation of cesium (Cs), potassium (K), and sodium (Na) tetraphenylborate (TPB) helps determine the efficiency of reagent usage in the Small Tank Precipitation Process. This process uses NaTPB to remove cesium from waste by means of precipitation. Previous studies by McCabe suggested that if the sodium ion concentration [Na + ] increased the rate at which cesium tetraphenylborate (CsTPB) precipitates also increases. Serkiz also demonstrated that the precipitation of potassium tetraphenylborate (KTPB) in the presence of high [Na + ] (∼5M) appears to produce a mixed solid phase composed of NaTPB and KTPB together in the crystal lattice. In the crystallographic structure of these three tetraphenylborate salts (Cs,K,NaTPB), the tetraphenylborate ion dominates the size of the crystals. Also, note that the three crystals have nearly identical structures with the exception of two additional peaks in the cesium pattern. Given these similarities, TPB precipitation in the presence of Na + , Cs + and K + likely produces an impure isomorphic crystalline mixture of CsTPB, KTPB and NaTPB. The authors speculate that the primary crystalline structure resembles that of KTPB with NaTPB and CsTPB mixed throughout the crystal structure. The precipitation of NaTPB makes some of the anticipated excess tetraphenylborate relatively unavailable for precipitation of cesium. Thus, the amount of excess tetraphenylborate required to completely precipitate all of the potassium and cesium may increase significantly

Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

International Nuclear Information System (INIS)

Singh, S.; Yamashita, A.; Gouaux, E.

2007-01-01

Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 (angstrom) above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational

Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

Energy Technology Data Exchange (ETDEWEB)

Singh,S.; Yamashita, A.; Gouaux, E.

2007-01-01

Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 {angstrom} above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the

Electrolyte transport in distal colon of sodium-depleted rats: Effect of sodium repletion

International Nuclear Information System (INIS)

Turnamian, S.G.; Binder, H.J.

1988-01-01

Dietary sodium depletion increases plasma aldosterone level and, as a result, induces amiloride-sensitive electrogenic sodium absorption and electrogenic potassium secretion and stimulates Na + -K + -ATPase activity in rat distal colon, while inhibiting electroneutral sodium chloride absorption. To assess the events that occur as the aldosterone-stimulated colon reverts to normal, unidirectional 22 Na and 36 Cl fluxes were measured under voltage-clamp conditions across isolated distal colonic mucosa of rats that were initially dietary sodium depleted for 7 days and then sodium repleted for varying periods of time before the study. Within 8 h of dietary sodium repletion, plasma aldosterone level and Na + -K + -ATPase activity declined to normal, amiloride-sensitive electrogenic sodium absorption decreased by >90%, and active electrogenic potassium secretion also decreased markedly. In contrast, electroneutral sodium chloride absorption did not completely return to levels seen in normal animals until ∼64-68 h. These results demonstrate that maintenance of electrogenic sodium absorption and potassium secretion are directly dependent on elevated plasma aldosterone levels. The inhibition of electroneutral sodium absorption, although initiated by excess aldosterone, persists after normalization of the plasma aldosterone level, thereby implying that the inhibition is dependent on additional factor(s)