bluuebunny/crossref_metadata_2025 huggingface dataset:
PHASE 2 RANDOMISED CONTROLLED TRIAL OF FUTURE CARE PLANNING IN PATIENTS WITH ADVANCED HEART DISEASE
Authors: Denvir M A , Highet G , Boyd K , Robertson S , Cudmore S , Donald L , Haga K , Weir C , Murray S
Published: February 2015

Introduction

Patients with advanced heart disease typically have a poor prognosis despite optimal cardiac therapy. These patients and families rarely receive coordinated holistic assessment and future care planning (FCP).

Aim(s) and method(s)

This Marie Curie funded phase 2 trial seeks to explore whether a FCP intervention is acceptable, feasible and deliverable to patients (and families) with advanced heart disease following a recent unscheduled hospital admission. Patients with an unscheduled admission for acute coronary syndrome (ACS) or heart failure (HF) were screened using a prognostic scoring tool. Patients with a 12 month estimated mortality risk of 20% or greater were randomly allocated to either early (upon discharge) or delayed (after 12 weeks) FCP for 12 weeks. The FCP intervention combines holistic needs-assessment by a cardiologist with creation of a written/shared FCP and nurse-led care in the community. Primary outcome is quality of life of patients and carers assessed using questionnaires.

Results

We recruited 50 patients (32 carers) – 22% with ACS, 68% HF and 10% valvular heart disease. There were 5 deaths and 5 withdrawals. For the whole cohort mean age is 81.1 years (SD=8.6), 60% male, mean Charlson comorbidity index was 4.2 (SD=1.7), median Canadian frailty scale=5 (Mildly frail). Intervention and follow up is currently on-going.

Conclusion(s)

Findings demonstrate that the intervention and outcome measures were feasible and deliverable. Further analysis will provide invaluable information on the nature and feasibility of a larger clinical trial sufficiently powered to address hard clinical end-points.
Risk factors for renal function decline in adults with normal kidney function: a 7-year cohort study
Authors: Qin Xianhui , Wang Yuejuan , Li Youbao , Xie Di , Tang Genfu , Wang Binyan , Wang Xiaobin , Xu Xin , Xu Xiping , Hou Fanfan
Published: February 2015

Background

We aimed to examine the risk factors for renal function decline (RFD) in a community-based cohort of a rural Chinese population with normal kidney function (estimated glomerular filtration rate, eGFR ≥60 mL/min/1.73 m2), both for the population as a whole and stratified by sex.

Methods

2518 participants were included in the current analysis. RFD was defined as follows: a drop in the eGFR category accompanied by a 25% or greater drop in eGFR from baseline; or a sustained decline in eGFR of more than 5 mL/min/1.73 m2/year.

Results

The incidence rate of RFD was 8.7% (women 7.4% and men 9.8%). In the multivariable logistic regression model, the ORs (95% CI) of developing RFD was 1.60 (1.01 to 2.54) for men versus women, and 1.51 (1.09 to 2.08) for participants with obesity or abdominal obesity versus none (1.35 (0.85 to 2.14) for men, and 1.65 (1.04 to 2.64) for women). However, prehypertension (OR=1.64; 95% CI 1.02 to 2.63) or hypertension (2.05; 1.21 to 3.47), higher mean blood pressure (≥90 vs <80 mm Hg, 2.63; 1.11 to 6.20), higher pulse pressure (≥50 vs <40 mm Hg, 2.00; 1.26 to 3.18), lower high-density lipoprotein cholesterol (<0.9 vs ≥0.9 mmol/L, 2.65; 1.08 to 6.50) and low physical activity levels (vs high, 3.11; 1.59 to 6.10) were major risk factors for RFD in men. Current smoking (3.22; 1.22 to 2.64) and worse self-reported health (vs better, 2.57; 1.20 to 5.50) were major risk factors for RFD in women.

Conclusions

Our findings suggested that sex-specific risk factors should be considered in prevention of RFD in the Chinese rural population with normal kidney function.
Optimization of treatment with recombinant FGF-2 for proliferation and differentiation of human dental stem cells, mesenchymal stem cells, and osteoblasts
Authors: Lee Tae-Hyung , Kim Won-Tae , Ryu Chun Jeih , Jang Young-Joo
Published: February 2015

Basic fibroblast growth factor (bFGF or FGF-2) is widely used to modulate the proliferation and differentiation of certain cell types. An expression and purification system for recombinant human FGF-2 in Escherichia coli was established for the purpose of securing a continuous supply of this protein. The purified recombinant FGF-2 significantly increased the population of human embryonic stem cells. The optimal concentrations of FGF-2 for cell proliferative induction in various adult stem cells including human dental pulp stem cells, full term human periodontal ligament stem cells, human gingival fibroblasts, mesenchymal stem cells, and osteogenic oseosarcoma were established in a dose-dependent manner. When cells were treated with recombinant FGF-2 for 6 days before osteogenic induction, the mRNA expression of the bone markers was upregulated in cells originated from human dental pulp tissue, indicating that pretreatment with FGF-2 during culture increase stem cell/progenitor population and osteogenic potential.
Free vibration of a thermoelastic hollow cylinder with one relaxation time
Authors: Abbas Ibrahim A. , Hobiny Aatef D.
Published: February 2015

The aim of this paper is to study the free vibration problem of a thermoelastic hollow cylinder in the context of the Lord and Shulman theory with one relaxation time. The eigenvalue approach is used to get the analytical solutions. The dispersion relations for the existence of various types of possible modes of vibrations are obtained. The validation of the roots for the dispersion relation is presented. The numerical results of frequency shift, natural frequency, and thermoelastic damping of vibrations have been presented graphically.
Quenching mechanism of 5BDTC by aniline using Stern–Volmer plots
Authors: Patil Shivaram N. , Sanningannavar F.M. , Navati B.S. , Nagaraja D. , Patil N.R. , Melavanki R.M.
Published: February 2015

The quenching mechanism of 5,6-benzo-3-[1-(4,5-dicarbomethoxy-1,2,3-triazoloacetyl)] coumarin (5BDTC) by aniline using Stern–Volmer plots in six different solvents, namely, 1,4 dioxane, dimethyl formamide, dichloromethane, toluene, tetrahydrofuran, and acetonitrile. The Stern–Volmer plots are found to be nonlinear with a positive deviation in all six solvents. To interpret these results we have invoked ground-state complex formation and sphere of action static quenching models. Using these models, various quenching rate parameters have been determined. The magnitudes of these parameters suggest that the sphere of action static quenching model agrees well with the experimental results. Hence, the positive deviation is attributed to the static and dynamic quenching. Further, with the use of the finite sink approximation model, it was possible to check these bimolecular reactions as diffusion-limited and to estimate independently distance parameter R′ and mutual diffusion coefficient D. Finally an effort has been made to correlate the values of R′ and D with the values of the encounter distance R and the mutual coefficient D determined using Edward’s empirical relation and the Stokes–Einstein relation.
Measurement of Li X-ray fluorescence production cross sections and intensity ratios of some elements at 59.54 keV
Authors: Akman F. , Durak R. , Kaçal M.R. , Turhan M.F.
Published: February 2015

The Li (i = l, α, β, γ) X-ray production cross section and Lα/Ll, Lα/Lβ, Lα/Lγ, Ll/Lβ, Ll/Lγ, and Lβ/Lγ intensity ratio values for Yb, Ta, W, Hg, Tl, Pb, Bi, Th, and U have been determined using an excitation geometry at 59.54 keV incident photon energy. The measurements were performed using an Am-241 annular radioactive source and a high resolution Si(Li) detector. The experimental results of Li X-ray production cross sections and intensity ratios were compared with three different theoretical results and other available experimental results in the literature. Reasonable agreement is typically observed between the present and theoretical results.
Parallel-Machine Scheduling with Delivery Times and Deteriorating Maintenance
Authors: Ma Wei-Min , Sun Li , Liu S. C. , Wu T. H.
Published: February 2015

In this paper, we consider parallel-machine scheduling with past-sequence-dependent (p-s-d) delivery times and deteriorating maintenance. The delivery time of a job is proportional to its waiting time in the system. Each machine has a deteriorating maintenance activity, i.e., delaying the maintenance increases the time required to perform it. We consider three versions of the problem to minimize the total absolute deviation of job completion times, the total load on all the machines, and the total completion time. We develop polynomial-time algorithms to solve them.
Transport properties of hadronic matter in magnetic field
Authors: Kadam Guru Prakash
Published: February 2015

We study the effect of magnetic field on the transport properties like shear and bulk viscosities of hot and dense hadronic matter within hadron resonance gas model. We estimate the bulk viscosity using low energy theorems for bilocal correlators of the energy–momentum tensor generalized to finite temperature, density and magnetic field. We use Gaussian ansatz for the spectral function at low frequency. We estimate shear viscosity coefficient using molecular kinetic theory. We find that vacuum contribution due to finite magnetic field dominates the bulk viscosity (ζ) for the temperatures up to 0.1 GeV and increases with magnetic field while ratio ζ/s decreases with magnetic field. We also find that shear viscosity coefficient of hadronic matter decreases with magnetic field.
Electrochemical pesticide sensor based on Langmuir–Blodgett film of cobalt phthalocyanine-anthraquinone hybrid
Authors: İpek Yeliz , Şener M. Kasım , Koca Atıf
Published: February 2015

A cathode active and selective pesticide electrochemical sensor based on Langmuir–Blodgett (LB) film of cobalt phthalocyanine-anthraquinone hybrid (CoPc-AQ) was constructed for the first time in this study. Cobalt-based, Pc ring-based, and anthraquinone-based reduction processes of CoPc-AQ indicated suitability of the complex as a possible electrochemical catalyst and sensor for detection of target species. LB film of CoPc-AQ on ITO (ITO/CoPc-AQ electrode) was titrated with eserine and carbofuran pesticides and interaction of the electrode with these pesticides was tested with square wave voltammetry (SWV), electrochemical impedance spectroscopy (EIS), and double potential step chronocoulometry (DPSCC) techniques. ITO/CoPc-AQ electrode selectively sensed carbofuran and eserine pesticides. While ITO/CoPc-AQ electrode senses carbofuran with the voltammetric responses recorded at anodic potentials (1.20 V), eserine sensing affected antraquinone based reduction peaks recorded at cathodic potentials (-0.80 V). Modification of ITO/CoPc-AQ electrode with nano-platinum and nano-gold particles (ITO/CoPc-AQ-n Pt and ITO/CoPc-AQ-n Au ) increased the sensitivity of the electrode. All basic sensor parameters of modified electrodes were derived with different measurement techniques and compared with each other. The lowest detection limit (2.30 × 10-9M) was recorded with EIS techniques on ITO/CoPc-AQ-n Pt electrode for sensing of eserine.
“Survivor” torches “Who Wants to Be a Physician?” in the educational games ratings war
Authors: Howard Mary G. , Collins Heidi L. , DiCarlo Stephen E.
Published: February 2015

We recently developed an educational game for reviewing respiratory physiology in a large classroom. The “Who Wants to be a Physician?” game encouraged medical students to be active participants in the learning process. An evaluation of the game documented that students enjoyed the active format, and the students reported that the game enhanced their ability to understand and retain information. However, the evaluation also revealed that the game had limitations. Specifically, the students recommended the use of multiple-choice questions to match the Medical Board Examination format and to speed up the game (i.e., cover more topics). The students also wanted to increase their level of participation and interaction. Finally, we wanted to emphasize the benefits of peer instruction as a collaborative learning tool. To address these limitations, we designed a new game, “Survivor.” Survivor incorporated multiple-choice questions and emphasized peer instruction and a capacity to gather information and solve novel problems. In addition, participation was increased by including the student audience in the game. Finally, an evaluation instrument was utilized to assess the effectiveness of this instructional tool in an academic setting. As a result of these improvements, the evaluation documents that the newly developed tool is a more effective educational game that couples fun and creative excitement with proven and effective educational concepts.
TRANSPORT OF SMALL MOLECULES ACROSS CELL MEMBRANES: WATER CHANNELS AND UREA TRANSPORTERS
Authors: Goodman Barbara E.
Published: February 2015

How do small hydrophilic nonelectrolytes cross cell membranes? Which pathways are most important for small lipid insoluble molecules to cross cell membranes? These are questions that have been basic to membrane transport physiology for decades. More importantly, these are questions whose answers have changed significantly within the last 10 years. This review discusses the evidence that pathways other than the lipid bilayer itself exist for the transport across cell membranes of specific small hydrophilic nonelectrolytes. The description begins with briefly analyzing the relevance of well accepted basic mathematical models for transport for understanding the permeability of representative physiologically important molecules across actual cell membranes. Particular emphasis is placed on describing recently discovered proteins that facilitate the transport of some of the smallest physiologically important lipid-insoluble molecules, water, and urea. Evidence also exists for transport proteins that selectively enhance the transmembrane transport of other small lipid-insoluble molecules. Do nonselective pores for small molecules exist in cell membranes?
GLIAL-NEURONAL INTERACTIONS IN THE MAMMALIAN BRAIN
Authors: Hatton Glenn I.
Published: February 2015

Recognition of the importance of glial cells in nervous system functioning is increasing, specifically regarding the modulation of neural activity. This brief review focuses on some of the morphological and functional interactions that take place between astroglia and neurons. Astrocyte-neuron interactions are of special interest because this glia cell type has intimate and dynamic associations with all parts of neurons, i.e., somata, dendrites, axons, and terminals. Activation of certain receptors on astrocytes produces morphological changes that result in new contacts between neurons, along with physiological and functional changes brought about by the new contacts. In response to activation of other receptors or changes in the extracellular microenvironment, astrocytes release neuroactive substances that directly excite or inhibit nearby neurons and may modulate synaptic transmission. Although some of these glial-neuronal interactions have been known for many years, others have been quite recently revealed, but together they are forming a compelling story of how these two major cell types in the brain carry out the complex tasks that mammalian nervous systems perform.
Research or Retrench: the teaching profession challenged
Authors: DICARLO STEPHEN E.
Published: February 2015

The editors welcome readers’ contributions in the form of letters about any aspect of physiology education. Please write to the Editor, Advances in Physiology Education, American Physiology Society, 9650 Rockville Pike, Bethesda, MD 20814-3991.
SIMPLE EXPERIMENTS TO UNDERSTAND THE IONIC ORIGINS AND CHARACTERISTICS OF THE VENTRICULAR CARDIAC ACTION POTENTIAL
Authors: Le Guennec Jean-Yves , Vandier Christophe , Bedfer Gilles
Published: February 2015

Electrophysiological experiments are helpful for students to understand the role of electrical activity in heart function. Papillary muscle, which belongs to the ventricle, offers the advantage of being easily studied using glass microelectrodes. In addition, there is commercially available software that simulates ventricular electrical activity and can help overcome some difficulties, such as voltage clamp experiments, which need expensive apparatus when used for studies on living preparations. Here, we present a class practical session that is taken by undergraduate students at our University. In the first part of this class, students record action potentials from papillary muscles with the use of glass microelectrodes, and they change extracellular conditions to study the ionic basis of the action potential. In the second part of the class, students simulate action potentials using the Oxsoft Heart model (v. 4.0) and model their previous experiments on papillary muscle to quantify the effects. In particular, the model is very helpful in promoting understanding of the effect that extracellular potassium has on cardiac action potential by simulating voltage clamp experiments. This twin approach of papillary muscle experiments and computer modeling leads to a good understanding of the functioning of the action potential and can help introduce discussion of some abnormal cardiac functioning.
WHAT ARE THE SIGNALING PATHWAYS USED BY NOREPINEPHRINE TO CONTRACT THE ARTERY? A DEMONSTRATION USING GUINEA PIG AORTIC RING SEGMENTS
Authors: Vandier Christophe , Le Guennec Jean-Yves , Bedfer Gilles
Published: February 2015

The laboratory exercise described in this article used a simple preparation and a straightforward protocol to illustrate how the neurotransmitter norepinephrine (NE) induces an increase of tension in an artery. This was a practical class designed for undergraduate students of the University of Tours. The students performed several protocols to understand how NE acts to contract aortic ring vessels, which sources of calcium are mobilized, and whether the calcium sensitivity of the contractile regulatory apparatus is involved. The design of this exercise allowed students to participate actively in an exercise demonstrating that many mechanisms are involved and act additively to allow arterial tone to develop. Furthermore, the students were introduced to an isolated organ chamber technique that is used to study cellular mechanisms of many tissues and that is still important for smooth muscle research.
Adrenalectomy enhances the insulin sensitivity of muscle protein synthesis
Authors: Long Wen , Barrett Eugene J. , Wei Liping , Liu Zhenqi
Published: February 2015

After confirming that adrenalectomy per se does not affect skeletal muscle protein synthesis rates, we examined whether endogenously produced glucocorticoids modulate the effect of physiological insulin concentrations on protein synthesis in overnight-fasted rats 4 days after either a bilateral adrenalectomy (ADX), ADX with dexamethasone treatment (ADX + DEX), or a sham operation (Sham; n = 6 each). Rats received a 3-h euglycemic insulin clamp (3 mU · min−1· kg−1). Rectus muscle protein synthesis was measured at the end of the clamp, and the phosphorylation states of protein kinase B (Akt), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and ribosomal protein S6 kinase (p70S6K) were quantitated before and after the insulin clamp. The basal phosphorylation states of Akt, 4E-BP1, and p70S6Kwere similar between ADX and Sham rats. Insulin significantly enhanced the phosphorylation of Akt ( P < 0.03), 4E-BP1 ( P = 0.003), and p70S6K( P < 0.002) in ADX but not in Sham rats. Protein synthesis was significantly greater after insulin infusion in ADX than in Sham rats ( P = 0.01). Glucocorticoid replacement blunted the effect of insulin on Akt, 4E-BP1, and p70S6Kphosphorylation and protein synthesis. In conclusion, glucocorticoid deficiency enhances the insulin sensitivity of muscle protein synthesis, which is mediated by increased phosphorylation of translation initiation-regulatory proteins.
Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ
Authors: Lam Tony K. T. , Yoshii Hidenori , Haber C. Andrew , Bogdanovic Elena , Lam Loretta , Fantus I. George , Giacca Adria
Published: February 2015

The mechanisms of the impairment in hepatic glucose metabolism induced by free fatty acids (FFAs) and the importance of FFA oxidation in these mechanisms remain unclear. FFA-induced peripheral insulin resistance has been linked to membrane translocation of novel protein kinase C (PKC) isoforms, but the role of PKC in hepatic insulin resistance has not been assessed. To investigate the biochemical pathways that are induced by FFA in the liver and their relation to glucose metabolism in vivo, we determined endogenous glucose production (EGP), the hepatic content of citrate (product of acetyl-CoA derived from FFA oxidation and oxaloacetate), and hepatic PKC isoform translocation after 2 and 7 h Intralipid + heparin (IH) or SAL in rats. Experiments were performed in the basal state and during hyperinsulinemic clamps (insulin infusion rate, 5 mU · kg−1· min−1). IH increased EGP in the basal state ( P < 0.001) and during hyperinsulinemia ( P < 0.001) at 2 and 7 h. Also, 7-h infusion of IH induced resistance to the suppressive effect of insulin on EGP ( P < 0.05). Glycerol infusion (resulting in plasma glycerol levels similar to IH infusion) did not have any effect on EGP. IH increased hepatic citrate content by twofold, independent of the insulin levels and the duration of IH infusion. IH induced hepatic PKC-δ translocation from the cytosolic to membrane fraction in all groups. PKC-δ translocation was greater at 7 compared with 2 h ( P < 0.05). In conclusion, 1) increased FFA oxidation may contribute to the FFA-induced increase in EGP in the basal state and during hyperinsulinemia but is not associated with FFA-induced hepatic insulin resistance, and 2) the progressive insulin resistance induced by FFA in the liver is associated with a progressive increase in hepatic PKC-δ translocation.
Differences between mouse and rat pancreatic islets: succinate responsiveness, malic enzyme, and anaplerosis
Authors: MacDonald Michael J.
Published: February 2015

Succinic acid methyl esters are potent insulin secretagogues in rat pancreatic islets, but they do not stimulate insulin release in mouse islets. Unlike rat and human islets, mouse islets lack malic enzyme and, therefore, are unable to form pyruvate from succinate-derived malate for net synthesis of acetyl-CoA. Dimethyl-[2,3-14C]succinate is metabolized in the citric acid cycle in mouse islets to the same extent as in rat islets, indicating that endogenous acetyl-CoA condenses with oxaloacetate derived from succinate. However, without malic enzyme, the net synthesis from succinate of the citric acid cycle intermediates citrate, isocitrate, and α-ketoglutarate cannot occur. Glucose and other nutrients that augment α-ketoglutarate formation are secretagogues in mouse islets with potencies similar to those in rat islets. All cycle intermediates can be net-synthesized from α-ketoglutarate. Rotenone, an inhibitor of site I of the electron transport chain, inhibits methyl succinate-induced insulin release in rat islets even though succinate oxidation forms ATP at sites II and III of the respiratory chain. Thus generating ATP, NADH, and anaplerosis of succinyl-CoA plus the four-carbon dicarboxylic acids of the cycle and its metabolism in the citric acid cycle is insufficient for a fuel to be insulinotropic; it must additionally promote anaplerosis of α-ketoglutarate or two intermediates interconvertible with α-ketoglutarate, citrate, and isocitrate.
Metabolism of recombinant progastrin in sheep
Authors: Paterson Adrienne C. , Baldwin Graham S. , Shulkes Arthur
Published: February 2015

Precursor forms of peptide hormones may be biologically active with effects distinct from the mature end product. Nonamidated progastrin-derived peptides stimulate growth of colonic epithelium and are elevated in the circulation of patients with colorectal carcinomas, whereas the amidated end product is the major regulator of gastric acidity. Using region-specific radioimmunoassays, we here compared the in vitro and in vivo metabolism of recombinant human progastrin-(6–80) and two other nonamidated gastrins, gastrin-17-Gly and Tyr70-progastrin-(71–80). Although progastrin-(6–80) was very stable in vitro, both progastrin-(6–80) and gastrin-17-Gly were degraded in vivo. The in vivo data were best fitted by a double-exponential decay curve, and the half-lives for progastrin-(6–80) ( t½α = 5.1 ± 1.1, t½β = 42 ± 11 min) were significantly ( P < 0.05) longer than for gastrin-17-Gly ( t½α = 2.2 ± 0.6, t½β = 13 ± 1 min). Tyr70-progastrin-(71–80) was degraded more rapidly. Comparison with amidated gastrins suggests that peptide length, rather than sequence, is the critical determinant of clearance. Progastrin has the clearance characteristics to be considered a circulating hormone.
Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators
Authors: Carlsson Per-Ola , Olsson Richard , Källskog Örjan , Bodin Birgitta , Andersson Arne , Jansson Leif
Published: February 2015

This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by A1receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine.
Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo 13C MRS
Authors: Rivenzon-Segal Dalia , Margalit Raanan , Degani Hadassa
Published: February 2015

Enhanced glycolysis represents a striking feature of cancers and can therefore serve to indicate a malignant transformation. We have developed a noninvasive, quantitative method to characterize tumor glycolysis by monitoring 13C-labeled glucose and lactate with magnetic resonance spectroscopy. This method was applied in MCF7 human breast cancer implanted in the mammary gland of female CD1-NU mice and was further employed to assess tumor response to hormonal manipulation with the antiestrogen tamoxifen. Analysis of the kinetic data based on a unique physiological-metabolic model yielded the rate parameters of glycolysis, glucose perfusion, and lactate clearance in the tumor, as well as glucose pharmacokinetics in the plasma. Treatment with tamoxifen induced a twofold reduction in the rate of glycolysis and of lactate clearance but did not affect the other parameters. This metabolic monitoring can thus serve to evaluate the efficacy of new selective estrogen receptor modulators and may be further extended to improve diagnosis and prognosis of breast cancer.
Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-α
Authors: Fernández-Celemín Laura , Pasko Nevi , Blomart Valérie , Thissen Jean-Paul
Published: February 2015

The role of TNF-α in muscle catabolism is well established, but little is known about the mechanisms of its catabolic action. One possibility could be that TNF-α impairs the production of local growth factors like IGF-I. The aim of this study was to investigate whether TNF-α can directly inhibit IGF-I gene and protein expression in muscle. First, we investigated whether the acute inflammation induced by endotoxin injection changes IGF-I and TNF-α mRNA in rat tibialis anterior muscle. Endotoxin rapidly increased TNF-α mRNA (7-fold at 1 h, P < 0.001) and later decreased IGF-I mRNA (−73% at 12 h, P < 0.001). Furthermore, in a model of C2C12 myotubes, TNF-α strongly inhibited IGF-I mRNA and protein (−73 and −47% after 72 h, P < 0.001 and P < 0.01, respectively). Other proinflammatory cytokines failed to inhibit IGF-I mRNA. The effect of TNF-α on IGF-I mRNA was not mediated by nitric oxide, and the activation of NF-κB was insufficient to inhibit IGF-I expression. Taken together, our data suggest that TNF-α induced in muscle after LPS injection can locally inhibit IGF-I expression. The inhibition of muscle IGF-I production could contribute to the catabolic effect of TNF-α.
Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats
Authors: Lynch Christopher J. , Hutson Susan M. , Patson Brian J. , Vaval Alain , Vary Thomas C.
Published: February 2015

Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes.
Behavioral, metabolic, and molecular correlates of lower insulin sensitivity in Mexican-Americans
Authors: Ho Richard C. , Davy Kevin P. , Hickey Matthew S. , Summers Scott A. , Melby Christopher L.
Published: February 2015

We determined whether lower insulin sensitivity persists in young, nonobese, nondiabetic Mexican-American [MA; n = 13, 27.0 ± 2.0 yr, body mass index (BMI) 23.0 ± 0.7] compared with non-Hispanic white (NHW; n = 13, 24.8 ± 1.5 yr, BMI 22.8 ± 0.6) males and females after accounting for cardiorespiratory fitness (maximal O2 uptake), abdominal fat distribution (computed tomography scans), dietary intake (4-day records), and skeletal muscle insulin-signaling protein abundance from muscle biopsies (Western blot analysis). MA were significantly less insulin sensitive compared with their NHW counterparts when estimated by homeostatic model assessment of insulin resistance (MA: 1.53 ± 0.22 vs. NHW: 0.87 ± 0.16, P < 0.05) and the revised quantitative insulin sensitivity check index (MA: 0.45 ± 0.08 vs. NHW: 0.58 ± 0.19, P = 0.05). However, skeletal muscle protein abundance of insulin receptor-β (IRβ), phosphatidylinositol 3-kinase p85 subunit, Akt1, Akt2, and GLUT4 were not significantly different. Differences in indexes of insulin sensitivity lost significance after percent dietary intake of palmitic acid, palmitoleic acid, and skeletal muscle protein abundance of IRβ were accounted for. We conclude that differences in insulin sensitivity between nonobese, nondiabetic MA and NHW persist after effects of chronic and acute exercise and total and abdominal fat distribution are accounted for. These differences may be mediated, in part, by dietary fat intake.
Fasting for 72 h increases intramyocellular lipid content in nondiabetic, physically fit men
Authors: Stannard S. R. , Thompson M. W. , Fairbairn K. , Huard B. , Sachinwalla T. , Thompson C. H.
Published: February 2015

The purpose of this study was to determine changes in intramyocellular lipid (IMCL) content in the vastus lateralis of nondiabetic, physically fit males over 72 h of fasting. Six men, mean age 35 yr (range 23–55 yr), body mass index 23.7 kg/m2(21.2–27.4 kg/m2), undertook a water-only fast for 84 h. Vastus lateralis IMCL content was determined using proton magnetic resonance spectroscopy after 12 and 84 h of fasting. Venous blood was sampled at 12-h intervals throughout the fast. IMCL-(CH2)n/water and IMCL-(CH2)n/total creatine ratios increased from 0.00623 ± 0.00065 to 0.0142 ± 0.0015 ( P = 0.002) and 6.82 ± 0.87 to 14.96 ± 1.73 ( P = 0.001), respectively. Plasma free fatty acid (FFA), serum triglyceride, and whole blood 3-hydroxybutyrate concentrations increased ( P < 0.001, <0.05, <0.03, respectively), whereas plasma glucose and serum insulin concentrations decreased (both P < 0.001) during fasting. In conclusion, 72-h water-only fasting produces a large increase in plasma FFA concentration, a drop in serum insulin concentration, and accumulation of IMCL in the vastus lateralis muscle of nondiabetic, physically fit men.
Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects
Authors: Qvigstad Elisabeth , Mostad Ingrid L. , Bjerve Kristian S. , Grill Valdemar E.
Published: February 2015

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60–120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60–120 in the 50% having the lowest levels of hemoglobin A1c(379 ± 34 vs. 326 ± 30 pmol · kg−1· min−1without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.
Diets enriched in sucrose or fat increase gluconeogenesis and G-6-Pase but not basal glucose production in rats
Authors: Commerford S. Renee , Ferniza Jennifer B. , Bizeau Michael E. , Thresher Jeffrey S. , Willis Wayne T. , Pagliassotti Michael J.
Published: February 2015

High-fat (HFD) and high-sucrose diets (HSD) reduce insulin suppression of glucose production in vivo, increase the capacity for gluconeogenesis in vitro, and increase glucose-6-phosphatase (G-6-Pase) activity in whole cell homogenates. The present study examined the effects of HSD and HFD on in vivo gluconeogenesis, the catalytic and glucose-6-phosphate translocase subunits of G-6-Pase, glucokinase (GK) translocation, and glucose cycling. Rats were fed a high-starch control diet (STD; 68% cornstarch), HSD (68% sucrose), or HFD (45% fat) for 7–13 days. The ratio of3H in C6:C2 of glucose after3H2O injection into 6- to 8-h-fasted rats was significantly increased in HSD (0.68 ± 0.07) and HFD (0.71 ± 0.08) vs. STD (0.40 ± 0.10). G-6-Pase activity was significantly higher in HSD and HFD vs. STD in both intact and disrupted liver microsomes. HSD and HFD significantly increased the amount of the p36 catalytic subunit protein, whereas the p46 glucose-6-phosphate translocase protein was increased in HSD only. Despite increased nonglycerol gluconeogenesis and increased G-6-Pase, basal glucose and insulin levels as well as glucose production were not significantly different among groups. Hepatocyte cell suspensions were used to ascertain whether diet-induced adaptations in glucose phosphorylation and GK might serve to compensate for upregulation of G-6-Pase. Tracer-estimated glucose phosphorylation and glucose cycling (glucose ↔ glucose 6-phosphate) were significantly higher in cells isolated from HSD only. After incubation with either 5 or 20 mM glucose and no insulin, GK activity (nmol · mg protein−1· min−1) in digitonin-treated eluates (translocated GK) was significantly higher in HSD (32 ± 4 and 146 ± 6) vs. HFD (4 ± 1 and 83 ± 10) and STD (9 ± 2 and 87 ± 9). Thus short-term, chronic exposure to HSD and HFD increase in vivo gluconeogenesis and the G-6-Pase catalytic subunit. Exposure to HSD diet also leads to adaptations in glucose phosphorylation and GK translocation.
Regulation of the acid-labile subunit in sustained endotoxemia
Authors: Kong Sung-Eun , Firth Sue M. , Baxter Robert C. , Delhanty Patric J. D.
Published: February 2015

The effect of sustained endotoxemia on expression of the acid-labile subunit (ALS) in relation to hepatic markers of altered GH and insulin sensitivity was examined. Juvenile rats were injected with endotoxin twice daily for 48 h, causing reduced food intake and attenuated growth. In pair-fed controls, food restriction caused marked suppression of ALS gene expression and circulating levels within 12 h, and endotoxemia augmented this effect. This acute effect of endotoxin corresponded temporally with transient induction of suppressor of cytokine signaling (SOCS)-3, cytokine-inducible SH2-containing protein (CIS), phospho enolpyruvate carboxykinase (PEPCK), and insulin-like growth factor-binding protein (IGFBP)-1 and suppression of GH receptor (GHR). During the subsequent 36 h of sustained endotoxin treatment, expression of ALS recovered to, and then rose above, that of their pair-fed controls. This effect was paralleled by other ternary complex components. The inductive effect of sustained endotoxemia relative to pair-fed controls could not be explained by differences in expression of GHR, SOCS-3, or CIS but coincided with normalized PEPCK and IGFBP-1 levels, suggesting better hepatic insulin sensitivity in these animals. These data may indicate that, in sustained endotoxemia, ALS levels are regulated through modulation of hepatic insulin sensitivity.
Hyposmotic shock stimulates insulin secretion by two distinct mechanisms. Studies with the βHC9 cell
Authors: Straub Susanne G. , Daniel Samira , Sharp Geoffrey W. G.
Published: February 2015

Exposure of βHC9 cells to a Krebs-Ringer bicarbonate-HEPES buffer (KRBH) made hypotonic by a reduction of 25 mM NaCl resulted in a prompt stimulation of insulin release. The stimulation was transient, and release rates returned to basal levels after 10 min. The response resembles that of the first phase of glucose-stimulated insulin release. The response did not occur if the reduction in NaCl was compensated for by the addition of an equivalent osmolar amount of sorbitol, so the stimulation of release was due to the osmolarity change and not the reduction in NaCl. The hyposmotic shock released insulin in KRBH with or without Ca2+. The L-type Ca2+channel blocker nitrendipine inhibited the response in normal KRBH but had no effect in KRBH without Ca2+despite the latter response being larger than in the presence of extracellular Ca2+. Similar data were obtained with calciseptine, which also blocks L-type channels. The T-type Ca2+channel blocker flunarizine was without effect, as was the chloride channel blocker DIDS. In parallel studies, the readily releasable pool of insulin-containing granules was monitored. Immunoprecipitation of the target-SNARE protein syntaxin and co-immunoprecipitation of the vesicle-SNARE VAMP-2 was used as an indicator of the readily releasable granule pool. After hypotonic shock in the presence of extracellular Ca2+, the amount of VAMP-2 coimmunoprecipitated by antibodies against syntaxin was much reduced compared with controls. Therefore, under these conditions, hypotonic shock stimulates exocytosis of the readily releasable pool of insulin-containing granules. No such reduction was seen in the absence of extracellular Ca2+. In conclusion, after reexamination of the effect of hyposmotic shock on insulin secretion in the presence and absence of Ca2+(with EGTA in the medium), it is clear that two different mechanisms are operative under these conditions. Moreover, these two mechanisms may be associated with the release of two distinct pools of insulin-containing granules.
Use of a novel triple-tracer approach to assess postprandial glucose metabolism
Authors: Basu Rita , Di Camillo Barbara , Toffolo Gianna , Basu Ananda , Shah Pankaj , Vella Adrian , Rizza Robert , Cobelli Claudio
Published: February 2015

Numerous studies have used the dual-tracer method to assess postprandial glucose metabolism. The present experiments were undertaken to determine whether the marked tracer nonsteady state that occurs with the dual-tracer approach after food ingestion introduces error when it is used to simultaneously measure both meal glucose appearance (Ra meal) and endogenous glucose production (EGP). To do so, a novel triple-tracer approach was designed: 12 subjects ingested a mixed meal containing [1-13C]glucose while [6-3H]glucose and [6,6-2H2]glucose were infused intravenously in patterns that minimized the change in the plasma ratios of [6-3H]glucose to [1-13C]glucose and of [6,6-2H2]glucose to endogenous glucose, respectively. Ra meal and EGP measured with this approach were essentially model independent, since non-steady-state error was minimized by the protocol. Initial splanchnic glucose extraction (ISE) was 12.9% ± 3.4%, and suppression of EGP (EGPS) was 40.3% ± 4.1%. In contrast, when calculated with the dual-tracer one-compartment model, ISE was higher ( P < 0.05) and EGPS was lower ( P < 0.005) than observed with the triple-tracer approach. These errors could only be prevented by using time-varying volumes different for Ra meal and EGP. Analysis of the dual-tracer data with a two-compartment model reduced but did not totally avoid the problems associated with marked postprandial changes in the tracer-to-tracee ratios. We conclude that results from previous studies that have used the dual-tracer one-compartment model to measure postprandial carbohydrate metabolism need to be reevaluated and that the triple-tracer technique may provide a useful approach for doing so.
E-selectin-inducing activity in plasma from type 2 diabetic patients with maculopathy
Authors: Knudsen S. T. , Foss C. H. , Poulsen P. L. , Bek T. , Ledet T. , Mogensen C. E. , Rasmussen L. M.
Published: February 2015

Diabetic maculopathy (DMa) is a leading cause of visual loss in the western world. We examined whether plasma from type 2 diabetic patients with DMa contains factor(s) capable of inducing expression of the adhesion molecules E-selectin and VCAM-1 or cellular proliferation in cultured endothelial cells. Four gender-, age-, and duration (diabetes groups)-matched groups of 20 subjects each participated: 1) subjects with normal glucose tolerance (NGT), 2) subjects with impaired glucose tolerance (IGT), 3) type 2 diabetic patients without retinopathy, and 4) type 2 diabetic patients with DMa. Fasting plasma was added to in vitro-grown human umbilical vein endothelial cells for 6 h, after which E-selectin and VCAM-1 expression was measured. Proliferation was evaluated by thymidine incorporation. The individuals were characterized by measurement of 24-h ambulatory blood pressure, urinary albumin excretion rate, Hb A1c, and blood lipids. Plasma from type 2 diabetic patients with DMa induced a significantly higher expression of E-selectin in endothelial cells than did plasma from subjects with NGT (259 ± 23 × 103 vs. 198 ± 19 × 103; arbitrary absorbance units; P < 0.05). There were no significant differences in plasma stimulatory effects on VCAM-1 expression or on thymidine incorporation between groups. These findings suggest that plasma from type 2 diabetic patients with DMa contains factor(s) capable of inducing the expression of E-selectin in endothelial cells. Enhanced expression of E-selectin may contribute to the development of DMa in type 2 diabetes.
Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice
Authors: Ahrén Bo , Pacini Giovanni
Published: February 2015

This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at 1 wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness (SG) and disposition index (DI), i.e., insulin sensitivity (SI) times early or total insulin secretion. Glucose disappearance (KG) and SI were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced SI, as judged by normal DI50 min. In contrast, early (10 min) insulin secretion was not sufficiently increased; DI10 min was reduced after 1, 3, and 10 mo. SG was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding.