Showing papers by "University of Dundee published in 2005"

Metformin and reduced risk of cancer in diabetic patients

Abstract: Metformin, widely given to patients with type 2 diabetes, works by targeting the enzyme AMPK (AMP activated protein kinase), which induces muscles to take up glucose from the blood. A recent breakthrough has found the upstream regulator of AMPK to be a protein kinase known as LKB1.1 2 LKB1 is a well recognised tumour suppressor. Activation of AMPK by metformin and exercise requires LKB1, and this would also explain why exercise is beneficial in the primary and secondary prevention of certain cancers.3 We hypothesise that metformin use in patients with type 2 diabetes may reduce their risk of cancer. We tested this hypothesis using record linkage databases developed in Tayside, Scotland: a diabetes clinical information system (DARTS) and a database of dispensed prescriptions (MEMO).4 We did a pilot case-control study using previously validated methods.5 From 314 127 people who were resident (or died) in Tayside in …

The Genome of the African Trypanosome Trypanosoma brucei

Abstract: African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including ∼900 pseudogenes and ∼1700 T. brucei–specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.

The genome of the social amoeba Dictyostelium discoideum

Abstract: The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.

Trends in Peer Learning

Abstract: Developments in forms of peer learning 1981–2006 are reviewed, focusing mainly on peer tutoring, cooperative learning, and peer assessment. Types and definitions of peer learning are explored, together with questions of implementation integrity and consequent effectiveness and cost‐effectiveness. Benefits to helpers are now emphasised at least as much as benefits to those helped. In this previously under‐theorised area, an integrated theoretical model of peer learning is now available. Peer learning has been extended in types and forms, in curriculum areas and in contexts of application beyond school. Engagement in helping now often encompasses all community members, including those with special needs. Social and emotional gains now attract as much interest as cognitive gains. Information technology is now often a major component in peer learning, operating in a variety of ways. Embedding and sustainability has improved, but further improvement is needed.

CO2 CONCENTRATING MECHANISMS IN ALGAE: Mechanisms, Environmental Modulation, and Evolution

Abstract: The evolution of organisms capable of oxygenic photosynthesis paralleled a long-term reduction in atmospheric CO2 and the increase in O2. Consequently, the competition between O2 and CO2 for the active sites of RUBISCO became more and more restrictive to the rate of photosynthesis. In coping with this situation, many algae and some higher plants acquired mechanisms that use energy to increase the CO2 concentrations (CO2 concentrating mechanisms, CCMs) in the proximity of RUBISCO. A number of CCM variants are now found among the different groups of algae. Modulating the CCMs may be crucial in the energetic and nutritional budgets of a cell, and a multitude of environmental factors can exert regulatory effects on the expression of the CCM components. We discuss the diversity of CCMs, their evolutionary origins, and the role of the environment in CCM modulation.

Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle

Abstract: The nature of the deficit underlying age-related muscle wasting remains controversial. To test whether it could be due to a poor anabolic response to dietary amino acids, we measured the rates of myofibrillar and sarcoplasmic muscle protein synthesis (MPS) in 44 healthy young and old men, of similar body build, after ingesting different amounts of essential amino acids (EAA). Basal rates of MPS were indistinguishable, but the elderly showed less anabolic sensitivity and responsiveness of MPS to EAA, possibly due to decreased intramuscular expression, and activation (phosphorylation) after EAA, of amino acid sensing/signaling proteins (mammalian target of rapamycin, mTOR; p70 S6 kinase, or p70(S6k); eukaryotic initiation factor [eIF]4BP-1; and eIF2B). The effects were independent of insulin signaling since plasma insulin was clamped at basal values. Associated with the anabolic deficits were marked increases in NFkappaB, the inflammation-associated transcription factor. These results demonstrate first, EAA stimulate MPS independently of increased insulin availability; second, in the elderly, a deficit in MPS in the basal state is unlikely; and third, the decreased sensitivity and responsiveness of MPS to EAA, associated with decrements in the expression and activation of components of anabolic signaling pathways, are probably major contributors to the failure of muscle maintenance in the elderly. Countermeasures to maximize muscle maintenance should target these deficits.

Nucleolar proteome dynamics

Abstract: The nucleolus is a key organelle that coordinates the synthesis and assembly of ribosomal subunits and forms in the nucleus around the repeated ribosomal gene clusters. Because the production of ribosomes is a major metabolic activity, the function of the nucleolus is tightly linked to cell growth and proliferation, and recent data suggest that the nucleolus also plays an important role in cell-cycle regulation, senescence and stress responses. Here, using mass-spectrometry-based organellar proteomics and stable isotope labelling, we perform a quantitative analysis of the proteome of human nucleoli. In vivo fluorescent imaging techniques are directly compared to endogenous protein changes measured by proteomics. We characterize the flux of 489 endogenous nucleolar proteins in response to three different metabolic inhibitors that each affect nucleolar morphology. Proteins that are stably associated, such as RNA polymerase I subunits and small nuclear ribonucleoprotein particle complexes, exit from or accumulate in the nucleolus with similar kinetics, whereas protein components of the large and small ribosomal subunits leave the nucleolus with markedly different kinetics. The data establish a quantitative proteomic approach for the temporal characterization of protein flux through cellular organelles and demonstrate that the nucleolar proteome changes significantly over time in response to changes in cellular growth conditions.

Global analysis of protein phosphorylation in yeast

Abstract: Protein phosphorylation is estimated to affect 30% of the proteome and is a major regulatory mechanism that controls many basic cellular processes. Until recently, our biochemical understanding of protein phosphorylation on a global scale has been extremely limited; only one half of the yeast kinases have known in vivo substrates and the phosphorylating kinase is known for less than 160 phosphoproteins. Here we describe, with the use of proteome chip technology, the in vitro substrates recognized by most yeast protein kinases: we identified over 4,000 phosphorylation events involving 1,325 different proteins. These substrates represent a broad spectrum of different biochemical functions and cellular roles. Distinct sets of substrates were recognized by each protein kinase, including closely related kinases of the protein kinase A family and four cyclin-dependent kinases that vary only in their cyclin subunits. Although many substrates reside in the same cellular compartment or belong to the same functional category as their phosphorylating kinase, many others do not, indicating possible new roles for several kinases. Furthermore, integration of the phosphorylation results with protein-protein interaction and transcription factor binding data revealed novel regulatory modules. Our phosphorylation results have been assembled into a first-generation phosphorylation map for yeast. Because many yeast proteins and pathways are conserved, these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.

Glycogen Synthase Kinase-3 from Rabbit Skeletal Muscle

Abstract: Publisher Summary This chapter discusses glycogen synthase kinase-3 from rabbit skeletal muscle. Glycogen synthase kinase-3 is one of the five glycogen synthase kinases that are identified in skeletal muscle, and is of major importance in determining the kinetic properties of glycogen synthase in vivo. It catalyzes the phosphorylation of three serine residues on glycogen synthase, converting the enzyme from a form that is almost fully active in the absence of glucose-6P, to one that is largely dependent on this allosteric activator. Glycogen synthase kinase-3 also has a second activity that is not shared by any other protein kinase—namely, the ability to activate an enzyme termed the MgATP-dependent protein phosphatase. Glycogen synthase may also contain traces of a modified form of phosphorylase kinase that has lost its sensitivity to regulation by calcium ions, and is therefore, no longer inhibited by ethylene glycol tetraacetic acid (EGTA). This is largely removed by passing glycogen synthase through phosphocellulose.

p53 isoforms can regulate p53 transcriptional activity

Abstract: The recently discovered p53-related genes, p73 and p63, express multiple splice variants and N-terminally truncated forms initiated from an alternative promoter in intron 3. To date, no alternative promoter and multiple splice variants have been described for the p53 gene. In this study, we show that p53 has a gene structure similar to the p73 and p63 genes. The human p53 gene contains an alternative promoter and transcribes multiple splice variants. We show that p53 variants are expressed in normal human tissue in a tissue-dependent manner. We determine that the alternative promoter is conserved through evolution from Drosophila to man, suggesting that the p53 family gene structure plays an essential role in the multiple activities of the p53 family members. Consistent with this hypothesis, p53 variants are differentially expressed in human breast tumors compared with normal breast tissue. We establish that p53 can bind differentially to promoters and can enhance p53 target gene expression in a promoter-dependent manner, while 133p53 is dominant-negative toward full-length p53, inhibiting p53-mediated apoptosis. The differential expression of the p53 isoforms in human tumors may explain the difficulties in linking p53 status to the biological properties and drug sensitivity of human cancer.

Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial

Abstract: Background and aims: Ulcerative colitis (UC) is an acute and chronic inflammatory disease of the large bowel with unknown aetiology. The immune response against normal commensal microorganisms is believed to drive inflammatory processes associated with UC. Therefore, modulation of bacterial communities on the gut mucosa, through the use of probiotics and prebiotics, may be used to modify the disease state. Methods: A synbiotic was developed for use in UC patients combining a probiotic, Bifidobacterium longum , isolated from healthy rectal epithelium, and a prebiotic (Synergy 1), a preferential inulin-oligofructose growth substrate for the probiotic strain. Treatment was employed in a double blinded randomised controlled trial using 18 patients with active UC for a period of one month. Clinical status was scored and rectal biopsies were collected before and after treatment, and transcription levels of epithelium related immune markers were measured. Results: Sigmoidoscopy scores (scale 0–6) were reduced in the test group (start 4.5 (1.4), end 3.1 (2.5)) compared with placebo (start 2.6 (2.1), end 3.2 (2.2)) (p = 0.06). mRNA levels for human beta defensins 2, 3, and 4, which are strongly upregulated in active UC, were significantly reduced in the test group after treatment (p = 0.016, 0.038, and 0.008, respectively). Tumour necrosis factor α and interleukin 1α, which are inflammatory cytokines that drive inflammation and induce defensin expression, were also significantly reduced after treatment (p = 0.018 and 0.023, respectively). Biopsies in the test group had reduced inflammation and regeneration of epithelial tissue. Conclusions: Short term synbiotic treatment of active UC resulted in improvement of the full clinical appearance of chronic inflammation in patients receiving this therapy.

Preventing re-replication of chromosomal DNA

Abstract: To ensure its duplication, chromosomal DNA must be precisely duplicated in each cell cycle, with no sections left unreplicated, and no sections replicated more than once. Eukaryotic cells achieve this by dividing replication into two non-overlapping phases. During late mitosis and G1, replication origins are 'licensed' for replication by loading the minichromosome maintenance (Mcm) 2-7 proteins to form a pre-replicative complex. Mcm2-7 proteins are then essential for initiating and elongating replication forks during S phase. Recent data have provided biochemical and structural insight into the process of replication licensing and the mechanisms that regulate it during the cell cycle.

Diverse taxa of cyanobacteria produce β-N-methylamino-l-alanine, a neurotoxic amino acid

Abstract: Cyanobacteria can generate molecules hazardous to human health, but production of the known cyanotoxins is taxonomically sporadic. For example, members of a few genera produce hepatotoxic microcystins, whereas production of hepatotoxic nodularins appears to be limited to a single genus. Production of known neurotoxins has also been considered phylogenetically unpredictable. We report here that a single neurotoxin, β-N-methylamino-l-alanine, may be produced by all known groups of cyanobacteria, including cyanobacterial symbionts and free-living cyanobacteria. The ubiquity of cyanobacteria in terrestrial, as well as freshwater, brackish, and marine environments, suggests a potential for wide-spread human exposure.

Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC)

Abstract: Objective: To improve equity in cardiovascular disease prevention by developing a cardiovascular risk score including social deprivation and family history. Design: The ASSIGN score was derived from cardiovascular outcomes in the Scottish Heart Health Extended Cohort (SHHEC). It was tested against the Framingham cardiovascular risk score in the same database. Setting: Random-sample, risk-factor population surveys across Scotland 1984–87 and North Glasgow 1989, 1992 and 1995. Participants: 6540 men and 6757 women aged 30–74, initially free of cardiovascular disease, ranked for social deprivation by residence postcode using the Scottish Index of Multiple Deprivation (SIMD) and followed for cardiovascular mortality and morbidity through 2005. Results: Classic risk factors, including cigarette dosage, plus deprivation and family history but not obesity, were significant factors in constructing ASSIGN scores for each sex. ASSIGN scores, lower on average, correlated closely with Framingham values for 10-year cardiovascular risk. Discrimination of risk in the SHHEC population was significantly, but marginally, improved overall by ASSIGN. However, the social gradient in cardiovascular event rates was inadequately reflected by the Framingham score, leaving a large social disparity in future victims not identified as high risk. ASSIGN classified more people with social deprivation and positive family history as high risk, anticipated more of their events, and abolished this gradient. Conclusion: Conventional cardiovascular scores fail to target social gradients in disease. By including unattributed risk from deprivation, ASSIGN shifts preventive treatment towards the socially deprived. Family history is valuable not least as an approach to ethnic susceptibility. ASSIGN merits further evaluation for clinical use.

pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.

Abstract: The effects of changes in the gut environment upon the human colonic microbiota are poorly understood. The response of human fecal microbial communities from two donors to alterations in pH (5.5 or 6.5) and peptides (0.6 or 0.1%) was studied here in anaerobic continuous cultures supplied with a mixed carbohydrate source. Final butyrate concentrations were markedly higher at pH 5.5 (0.6% peptide mean, 24.9 mM; 0.1% peptide mean, 13.8 mM) than at pH 6.5 (0.6% peptide mean, 5.3 mM; 0.1% peptide mean, 7.6 mM). At pH 5.5 and 0.6% peptide input, a high butyrate production coincided with decreasing acetate concentrations. The highest propionate concentrations (mean, 20.6 mM) occurred at pH 6.5 and 0.6% peptide input. In parallel, major bacterial groups were monitored by using fluorescence in situ hybridization with a panel of specific 16S rRNA probes. Bacteroides levels increased from ca. 20 to 75% of total eubacteria after a shift from pH 5.5 to 6.5, at 0.6% peptide, coinciding with high propionate formation. Conversely, populations of the butyrate-producing Roseburia group were highest (11 to 19%) at pH 5.5 but fell at pH 6.5, a finding that correlates with butyrate formation. When tested in batch culture, three Bacteroides species grew well at pH 6.7 but poorly at pH 5.5, which is consistent with the behavior observed for the mixed community. Two Roseburia isolates grew equally well at pH 6.7 and 5.5. These findings suggest that a lowering of pH resulting from substrate fermentation in the colon may boost butyrate production and populations of butyrate-producing bacteria, while at the same time curtailing the growth of Bacteroides spp.

Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis

Abstract: The inactivation of glycogen synthase kinase (GSK)3 has been proposed to play important roles in insulin and Wnt signalling. To define the role that inactivation of GSK3 plays, we generated homozygous knockin mice in which the protein kinase B phosphorylation sites on GSK3α (Ser21) and GSK3β (Ser9) were changed to Ala. The knockin mice were viable and were not diabetic. Using these mice we show that inactivation of GSK3β rather than GSK3α is the major route by which insulin activates muscle glycogen synthase. In contrast, we demonstrate that the activation of muscle glycogen synthase by contraction, the stimulation of muscle glucose uptake by insulin, or the activation of hepatic glycogen synthase by glucose do not require GSK3 phosphorylation on Ser21/Ser9. GSK3 also becomes inhibited in the Wnt-signalling pathway, by a poorly defined mechanism. In GSK3α/GSK3β homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of β-catenin and stimulation of Wnt-dependent transcription. These results establish the function of Ser21/Ser9 phosphorylation in several processes in which GSK3 inactivation has previously been implicated.

Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise

Abstract: We hypothesized that an acute bout of strenuous, non-damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n = 8 and 6) of healthy young men were studied over 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload (W(max)). To label tissue proteins in muscle and tendon primed, constant infusions of [1-(13)C]leucine or [1-(13)C]valine and flooding doses of [(15)N] or [(13)C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h(-1)), muscle collagen (0.054% h(-1)), myofibrillar protein (0.121% h(-1)), and sarcoplasmic protein (0.134% h(-1))). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF-I and IGF binding proteins (IGFBP-3 and IGFBP-4) or procollagen type I N-terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.

A hybrid mathematical model of solid tumour invasion: the importance of cell adhesion

Abstract: In this paper we present a hybrid mathematical model of the invasion of healthy tissue by a solid tumour. In particular we consider early vascular growth, just after angiogenesis has occurred. We examine how the geometry of the growing tumour is affected by tumour cell heterogeneity caused by genetic mutations. As the tumour grows, mutations occur leading to a heterogeneous tumour cell population with some cells having a greater ability to migrate, proliferate or degrade the surrounding tissue. All of these cell properties are closely controlled by cell-cell and cell-matrix interactions and as such the physical geometry of the whole tumour will be dependent on these individual cell interactions. The hybrid model we develop focuses on four key variables implicated in the invasion process: tumour cells, host tissue (extracellular matrix), matrix-degradative enzymes and oxygen. The model is considered to be hybrid since the latter three variables are continuous (i.e. concentrations) and the tumour cells are discrete (i.e. individuals). With this hybrid model we examine how individual-based cell interactions (with one another and the matrix) can affect the tumour shape and discuss which of these interactions is perhaps most crucial in influencing the tumour's final structure.

Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction

Abstract: Recent studies indicate that the LKB1 tumour suppressor protein kinase is the major 9upstream9 activator of the energy sensor AMP‐activated protein kinase (AMPK). We have used mice in which LKB1 is expressed at only ∼10% of the normal levels in muscle and most other tissues, or that lack LKB1 entirely in skeletal muscle. Muscle expressing only 10% of the normal level of LKB1 had significantly reduced phosphorylation and activation of AMPKα2. In LKB1‐lacking muscle, the basal activity of the AMPKα2 isoform was greatly reduced and was not increased by the AMP‐mimetic agent, 5‐aminoimidazole‐4‐carboxamide riboside (AICAR), by the antidiabetic drug phenformin, or by muscle contraction. Moreover, phosphorylation of acetyl CoA carboxylase‐2, a downstream target of AMPK, was profoundly reduced. Glucose uptake stimulated by AICAR or muscle contraction, but not by insulin, was inhibited in the absence of LKB1. Contraction increased the AMP:ATP ratio to a greater extent in LKB1‐deficient muscles than in LKB1‐expressing muscles. These studies establish the importance of LKB1 in regulating AMPK activity and cellular energy levels in response to contraction and phenformin.

Making sense of focus groups

Abstract: CONTEXT: This paper provides an overview of the contribution of medical education research which has employed focus group methodology to evaluate both undergraduate education and continuing professional development. PRACTICALITIES AND PROBLEMS: It also examines current debates about the ethics and practicalities involved in conducting focus group research. It gives guidance as to how to go about designing and planning focus group studies, highlighting common misconceptions and pitfalls, emphasising that most problems stem from researchers ignoring the central assumptions which underpin the qualitative research endeavour. PRESENTING AND DEVELOPING FOCUS GROUP RESEARCH: Particular attention is paid to analysis and presentation of focus group work and the uses to which such information is put. Finally, it speculates about the future of focus group research in general and research in medical education in particular.

Social identity and the dynamics of leadership: Leaders and followers as collaborative agents in the transformation of social reality

Abstract: Traditional models see leadership as a form of zero-sum game in which leader agency is achieved at the expense of follower agency and vice versa. Against this view, the present article argues that leadership is a vehicle for social identity-based collective agency in which leaders and followers are partners. Drawing upon evidence from a range of historical sources and from the BBC Prison Study, the present article explores the two sides of this partnership: the way in which a shared sense of identity makes leadership possible and the way in which leaders act as entrepreneurs of identity in order to make particular forms of identity and their own leadership viable. The analysis also focuses (a) on the way in which leaders' identity projects are constrained by social reality, and (b) on the manner in which effective leadership contributes to the transformation of this reality through the initiation of structure that mobilizes and redirects a group's identity-based social power.

Membrane disruption by optically controlled microbubble cavitation

Abstract: In fluids, pressure-driven cavitation bubbles have a nonlinear response that can lead to extremely high core-energy densities during the collapse phase—a process underpinning phenomena such as sonoluminescence1 and plasma formation2. If cavitation occurs near a rigid surface, the bubbles tend to collapse asymmetrically, often forming fast-moving liquid jets that may create localized surface damage3. As encapsulated microbubbles are commonly used to improve echo generation in diagnostic ultrasound imaging, it is possible that such cavitation could also lead to jet-induced tissue damage. Certainly ultrasonic irradiation (insonation) of cells in the presence of microbubbles can lead to enhanced membrane permeabilization and molecular uptake (sonoporation)4,5,6,7, but, although the mechanism during low-intensity insonation is clear8, experimental corroboration for higher pressure regimes has remained elusive. Here we show direct observational evidence that illuminates the energetic micrometre-scale interactions between individual cells and violently cavitating shelled microbubbles. Our data suggest that sonoporation at higher intensities may arise through a synergistic interplay involving several distinct processes.

Selective activation of AMPK-PGC-1α or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation

Abstract: SPECIFIC AIMSEndurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis, but it usually induces no growth. In contrast, resistance training stimulates muscle growth but has little effect on phenotype. We used 3 h of low-frequency stimulation (LFS) of isolated rat skeletal muscle to mimic endurance training and sixty 3 s bursts of high-frequency stimulation (HFS) to mimic resistance training. The specific aims were to identify signaling events that are activated by either LFS or HFS and that can explain the specific muscle adaptations to such stimulation patterns.PRINCIPAL FINDINGSLFS and HFS had specific effects on adaptation markers and on the activation of numerous signal transduction proteins.1. LFS, but not HFS, increases AMPK Thr172 phosphorylation and induces PGC-1α and UCP-3AMP kinase (AMPK) Thr172 phosphorylation and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) increased significantly to 2.02 ± 0.11 and 1.30 ± 0.04 of ...

Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study

Abstract: Aims To ascertain the frequency and identify predictors of self-reported hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes. Methods A random sample of 267 people with insulin-treated diabetes were recruited from a population-based diabetes register in Tayside, Scotland. Each subject prospectively recorded the number of mild and severe hypoglycaemic episodes experienced over a 1-month period. Ordinal logistic regression was performed to identify potential predictors of hypoglycaemia. Results Five hundred and seventy-two hypoglycaemic events were reported by 155 patients. The participants with Type 1 diabetes had a total of 336 hypoglycaemic events with a rate of 42.89 events per patient per year. Of these, nine were severe hypoglycaemic events, with a rate of 1.15 events per patient per year. Participants with insulin-treated Type 2 diabetes experienced a total of 236 hypoglycaemic events with a rate of 16.37 events per patient per year. Of these, five were severe hypoglycaemic events, which would be equivalent to 0.35 events per patient per year. Predictors of hypoglycaemia in Type 1 diabetes were a history of previous hypoglycaemia (P = 0.006) and co-prescribing of any oral drug (P = 0.048). In patients with insulin-treated Type 2 diabetes, a history of previous hypoglycaemia (P < 0.0001) and duration of insulin treatment (P = 0.014) were significant predictors. Conclusion The incidence of self-reported severe hypoglycaemia in insulin-treated Type 2 diabetes is lower than in Type 1 diabetes but does occur more often than previously reported and with sufficient frequency to cause significant morbidity. Duration of insulin treatment is a key predictor of hypoglycaemia in insulin-treated Type 2 diabetes.