bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin signalling: effects of prior exercise
Authors: Wojtaszewski J. F. P. , Jørgensen S. B. , Frøsig C. , MacDonald C. , Birk J. B. , Richter E. A. 
Published: July 2003

AbstractAfter the discovery and clinical use of insulin for treatment of diabetes it became clear that some of the biological effect of insulin was dependent on the circumstances under which it was given. Relevant for this review is the notion that physical activity, in addition to its own direct metabolic effects also markedly affects the ability of insulin to stimulate a range of metabolic processes. More specifically, during and for a prolonged period after, exercise elicits effects on processes such as insulin‐induced muscle glucose uptake and glucose metabolism which influence systemic glucose homeostasis. These phenomena are probably responsible for the improvement in glucose homeostasis and metabolic control that typically occurs with exercise in people with insulin resistance and probably contributes to the reduced risk for development of type 2 diabetes in individuals who engage in regular exercise. Here we focus on the influence of a single bout of exercise on the action of insulin on processes such as glucose uptake and glucose storage in skeletal muscle.
Regulatory mechanisms in the interaction between carbohydrate and lipid oxidation during exercise
Authors: Spriet L. L. , Watt M. J. 
Published: July 2003

AbstractAt the onset of exercise, signals from inside and outside the muscle cell increase the availability of carbohydrate (CHO) and fat to provide the fuel required for ATP production. CHO and fat oxidation are the dominant sources of aerobic ATP production and both pathways must be heavily upregulated during exercise to meet the increased energy demand. Within this paradigm, there is room for shifts between the proportion of energy that is provided from CHO and fat. It has long been known that increasing the availability of endogenous or exogenous CHO can increase the oxidation of CHO and decrease the oxidation of fat. The opposite is also true. While descriptive studies documenting these changes are numerous, the mechanisms regulating these shifts in fuel use in the face of constant energy demand have not been thoroughly elucidated. It would be expected, for example, that any fat‐induced shift in CHO metabolism would target the enzymes that play key roles in regulating CHO metabolism and oxidation. Inside the muscle these could include glucose uptake (GLUT4) and phosphorylation (hexokinase), glycogenolysis (glycogen phosphorylase), glycolysis (phosphofructokinase) and conversion to acetyl CoA (pyruvate dehydrogenase). The same would be expected for a CHO‐induced down regulation of fat metabolism and oxidation and might target transport of long chain fatty acids into the cell (fatty acid translocase CD36), release of fatty acids from intramuscular triacylglycerol (hormone sensitive lipase) and transport into the mitochondria (carnitine palmitoyl transferase complex). This review summarizes the work describing the interaction between CHO and fat metabolism in human skeletal muscle during exercise and presents the theories that may account for CHO/fat interaction during exercise.
Energy translocation across cell membranes and membrane models
Authors: Pownall H. J. , Hamilton J. A. 
Published: July 2003

AbstractFatty acid transport is an important process in cellular energy distribution and storage in both normal and pathological states, especially obesity‐linked type 2 diabetes mellitus. Fatty acid transport has been studied by the complementary approaches of cell biology and biophysics. According to the latter approach, specific proteins that enhance the uptake and storage of fatty acids are posited as fatty acid translocases, which facilitate fatty acid movement from the outer to inner leaflets of the plasma membrane. According to biophysical studies conducted in vitro, fatty acid translocation occurs by a rapid diffusive process that does not require a protein. Herein, we critically review these two mechanisms and their importance in the regulation of fatty acid uptake in vivo.
Hormone‐sensitive lipase in skeletal muscle: regulatory mechanisms
Authors: Langfort J. , Donsmark M. , Ploug T. , Holm C. , Galbo H. 
Published: July 2003

AbstractAim:  The enzymatic regulation of intramuscular triacylglycerol (TG) breakdown has until recently not been well understood. Our aim was to elucidate the role of hormone‐sensitive lipase (HSL), which controls TG breakdown in adipose tissue.Methods:  Isolated rat muscle as well as exercising humans were studied.Results:  The presence of HSL was demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze‐drying. The content of HSL varies between fibre types, being higher in oxidative than in glycolytic fibres. Analysed under conditions optimal for HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by presence of anti‐HSL antibody during analysis. Moreover, immunoprecipitation with affinity‐purified anti‐HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via beta‐adrenergic activation of protein kinase A (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser563, Ser659 and Ser660. Contraction probably also enhances muscle‐HSL activity by phosphorylation, because the contraction‐induced increase in HSL activity is increased by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction‐induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser600. So, phosphorylation of different sites may explain that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases the contraction‐mediated, but diminishes the adrenaline mediated HSL activation in muscle.Conclusion:  The existence and regulation of HSL in skeletal muscle indicate a role of HSL in muscle TG metabolism.
Molecular regulation of individual skeletal muscle fibre types
Authors: Spangenburg E. E. , Booth F. W. 
Published: July 2003

AbstractThe purpose of this review is to present current understanding of cellular and molecular regulation of fibre type expression in skeletal muscle. Published literature seems to conclusively suggest that muscle fibre type expression is regulated by multiple signalling pathways and transcription factors rather than a single ‘master’ switch or signalling pathway. While the current nomenclature for fibre types is convenient for communication, based upon the evolution of this nomenclature, the prediction that fibre type classifications may change in the future to incorporate post‐genomic information is made. It is predicted that future fibre type classifications could be based upon the contractile‐activity‐induced changes in a common regulatory factor(s) within a subpopulation of genes whose expressions are altered to modify and maintain the new muscle fibre phenotype.
AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise
Authors: Ruderman N. B. , Park H. , Kaushik V. K. , Dean D. , Constant S. , Prentki M. , Saha A. K. 
Published: July 2003

AbstractAn increasing body of evidence has revealed that activation of adenosine monophosphate (AMP)‐activated protein kinase (AMPK)‐activated protein kinase increases fatty acid oxidation by lowering the concentration of malonyl coenzyme A (CoA), an inhibitor of carnitine palmitoyl transferase 1. Studies carried out primarily in skeletal muscle suggest that AMPK modulates the concentration of malonyl CoA by concurrently phosphorylating and inhibiting acetyl CoA carboxylase (ACC), the rate limiting enzyme in malonyl CoA synthesis, and phosphorylating and activating malonyl CoA decarboxylase (MCD), an enzyme involved in its degradation. We have recently observed that AMPK and MCD activities are increased and ACC activity diminished in skeletal muscle, liver and, surprisingly, in adipose tissue 30 min following exercise (treadmill run) in normal rats. In liver and adipose tissue these changes were associated with a decrease in the activity of glycerol‐3‐phosphate acyltransferase (GPAT), which catalyses the first committed reaction in glycerolipid synthesis and, which like ACC, is phosphorylated and inhibited by AMPK. Similar changes in ACC, MCD and GPAT were observed following the administration of 5‐aminoimidazole 4‐carboxamide‐riboside (AICAR), further indicating that the exercise‐induced alterations in these enzymes were AMPK‐mediated.Conclusions:  (1) AMPK plays a major role in regulating lipid metabolism in multiple tissues following exercise. (2) The net effect of its activation is to increase fatty acid oxidation and diminish glycerolipid synthesis. (3) The relevance of these findings to the regulation of muscle glycogen repletion in the post‐exercise state and to the demonstrated ability of AMPK activation to decrease adiposity and increase insulin sensitivity in rodents remains to be determined.
AMP‐activated protein kinase and muscle glucose uptake
Authors: Musi N. , Goodyear L. J. 
Published: July 2003

AbstractThe AMP‐activated protein kinase (AMPK) is an enzyme that is activated in situations where there are changes in the cellular energy status such as muscle contraction and hypoxia. AMPK can also be pharmacologically activated by the compound 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR) and the antidiabetic agent metformin. Several studies support the hypothesis that AMPK plays an important role in the stimulation of muscle glucose uptake by these physiological and pharmacological stimuli. In isolated rat muscles, activation of AMPK is associated with increases in glucose uptake through an insulin‐independent mechanism. Studies done in rodents have shown that the activation of AMPK by AICAR is accompanied by decreases in blood glucose concentrations, in part due to enhanced muscle glucose uptake. Similar to exercise, AICAR not only directly stimulates glucose uptake into the skeletal muscle, but also enhances insulin sensitivity. The activation of AMPK and associated increases in muscle glucose uptake are affected by factors such as glycogen content, exercise training and fibre type. The effects of AMPK on muscle glucose uptake makes this protein a promising pharmacological target for the treatment of type 2 diabetes.
Variants in the aromatase gene and on the Y‐chromosome are not associated with adult height or insulin resistance in a UK population
Authors: Weedon Michael N. , Turner Martina , Knight Beatrice , Clark Penny , Hattersley Andrew T. , Frayling Timothy M. 
Published: July 2003

Summaryobjective  To assess the association of polymorphisms in the aromatase gene (CYP19) and on the Y‐chromosome, with adult height and insulin resistance in a UK Caucasian population, after a recent report indicated these variants explain 4 cm of adult male height variation.patients and design  We performed an association study using 917 healthy UK Caucasian subjects from the Exeter Family Study, an ongoing consecutive‐birth cohort. Our study had > 85% (95% for the CYP19 variant; 85% for the Y variant) power to detect the association suggested by the previous study.measurements  Subjects’CYP19 genotype were determined using tetra‐primer PCR, and the Y‐chromosome variant genotype was identified using a restriction fragment length polymorphism (RFLP) method. Trained research nurses were responsible for measurement of height. Fasting insulin concentration was determined by an immunoenzymometric assay.results  We did not find any evidence for an effect of the CYP19 polymorphism or Y‐RFLP on adult height (P > 0·83 for both variants). In addition, there was no evidence for an effect on insulin resistance in a subset of 416 subjects (P > 0·46).conclusion  We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies.
Recent concerns surrounding HRT
Authors: Armitage Mary , Nooney Janet , Evans Stephen 
Published: July 2003

SummaryMillions of women are treated with hormone replacement therapy (HRT) for relief of menopausal symptoms, including vasomotor flushes and sweats for which oestrogen is uniquely and highly effective. Others may continue longer‐term treatment in the hope that HRT will help to prevent chronic disease. The preservation of bone mass with continuing oestrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of oestrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrate no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may be a small increased risk of ovarian cancer associated with longer‐term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors and pharmaceutical companies. There are difficulties in extrapolating the results from trials using a specific HRT product to advise women on the wide range of other hormone products, doses, combinations and routes of administration. However, in the absence of evidence that other products are safer, the data suggest that for many women the risks associated with long‐term use of HRT outweigh the benefits. There are nonhormonal strategies for the prevention and treatment of osteoporosis. HRT is not, and has never been, licensed in the UK for the prevention or treatment of vascular disease, and the data suggesting potential benefit should now be regarded as biased. The absolute incidence of an adverse event is low, and the risk in an individual woman in a single year is very small, but the risks are cumulative over time with long‐term use. The risk–benefit balance of each woman needs regular reappraisal with continued use.
Detection and localization of chemokine gene expression in autoimmune thyroid disease
Authors: Kemp E. Helen , Metcalfe Russell A. , Smith Karen A. , Woodroofe M. Nicola , Watson Philip F. , Weetman Anthony P. 
Published: July 2003

Summaryobjective Autoimmune thyroid disease (Hashimoto's thyroiditis and Graves’ disease) is characterized by lymphocytic infiltration of the thyroid gland. Chemokines are cytokines with chemoattractant properties for a range of immune effector cells and might therefore play a significant role in the initiation and maintenance of the autoimmune process. The aim of this study was to analyse chemokine gene expression in autoimmune thyroid tissue and in cultured thyroid follicular cells (TFC).design and patients Immunocytochemistry and reverse‐transcriptase polymerase chain reaction (RT–PCR) amplification were used to analyse the expression of monocyte chemoattractant protein (MCP)‐1, RANTES (regulated upon activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)‐1α, MIP‐1β, interferon (IFN)‐γ‐inducible protein (IP)‐10 and monokine induced by IFN‐γ (Mig) in thyroid tissue from patients with Hashimoto's thyroiditis (n = 4), Graves’ disease (n = 6) and nonautoimmune multinodular goitre (n = 4). Chemokine gene expression was also examined in cultured TFC by RT–PCR.results Expression of MCP‐1, RANTES, MIP‐1α, MIP‐1β, IP‐10 and Mig was demonstrated in all Hashimoto's and most Graves’ thyroid specimens but very little expression was detected in the nonautoimmune goitre samples. In thyroid tissue from Graves’ disease patients, positive staining for chemokines was largely restricted to the lymphocytic cell infiltrate. Within thyroid tissue from Hashimoto's patients, there was evidence for the expression of all chemokines by thyroid follicular cells, suggesting a role for local chemokine synthesis by the glandular epithelial cells in the recruitment of inflammatory cells into the gland in autoimmunity. The present work also showed that expression all the chemokine genes analysed could be induced in cultured thyroid cells by IFN‐γ and interleukin (IL)‐1α. Expression of all the chemokines examined was not stimulated by TSH.conclusion We postulate that TFC may play a role in the pathogenesis of autoimmune thyroid disease as they are able to express the chemokines MIP‐1α, MIP‐1β, MCP‐1, RANTES, IP‐10 and Mig that would promote the infiltration of immune cells into the thyroid gland.
The pituitary–testicular axis in Klinefelter's syndrome and in oligo‐azoospermic patients with and without deletions of the Y chromosome long arm
Authors: Tomasi Paolo A. , Oates Robert , Brown Laura , Delitala Giuseppe , Page David C. 
Published: July 2003

Summaryobjective The most frequent known genetic causes of severe oligospermia (< 5 million sperm/ml) or azoospermia in men are Klinefelter's syndrome (KS), and deletions in the Y chromosome long arm (Yq). We aimed to compare the function of the pituitary–testicular axis in patients with severe oligospermia or azoospermia, idiopathic or associated with Y chromosome deletions or Klinefelter's syndrome (KS) and in control subjects.patients We studied 47 men with idiopathic oligo‐azoospermia, 42 with Yq deletions (27 AZFc, 13 AZFb and two AZFa) and oligo‐azoospermia, 14 with KS and 39 control subjects (total 143).measurements We analysed levels of FSH, inhibin‐B, LH, free testosterone and oestradiol in all subjects, and we calculated indexes based on those hormones.results Inhibin‐B levels were indistinguishable between patients with idiopathic and Y deletion‐associated oligo‐azoospermia, lowest in the Klinefelter's patients and highest in controls. FSH levels followed the reverse pattern: indistinguishable between patients with idiopathic and deletion‐associated oligo‐azoospermia, highest in Klinefelter's patients and lowest in controls. Oestradiol, free testosterone and the derived indeces were not different in subjects with Yq deletions compared to those with idiopathic oligo‐azoospermia. Among the Yq‐deleted patients, no measured or derived parameter differed between the subjects with AZFc deletion and those with AZFb deletion. When non‐KS oligo‐azoospermic patients were classified according to histology [Sertoli cell‐only (SCO), n = 18 or non‐Sertoli cell only (non‐SCO), n= 18] and compared to KS patients, the hormonal pattern did not differ between SCO and non‐SCO subjects, but levels in KS patients were significantly different for FSH, inhibin‐B and the FSH/inhibin‐B ratio. KS patients not only had lower inhibin‐B than SCO and non‐SCO oligo‐azoospermic men, but also higher FSH levels for any given inhibin‐B concentration.conclusion Our data show that Y‐deleted patients do not have a lesser impairment of Sertoli cell function than patients with idiopathic oligo‐azoospermia, and support the concept that the main determinant of inhibin‐B production is the germ cell mass. Also, our results suggest that one or more other factors, apart from inhibin‐B, may contribute to increased pituitary secretion of FSH in KS patients.
Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during l‐thyroxine replacement
Authors: Fugazzola Laura , Persani Luca , Mannavola Deborah , Reschini Eugenio , Vannucchi Guia , Weber Giovanna , Beck‐Peccoz Paolo 
Published: July 2003

Summaryobjective The differential diagnosis of congenital hypothyroidism (CH) is aimed to distinguish transitory from permanent forms, to optimize l‐thyroxine (l‐T4) therapy to replacement or TSH‐suppressive regimens, and to reach accurate definition of the clinical and biochemical phenotype for subsequent genetic investigations and counselling. Therefore, l‐T4 therapy is presently withdrawn in most instances and investigations are performed in a disturbing hypothyroid state.design The availability of recombinant human TSH (rhTSH) prompted us to assess its efficacy in the differential diagnosis of CH during l‐T4 therapy.patients and measurements Eight adult patients with permanent CH remained on l‐thyroxine and underwent a new protocol for rhTSH (Thyrogen®) testing with injections [4 g/kg/day intramuscularly (i.m.)] at days 1, 2 and 3. At day 3, 123I was administered and uptake obtained after 2 and 24 h. Serum TSH and thyroglobulin (Tg) levels were measured at days 1–4. Neck ultrasound was carried out in all cases.results Serum TSH reached levels > 20 mU/l at day 2 and remained above 30 mU/l on days 3 and 4. Stimulation of Tg levels was seen in five patients with peak at day 4. Lingual thyroid was documented at scintigraphy (TS) in three Tg‐responsive patients who were previously diagnosed as having thyroid agenesia. In one patient with dyshormonogenesis and high Tg, TS confirmed the presence of goitre with positive perchlorate test. TS was negative in the remaining four cases. All tests indicated complete agenesia in one, whereas a minimal Tg response was marker of nearly complete agenesia in another. The last two TS‐negative patients had hypoplastic glands at ultrasound, and refractoriness to TSH stimulation was confirmed by absent Tg response.conclusions We report the first application of rhTSH for differential diagnosis of patients with permanent CH, avoiding the undesirable transient hypothyroidism consequent to l‐T4 withdrawal. The data obtained led to the change of the diagnosis at presentation in 4/8 patients and to a more accurate description of the clinical picture in all patients. The proposed protocol has been proved to cause Tg increases even in the presence of small amounts of responsive thyroid cells. The rhTSH testing led to the desired disease characterization, thus allowing specific management and targeted genetic analyses.