Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications

Résumé : Les concentrations plasmatiques du peptide natriurétique de type B sont augmentées chez les diabétiques de type 2 atteints de complications vasculaires. But : Les concentrations plasmatiques du peptide natriurétique de type B (NT-proBNP) sont augmentées chez les diabétiques de type 2 atteints de complications vasculaires. Les concentrations plasmatiques du peptide natriurétique de type B (BNP), ou de sa pro-hormone (NT-proBNP), sont reconnues depuis peu comme marqueur de choix de la dysfonction cardiaque. Les diabétiques de type 2 sont à haut risque de développer des complications cardiovasculaires. L'objectif de cette étude a été de déterminer si les concentrations plasmatiques de NT-proBNP étaient comparables chez des diabétiques de type 2 avec ou sans complications vasculaires. Méthodes : Nous avons mesuré le NT-proBNP plasmatique chez 54 diabétiques de type 2, 27 sans complications micro- ou macrovasculaires et 27 présentant des complications soit micro- soit macrovasculaires, soit les deux. Le même dosage a été effectué chez 38 témoins sains, appariés pour l'âge et le sexe avec les diabétiques. Résultat : Le NT-proBNP plasmatique était plus élevé chez les diabétiques avec complications (médiane 121 pg/ml, intervalle interquartile 50-240 pg/ml) que chez ceux sans complications (37 pg/ml, 21-54 pg/ml, P < 0,01). Comparés au groupe témoin (55 pg/ml, 40-79 pg/ml), seuls les diabétiques avec complications vasculaires avaient un NT-proBNP plasmatique significativement augmenté (P < 0,001). Chez les diabétiques la maladie coronarienne et la néphropathie (définie selon l'excrétion urinaire d'albumine) étaient chacune associée de façon indépendante avec une augmentation des concentrations plasmatiques de NT-proBNP. Conclusion : Chez les diabétiques de type 2 souffrant de complications micro- ou macrovasculaires, les concentrations plasmatiques de NT-proBNP sont augmentées par rapport à celles des malades indemnes de complications vasculaires. L'augmentation de sécrétion de ce peptide est associée de façon indépendante avec la maladie coronarienne et la néphropathie. La mesure du NT-proBNP plasmatique pourrait donc être utile pour dépister la présence de complications micro- ou macrovasculaires.

Epidermal growth factor (EGF) stimulation of cultured brain cells. II. Increased production of extracellular soluble proteins.

The production of extracellular soluble proteins was studied in serum-free aggregating cell cultures of fetal rat telencephalon labeled on culture day 7 with a mixture of radioactive amino acid precursors. Cultures treated continuously with epidermal growth factor (EGF; 20 ng/ml) showed a generally increased protein secretion and a particularly enhanced production of a few distinct extracellular proteins. The time lag of this response after an initial dose of EGF (25 ng/ml) on day 7 was 48 h. The total macromolecular radioactivity that accumulated within 96 h of labeling in the media of EGF-treated cultures was 175% of untreated controls, whereas no difference was found in the proportions of intracellular amino acid incorporation. Cultures which received a single dose of EGF (25 ng/ml) on day 1 showed still a greatly increased protein secretion on day 7. Prevention of extracellular protein accumulation by reducing the initial cell number and increasing the rate of media changes did not affect the EGF-induced stimulation of the two glial enzymes, glutamine synthetase and 2',3'-cyclic nucleotide 3'-phosphohydrolase. The results suggest that both the increased production of extracellular proteins and the enhanced development of glial enzymatic activities reflect the stimulated phenotypic expression of EGF-sensitive brain cells.

Cartilage thickness at the posterior medial femoral condyle is increased in femorotibial knee osteoarthritis: a cross-sectional CT arthrography study (Part 2).

OBJECTIVE: To evaluate the thickness of cartilage at the posterior aspect of the medial and lateral condyle in Osteoarthritis (OA) knees compared to non-OA knees using computed tomography arthrography (CTA). DESIGN: 535 consecutive knee CTAs (mean patient age = 48.7 ± 16.0; 286 males), were retrospectively analyzed. Knees were radiographically classified into OA or non-OA knees according to a modified Kellgren/Lawrence (K/L) grading scheme. Cartilage thickness at the posterior aspect of the medial and lateral femoral condyles was measured on sagittal reformations, and compared between matched OA and non-OA knees in the whole sample population and in subgroups defined by gender and age. RESULTS: The cartilage of the posterior aspect of medial condyle was statistically significantly thicker in OA knees (2.43 mm (95% confidence interval (CI) = 2.36, 2.51)) compared to non-OA knees (2.13 mm (95%CI = 2.02, 2.17)) in the entire sample population (P < 0.001), as well as for all subgroups of patients over 40 years old (all P ≤ 0.01), except for females above 60 years old (P = 0.07). Increase in cartilage thickness at the posterior aspect of the medial condyle was associated with increasing K/L grade in the entire sample population, as well as for males and females separately (regression coefficient = 0.10-0.12, all P < 0.001). For the lateral condyle, there was no statistically significant association between cartilage thickness and OA (either presence of OA or K/L grade). CONCLUSIONS: Cartilage thickness at the non-weight-bearing posterior aspect of the medial condyle, but not of the lateral condyle, was increased in OA knees compared to non-OA knees. Furthermore, cartilage thickness at the posterior aspect of the medial condyle increased with increasing K/L grade.

Increased therapeutic window for the R91W mutant form of Rpe65 compared to Rpe65 null backgroud

Purpose:Given the advances of gene therapy studies to cure RPE65-derived Leber Congenital Amaurosis (LCA) (clinical trials phase I) and the heterogeneity of the targeted patients both genetically and phenotypically, it is of prime importance to examine the rescue efficiency of gene transfer in different mutant contexts. Indeed, half of these mutations are missense mutations, leading to potential residual RPE65 activity. Consequently, we wanted to evaluate the effect on retinal activity and cone survival of lentivirus-mediated gene therapy in the R91W knock-in mouse model expressing the mutant Rpe65R91W gene (Samardzija et al. 2008), a mutation found in LCA patients. Notably we investigated whether if the therapeutic window is prolonged in comparison to null mutations. Methods:An HIV-1-derived lentiviral vector (LV) expressing either the GFP or the mouse Rpe65 cDNA under the control of a 0.8 kb fragment of the human Rpe65 promoter (R0.8) was produced by transient transfection of 293T cells. LV-R0.8-RPE65 or GFP was injected into 5-days-old (P5) or 1 month-old R91W mice. Functional rescue was assessed by ERG (1 and 4 months post-injection) and pupillary light response (PLR) recordings and cone survival by histological analysis. Results:Increased light sensitivity was detected by scotopic ERG in animals injected with LV-R0.8-RPE65 at both P5 and 1 month compared to GFP-treated animals or untreated mice. PLR was also improved in some eyes and histological analysis of cone markers showed that the density of cones reached the wild type level in the region of wt RPE65 delivery after treatment at P5. However, the rescue effect of the injection at 1 month was limited and attained 60% of the wild type level, but still more cones were observed in the treated area than in 1 month-old untreated Rpe65R91W mice. Conclusions:We were able to show that lentivirus-mediated Rpe65 gene transfer not only increases retinal activity of the Rpe65R91W mouse and survival of cones after treatment at P5 but also after treatment at 1 month. However even if the treatment at 1 month is more limited (60% of the wild type level) than treatment at P5, the amount of cone markers is increased compared to the proportion found at 1 month of age in untreated animals. This results contrast with the lack of cone rescue by treatment at 1 month of age in Rpe65-/- (Bemelmans et al, 2006). Thus patient suffering from R91W mutation might benefit from a prolonged therapeutic window.

The effects of tourism, beachfront development and increased light pollution on nesting Loggerhead turtles Caretta caretta (Linnaeus, 1758) on Sal, Cape Verde Islands

Loggerhead Caretta caretta is now the only species of marine turtle nesting on the island of Sal, Cape Verde Islands. Since 2008, ADTMA - SOS Tartarugas has patrolled all the southern beaches of the island in order to protect nesting females and to collect nesting data. Although hunting is still a major issue, with 90 turtles killed in 2009, habitat loss and light pollution are becoming an ever more serious threat. Construction sites, hotels, apartment buildings and restaurants close to beaches, bright lights and illegal removal of sand are contributing to a marked decrease in the total number of nesting turtles on some beaches. In 2009, beaches on Sal experienced an average increase in nests of 200%, while the beach most affected by construction (Tortuga Beach) saw a decrease of nests of 7.3% (from 19.1% of total number of nests in 2008 to 11.8% in 2010). This beach also recorded a much lower nest to emergence ratio than normal (17.6% of emergences resulting in nests compared to 29.9% in other areas), indicating reluctance to nest due to light pollution and other disturbances.

Increased connexin43 expression in human sphenous veins in culture is associated with intimal hyperplasia

Résumé Objectif : L'hyperplasie intimale est un processus de remodelage vasculaire qui apparaît après une lésion vasculaire. Les mécanismes impliqués dans l'hyperplasie intimale sont la prolifération, la dédifférentiation et la migration des cellules musculaires lisses depuis la média vers l'espace sous-intimal. Nous avons émis l'hypothèse que les jonctions communicantes de type gap, qui coordonnent certains processus physiologiques tels que la croissance et la différentiation cellulaire, pouvaient participer au développement de l'hyperplasie intimale. Méthodes : Des segments de veines saphènes humaines prélevées chirurgicalement lors de pontages, ont été ouverts longitudinalement avec la surface luminale placée vers le haut et maintenus en culture pendant 14 jours. Des fragments veineux ont été préparés pour une évaluation histologique, pour des mesures de l'épaisseur de la néointima, et pour des analyses immunocytochimiques de l'ARN messager ainsi que des protéines. Résultats : Parmi les 4 connexines (Cxs 37, 40, 43 et 45) qui forment les jonctions communicantes dans les veines, nous avons focalisé notre étude sur l'expression des Cxs 43 et 40; nous avons démontré que la Cx43 est exprimée dans les cellules musculaires lisses et les cellules endothéliales alors que la Cx40 est uniquement présente dans l'endothélium. Après 14 jours en culture, des analyses histomorphométriques ont montré une augmentation significative de l'épaisseur de l'intima démontrant la présence d'hyperplasie intimale. Une analyse temporelle a révélé une augmentation progressive de la Cx43 jusqu'à une augmentation maximale de six à huit fois au niveau de l'ARN messager et des protéines après 14 jours en culture. Au contraire, l'expression de la Cx40 n'était pas modifiée. Des analyses par immunofluorescence ont montré également une augmentation de la Cx43 dans les membranes des cellules musculaires lisses de la média. Le développement de l'hyperplasie intimale in vitro est diminué en présence de fluvastatin et cette diminution est associée à une réduction de l'expression de la Cx43. Conclusions : Ces données démontrent que la Cx43 est augmentée in vitro pendant le processus d'hyperplasie intimale et que la fluvastatin prévient cette induction. Ces résultats suggèrent un rôle crucial joué par la communication intercellulaire impliquant la Cx43 dans la veine humaine durant le développement de l'hyperplasie intimale. Abstract Objective: Intimal hyperplasia is a vascular remodelling process that occurs after a vascular injury. The mechanisms involved in intimal hyperplasia are proliferation, dedifferentiation, and migration of medial smooth muscle cells towards the subintimal space. We postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, might participate in the development of intimal hyperplasia. connexin43 (Cx43) expression levels may be altered in intimal hyperplasia, and we therefore evaluated the regulated expression of Cx43 in human saphenous veins in culture in the presence or not of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Methods: Segments of harvested human saphenous veins, obtained at the time of bypass graft, were opened longitudinally with the luminal surface uppermost and maintained in culture for 14 days. Vein fragments were then processed for histologic examination, neointimal thickness measurements, immunocytochemistry, RNA, and proteins analysis. Results: Of the four connexins (Cx37, 40, 43, and 45), we focused on Cx43 and Cx40, which we found by real-time polymerase chain reaction to be expressed in the saphenous vein because they are the predominant connexins expressed by smooth muscle cells and endothelial cells. Afrer 14 days of culture, histomorphometric analysis showed a significant increase in the intimal thickness as observed during the process of intimal hyperplasia. Atime-course analysis revealed a progressive upregulation of Cx43 to reach a maximal increase of sixfold to eightfold at both transcript and protein levels after 14 days in culture. In contrast, the expression of Cx40, abundantly expressed in the endothelial cells, was not altered. Immunofluorescence showed a large increase in Cx43 within smooth muscle cell membranes of the media layer. The development of intimal hyperplasia in vitro was decreased in presence of fluvastatin and was associated with reduced Cx43 expression. Conclusions: These data show that Cx43 is increased in vitro during the process of intimal hyperplasia and that fluvastatin could prevent this induction, supporting a critical role for Cx43-mediated gap-junctional communication in the human vein during the development of intimal hyperplasia. (J Vasc Surg 2005;41:1043-52.)

Endogenous spillovers, increased competition and re-organization waves

We consider an entrepreneur that is the sole producer of a costreducing skill, but the entrepreneur that hires a team to usethe skill cannot prevent collusive trade for the innovation related knowledge between employees and competitors. We showthat there are two types of diffusion avoiding strategies forthe entrepreneur to preempt collusive communication i) settingup a large productive capacity (the traditional firm) and ii)keeping a small team (the lean firm). The traditional firm ischaracterized by its many "marginal" employees that work shortdays, receive flat wages and are incompletely informed about the innovation. The lean firm is small in number of employees,engages in complete information sharing among members, that are paid with stock option schemes. We find that the lean firm is superior to the traditional firm when technological entry costsare low and when the sector is immature.

Increased mobility of major histocompatibility complex I-peptide complexes decreases the sensitivity of antigen recognition.

CD8(+) cytotoxic T lymphocytes (CTL) can recognize and kill target cells expressing only a few cognate major histocompatibility complex (MHC) I-peptide complexes. This high sensitivity requires efficient scanning of a vast number of highly diverse MHC I-peptide complexes by the T cell receptor in the contact site of transient conjugates formed mainly by nonspecific interactions of ICAM-1 and LFA-1. Tracking of single H-2K(d) molecules loaded with fluorescent peptides on target cells and nascent conjugates with CTL showed dynamic transitions between states of free diffusion and immobility. The immobilizations were explained by association of MHC I-peptide complexes with ICAM-1 and strongly increased their local concentration in cell adhesion sites and hence their scanning by T cell receptor. In nascent immunological synapses cognate complexes became immobile, whereas noncognate ones diffused out again. Interfering with this mobility modulation-based concentration and sorting of MHC I-peptide complexes strongly impaired the sensitivity of antigen recognition by CTL, demonstrating that it constitutes a new basic aspect of antigen presentation by MHC I molecules.

Step count is associated with lower nighttime systolic blood pressure and increased dipping.

BACKGROUND: Higher nighttime blood pressure (BP) and the loss of nocturnal dipping of BP are associated with an increased risk for cardiovascular events. However, the determinants of the loss of nocturnal BP dipping are only beginning to be understood. We investigated whether different indicators of physical activity were associated with the loss of nocturnal dipping of BP. METHODS: We conducted a cross-sectional study of 103 patients referred for 24-hour ambulatory monitoring of BP. We measured these patients' step count (SC), active energy expenditure (AEE), and total energy expenditure simultaneously, using actigraphs. RESULTS: In our study population of 103 patients, most of whom were hypertensive, SC and AEE were associated with nighttime systolic BP in univariate (SC, r = -0.28, P < 0.01; AEE, r = -0.20, P = 0.046) and multivariate linear regression analyses (SC, coefficient beta = -5.37, P < 0.001; AEE, coefficient beta = -0.24, P < 0.01). Step count was associated with both systolic (r = 0.23, P = 0.018) and diastolic (r = 0.20, P = 0.045) BP dipping. Nighttime systolic BP decreased progressively across the categories of sedentary, moderately active, and active participants (125mm Hg, 116mm Hg, 112mm Hg, respectively; P = 0.002). The degree of BP dipping of BP increased progressively across the same three categories of activity (respectively 8.9%, 14.6%, and 18.6%, P = 0.002, for systolic BP and respectively 12.8%, 18.1%, and 22.2%, P = 0.006, for diastolic BP). CONCLUSIONS: Step count is continuously associated with nighttime systolic BP and with the degree of BP dipping independently of 24-hour mean BP. The combined use of an actigraph for measuring indicators of physical activity and a device for 24-hour measurement of ambulatory BP may help identify patients at increased risk for cardiovascular events in whom increased physical activity toward higher target levels may be recommended.

Long diagnostic delay in Crohn's disease is associated with complicated disease course and increased operation rate

Background: We have recently shown that the median diagnostic delay to establish Crohn's disease (CD) diagnosis (i.e. the period from first symptom onset to diagnosis) in the Swiss IBD Cohort (SIBDC) was 9 months. Seventy five percent of all CD patients were diagnosed within 24 months. The clinical impact of a long diagnostic delay on the natural history of CD is unknown. Aim: To compare the frequency and type of CD-related complications in the patient groups with long diagnostic delay (>24 months) vs. the ones diagnosed within 24 months. Methods: Retrospective analysis of data from the SIBDCS, comprising a large sample of CD patients followed in hospitals and private practices across Switzerland. The proportions of the following outcomes were compared between groups of patients diagnosed 1, 2-5, 6-10, 11-15, and ≥ 16 years ago and stratified according to the length of diagnostic delay: bowel stenoses, internal fistulas, perianal fistulas, CD-related surgical interventions, and extraintestinal manifestations. Results: Two hundred CD patients (121 female, mean age 44.9 ± 15.0 years, 38% smokers, 71% ever treated with immunomodulators and 35% with anti-TNF) with long diagnostic delay were compared to 697 CD patients (358 female, mean age 39.1 ± 14.9 years, 33% smokers, 74% ever treated with immunomodulators and 33% with anti-TNF) diagnosed within 24 months. No differences in the outcomes were observed between the two patient groups within year one after CD diagnosis. Among those diagnosed 2-5 years ago, CD patients with long diagnostic delay (n = 45) presented more frequently with internal fistulas (11.1% vs. 3.1%, p = 0.03) and bowel stenoses (28.9% vs. 15.7%, p = 0.05), and they more frequently underwent CD-related operations (15.6% vs. 5.0%, p = 0.02) compared to the patients diagnosed within 24 months (n = 159). Among those diagnosed 6-10 years ago, CD patients with long diagnostic delay (n = 48) presented more frequently with extraintestinal manifestations (60.4% vs. 34.6%, p = 0.001) than those diagnosed within 24 months (n = 182). For the patients diagnosed 11-15 years ago, no differences in outcomes were found between the long diagnostic delay group (n = 106) and the one diagnosed within 24 months (n = 32). Among those diagnosed ≥ 16 years ago, the group with long diagnostic delay (n = 71) more frequently underwent CD-related operations (63.4% vs. 46.5%, p = 0.01) compared to the group diagnosed with CD within 24 months (n = 241). Conclusions: A long diagnostic delay in CD patients is associated with a more complicated disease course and higher number of CD-related operations in the years following the diagnosis. Our results indicate that efforts should be undertaken to shorten the diagnostic delay in CD patients in order to reduce the risk for progression towards a complicated disease phenotype.

Connexins 43 and 26 are differentially increased after rat bladder outlet obstruction.

To evaluate the regulation of connexin expression by fluid pressure, we have studied the effects of elevated transmural urine pressure on Connexin43 (Cx43) and Cx26. We chose to focus on these two proteins out of the five connexins (Cx26, 43, 40, 37, and 45) which we found by RT-PCR to be expressed in the rat bladder, since in situ hybridization and immunofluorescence showed that Cx43 is the predominant connexin expressed by smooth muscle cells (SMC), whereas Cx26 is abundantly expressed only in the latter cell type. To evaluate whether these connexins are affected by changes in transmural urine pressure, we used a rat model of bladder outlet obstruction, in which a ligature is placed around the urethra. Under conditions of increased fluid pressure due to urine retention, we observed that the expression of both Cx43 and Cx26 increased at both transcript and protein levels, reaching a maximum 7-9 h after the ligature. Further analysis revealed that these changes were accounted for by a fourfold increase in Cx43 mRNA of SMC but not urothelial cell and by a fivefold increase in Cx26 mRNA of urothelium. Scrape-loading of propidium iodide showed that the latter change was paralleled by a twofold increase in coupling between urothelial cells. The data show that Cx43 and Cx26 are differentially regulated during bladder outlet obstruction and contribute to the response of the bladder wall to increased voiding pressure, possibly to control its elasticity.

Substance P-like-immunoreactive sensory neurons in dorsal root ganglia of the chick embryo: ontogenesis and influence of peripheral targets.

The expression of substance P (SP) was studied in sensory neurons of developing chick lumbosacral dorsal root ganglia (DRG) by using a mixture of periodic acid, lysine and paraformaldehyde as fixative and a monoclonal antibody for SP-like immunostaining. The first SP-like-immunoreactive DRG cells appeared first at E5, then rapidly increased in number to reach a peak (88% of ganglion cells) at E8, and finally declined (59% at E12, 51% after hatching). The fall of the SP-like-positive DRG cells resulted from two concomitant events affecting a subset of small B-neurons: a loss of neuronal SP-like immunoreactivity and cell death. After one hindlimb resection at an early (E6) or late (E12) stage of development (that is before or after establishment of peripheral connections), the DRG were examined 6 days later. In both cases, a drastic neuronal death occurred in the ispilateral DRG. However, the resection at E6 did not change the percentage of SP-like-positive neurons, while the resection at E12 severely reduced the proportion of SP-like-immunoreactive DRG cells (25%). In conclusion, connections established between DRG and peripheral target tissues not only promote the survival of sensory neurons, but also control the maintenance of SP-like-expression. Factors issued from innervated targets such as NGF would support the survival of SP-expressing DRG cells and enhance their SP content while other factors present in skeletal muscle or skin would hinder SP expression and therefore lower SP levels in a subset of primary sensory neurons.

High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients.

BACKGROUND AND AIMS: Hypoxia can induce inflammation in the gastrointestinal tract. However, the impact of hypoxia on the course of inflammatory bowel disease (IBD) is poorly understood. We aimed to evaluate whether flights and/or journeys to regions lying at an altitude of >2000 m above the sea level are associated with flare-ups within 4 weeks of the trip. METHODS: IBD patients with at least one flare-up during a 12-month observation period were compared to a group of patients in remission. Both groups completed a questionnaire. RESULTS: A total of 103 IBD patients were included (43 with Crohn's disease (CD): mean age 39.3 ± 14.6 years; 60 with ulcerative colitis (UC): mean age 40.4 ± 15.1 years). Fifty-two patients with flare-ups were matched to 51 patients in remission. IBD patients experiencing flare-ups had more frequently undertaken flights and/or journeys to regions >2000 m above sea level within four weeks of the flare-up when compared to patients in remission (21/52 [40.4%] vs. 8/51 [15.7%], p=0.005). CONCLUSIONS: Journeys to high altitude regions and/or flights are a risk factor for IBD flare-ups occurring within 4 weeks of travel.

Increasing lactate turnover rate during exercise by means of altitude training and fructose ingestion : effects on substrate metabolism and endurance performance

Summary : With regard to exercise metabolism, lactate was long considered as a dead-end waste product responsible for muscle fatigue and a limiting factor for motor performance. However, a large body of evidence clearly indicates that lactate is an energy efficient metabolite able to link the glycolytic pathway with aerobic metabolism and has endocrine-like actions, rather than to be a dead-end waste product. Lactate metabolism is also known to be quickly upregulated by regular endurance training and is thought to be related to exercise performance. However, to what extent its modulation can increase exercise performance in already endurance-trained subjects is unknown. The general hypothesis of this work was therefore that increasing either lactate metabolic clearance rate or lactate availability could, in turn, increase endurance performance. The first study (Study I) aimed at increasing the lactate clearance rate by means of assumed interaction effects of endurance training and hypoxia on lactate metabolism and endurance performance. Although this study did not demonstrate any interaction of training and hypoxia on both lactate metabolism and endurance performance, a significant deleterious effect of endurance training in hypoxia was shown on glucose homeostasis. The methods used to determine lactate kinetics during exercise exhibited some limitations, and the second study did delineate some of the issues raised (Study 2). The third study (Study 3) investigated the metabolic and performance effects of increasing plasma lactate production and availability during prolonged exercise in the fed state. A nutritional intervention was used for this purpose: part of glucose feedings ingested during the control condition was substituted by fructose. The results of this study showed a significant increase of lactate turnover rate, quantified the metabolic fate of fructose; and demonstrated a significant decrease of lipid oxidation and glycogen breakdown. In contrast, endurance performance appeared to be unmodified by this dietary intervention, being at odds with recent reports. Altogether the results of this thesis suggest that in endurance athletes the relationship between endurance performance and lactate turnover rate remains unclear. Nonetheless, the result of the present study raises questions and opens perspectives on the rationale of using hypoxia as a therapeutic aid for the treatment of insulin resistance. Moreover, the results of the second study open perspectives on the role of lactate as an intermediate metabolite and its modulatory effects on substrate metabolism during exercise. Additionally it is suggested that the simple nutritional intervention used in the third study can be of interest in the investigation on the aforementioned roles of lactate. Résumé : Lorsque le lactate est évoqué en rapport avec l'exercice, il est souvent considéré comme un déchet métabolique responsable de l'acidose métabolique, de la fatigue musculaire ou encore comme un facteur limitant de la performance. Or la littérature montre clairement que le lactate se révèle être plutôt un métabolite utilisé efficacement par de nombreux tissus par les voies oxydatives et, ainsi, il peut être considéré comme un lien entre le métabolisme glycolytique et le métabolisme oxydatif. De plus on lui prête des propriétés endocrines. Il est connu que l'entraînement d'endurance accroît rapidement le métabolisme du lactate, et il est suggéré que la performance d'endurance est liée à son métabolisme. Toutefois la relation entre le taux de renouvellement du lactate et la performance d'endurance est peu claire, et, de même, de quelle manière la modulation de son métabolisme peut influencer cette dernière. Le but de cette thèse était en conséquence d'investiguer de quelle manière et à quel degré l'augmentation du métabolisme du lactate, par l'augmentation de sa clearance et de son turnover, pouvait à son tour améliorer la performance d'endurance de sujets entraînés. L'objectif de la première étude a été d'augmenter la clearance du lactate par le biais d'un entraînement en conditions hypoxiques chez des cyclistes d'endurance. Basé sur la littérature scientifique existante, on a fait l'hypothèse que l'entraînement d'endurance et l'hypoxie exerceraient un effet synergétique sur le métabolisme du lactate et sur la performance, ce qui permettrait de montrer des relations entre performance et métabolisme du lactate. Les résultats de cette étude n'ont montré aucun effet synergique sur la performance ou le métabolisme du lactate. Toutefois, un effet délétère sur le métabolisme du glucose a été démontré. Quelques limitations de la méthode employée pour la mesure du métabolisme du lactate ont été soulevées, et partiellement résolues dans la seconde étude de ce travail, qui avait pour but d'évaluer la sensibilité du modèle pharmacodynamique utilisé pour le calcul du turnover du lactate. La troisième étude a investigué l'effet d'une augmentation de la lactatémie sur le métabolisme des substrats et sur la performance par une intervention nutritionnelle substituant une partie de glucose ingéré pendant l'exercice par du fructose. Les résultats montrent que les composants dynamiques du métabolisme du lactate sont significativement augmentés en présence de fructose, et que les oxydations de graisse et de glycogène sont significativement diminuées. Toutefois aucun effet sur la performance n'a été démontré. Les résultats de ces études montrent que la relation entre le métabolisme du lactate et la performance reste peu claire. Les résultats délétères de la première étude laissent envisager des pistes de travail, étant donné que l'entraînement en hypoxie est considéré comme outil thérapeutique dans le traitement de pathologies liées à la résistance à l'insuline. De plus les résultats de la troisième étude ouvrent des perspectives de travail quant au rôle du lactate comme intermédiaire métabolique durant l'exercice ainsi que sur ses effets directs sur le métabolisme. Ils suggèrent de plus que la manipulation nutritionnelle simple qui a été utilisée se révèle être un outil prometteur dans l'étude des rôles et effets métaboliques que peut revêtir le lactate durant l'exercice.