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Napolitano, Tiziana. "Confidentiel." Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4141.
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CARTOTTO, DENIS. "Syndrome d'alstrom et insulinoresistance : a propos de trois observations." Aix-Marseille 2, 1988. http://www.theses.fr/1988AIX20367.
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FIMBEL, SYLVIE. "Les troubles endocriniens lies a l'acanthosis nigricans : insulinoresistance et hyperandrogenie ; implications cliniques et physiopathologiques ; a propos de 13 observations." Lyon 1, 1992. http://www.theses.fr/1992LYO1M075.
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Morzyglod, Lucille. "L’adaptateur moléculaire Grb14 contrôle les actions métaboliques et mitogéniques de l’insuline dans le foie." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T041.
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L'insuline, hormone clé du contrôle de l'homéostasie métabolique, exerce également des effets trophiques sur la croissance et la prolifération cellulaire. Des études épidémiologiques ont récemment montré que les individus obèses ou diabétiques de type 2 ont un risque plus élevé de développer des cancers et elles ont également suggéré que l’insuline jouerait un rôle dans ce développement tumoral. Ainsi, une signalisation adéquate en aval du récepteur de l’insuline est indispensable pour éviter des processus physiopathologiques. La signalisation de l’insuline est contrôlée par des mécanismes de rétrocontrôle, dont l’adaptateur moléculaire Grb14 qui agit comme un inhibiteur endogène de l’activité catalytique du RI. L’objectif de ma thèse a été d’étudier les conséquences métaboliques et mitogéniques de l’inhibition de Grb14 in#vivo spécifiquement dans le foie de souris. Dans une première étude, nous montrons que sept jours après l’invalidation de Grb14, les souris présentent une activation des voies de signalisation de l’insuline, qui s’accompagne d’une amélioration de la tolérance au glucose et de la production hépatique de glucose. Cependant, de façon paradoxale, la voie de la lipogenèse est très fortement diminuée. En décryptant le mécanisme moléculaire impliqué, nous montrons que l’inhibition de Grb14 permet la libération de la protéine p62/sqstm1 qui active le facteur de transcription Nrf2, ce qui entraine une inhibition du récepteur nucléaire pro-lipogénique LXR. De façon intéressante, l’invalidation de Grb14 chez des souris ob/ob permet de restaurer la glycémie et la stéatose hépatiques à des valeurs comparables aux témoins. Cette étude a ainsi permis de mettre en évidence une nouvelle voie de régulation de la lipogenèse hépatique. Dans une deuxième étude, nous nous sommes intéressés à l'action mitogénique de l'insuline. Nous montrons que 48 heures après l'inhibition de Grb14, les hépatocytes, qui sont des cellules quiescentes, entrent massivement dans le cycle cellulaire. Ce processus est dépendant de l’expression du RI et est médié par la signalisation PI3K/Akt/mTORC1 et la voie Rb/E2F1. Ces données révèlent ainsi que l'insuline est un puissant facteur mitogène dans le foie et que son action est étroitement contrôlée par l’adaptateur Grb14. D’un point de vue physiopathologique, nous avons pu mettre en évidence une diminution de significative de 58% de l’expression de Grb14 dans une collection de 70 CHC humains, apportant ainsi une explication moléculaire à une action pro-tumorigène de l’insuline dans le foie. L’ensemble de ces deux études permet de placer Grb14 au centre de la régulation des actions métaboliques et mitogéniques de l’insuline dans le foieInsulin is a key hormone controling metabolic homeostasis which also exerts having trophic effects on cell growth and proliferation. Epidemiological studies have recently shown that obese and type 2 diabetes patients are at higher risk of developing cancers, suggesting that insulin could be involved in tumor development. Proper signaling downstream the insulin receptor is thus essential to prevent pathophysiological processes. Insulin signaling is controlled by feedback mechanisms including the molecular adapter Grb14 which acts as an endogenous inhibitor of the IR catalytic activity. The aim of my PhD was to investigate the metabolic and mitogenic consequences of liver specific Grb14 inhibition in mouse. In the first study, we showed that after seven days of Grb14 invalidation, liver insulin signaling is enhanced, resulting in improved glucose tolerance and diminished hepatic glucose production. However, paradoxically, lipogenesis was greatly decreased. Deciphering the molecular mechanism, we show that Grb14 inhibition leads to the release of its partner p62/SQSTM1, inducing the activation of the Nrf2 transcription factor, which ultimatly inhibited the pro-lipogenic LXR nuclear receptor. Interestingly, Grb14 invalidation in ob/ob mice can restore blood glucose and hepatic steatosis comparable to control values. The study thus highlighted a new pathway controlling lipogenesis that could be targetted to improve metabolic diseases. In the second study, we were interested in insulin mitogenic action. We showed that 48 hours after Grb14 inhibition, hepatocytes that are quiescent cells, massively go through one cell cycle. This process depend on IR expression and is mediated by the PI3K/Akt/mTORC1 pathway and the Rb/E2F1 complex. Our data thus suggest that insulin is a potent mitogenic factor in the liver whose action is closely controlled by the Grb14 adapter in physiological conditions. Importantly, Grb14 expression is significantly decreased in a collection of human HCC, hence bringing out a molecular basis for a pro-tumorigenic action of hyperinsulinemia. Together these two studies reveal that Grb14 is a crucial gatekeeper of insulin metabolic and mitogenic actions in the liver
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Izard-Sudres, Hélène. "Evaluation de la sensibilité à l'insuline et de l'insulinosécrétion selon la méthode du Minimal Model de Bergman dans une population de sujets obèses." Montpellier 1, 1996. http://www.theses.fr/1996MON11031.
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Papazoglou, Ioannis. "Cross-talk between insulin and serotonin signaling in the brain : Involvement of the PI3K/Akt pathway and behavioral consequences in models of insulin resistance." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T039/document.
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L’insuline et la sérotonine (5-HT) sont deux acteurs majeurs du maintien de l’homéostasie énergétique, fonction placée sous le contrôle de l’hypothalamus. En ciblant cette région, l’insuline remplit de nombreuses fonctions métaboliques via l’activation de la voie PI3K/Akt. La 5-HT exercent des effets biologiques similaires mais les voies de signalisation impliquées dans ces processus étaient jusqu’alors mal connues. De plus, il avait été démontré que la 5-HT est capable d’activer la voie PI3K/Akt/GSK3β dans l’hippocampe, mécanisme sous-tendant potentiellement les effets antidépresseurs du neurotransmetteur. Les principaux objectifs de cette thèse étaient d’étudier 1/ l’activation de la voie PI3K/Akt par la 5-HT dans l’hypothalamus de rats diabétiques (modèle Goto-Kakizaki) et chercher un potentiel dialogue avec l’insuline and 2/ les mécanismes sous-tendant l’induction de la dépression par une alimentation hyperlipidique, par l’analyse de la phosphorylation d’Akt et GSK3β sous l’action de l’insuline, de la leptine et de la 5-HT dans l’hippocampe de rat.Ici on montre que 1/ la 5-HT stimule la voie PI3K/Akt dans l’hypothalamus et que la phosphorylation d’Akt induite par la 5-HT est atténuée dans des conditions d’insulino-résistance, suggérant l’existence d’un dialogue entre les voies de signalisation de l’insuline et de la 5-HT. Par ailleurs, nos résultats indiquent qu’une alimentation hyperlipidique induit un comportement dépressif réversible chez le rat, qui pourrait impliquer la voie PI3K/Akt/GSK3β dans les neurones subgranulaires du gyrus denté. La mise en évidence d’un dialogue entre les voies de signalisation de la 5-HT, de la leptine et de l’insuline au niveau central enrichit nos connaissances sur le rôle de ces facteurs dans la régulation de l’homéostasie énergétique et de l’humeur, et propose un lien moléculaire entre diabète de type 2, obésité et dépressionInsulin and serotonin (5-HT) are two key players in the maintenance of energy homeostasis which is controlled by the hypothalamus. In this brain region, insulin mediates numerous metabolic effects via the activation of the PI3K/Akt signaling pathway. 5-HT exerts similar biological properties by acting in the hypothalamus but the signaling pathways accountable for these effects are still unclear. Moreover, it has been reported that 5-HT induces the activation of the PI3K/Akt pathway in the hippocampus and the inhibition of GSK3β, suggesting this action as a potential mechanism for the antidepressant effects of this neurotransmitter.The main objectives of this thesis were to study 1/ the serotonin-induced activation of the PI3K/Akt in the hypothalamus of wild type and diabetic rats (Goto-Kakizaki model) and search a potential cross-talk with insulin and, 2/ the mechanisms underlying the high-fat diet induced depression by investigating the role of the phosphorylation of Akt and GSK3β by 5-HT, insulin and leptin in the hippocampus of rats.Here, we show that 5-HT triggers the PI3K/Akt signaling pathway in the rat hypothalamus, and that this activation is attenuated in insulin-resistant conditions, suggesting a cross-talk between insulin and 5-HT. Moreover, we reported that high-fat diet feeding induces a reversible depressive-like behavior, which may involve the PI3K/Akt/GSK3β pathway in subgranular neurons of the dentate gyrus. In conclusion, the activation of the PI3K/Akt pathway and its target GSK3β by 5-HT in the hypothalamus and in the dentate gyrus, respectively, can be impaired in insulin-/leptin-resistant states, which may underlie a link between metabolic diseases and depression
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Boisvilliers, Fabienne de. "L'insulinorésistance dans le syndrome des ovaires polykystiques avec acanthosis nigricans : étude clinique et biologique de cinq cas." Montpellier 1, 1992. http://www.theses.fr/1992MON11050.
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Jaecker, Pierre. "Exploration, par le clamp euglycemique hyper-insulinique, de l'insulino-resistance et des consequences de l'hyperinsulinemie sur le metabolisme azote dans la cirrhose." Université Louis Pasteur (Strasbourg) (1971-2008), 1989. http://www.theses.fr/1989STR1M151.
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Guillot, Alexandre. "Couplage "complexe récepteur de l'élastine / récepteur de l'insuline" : la désialylation des glycanes comme facteur d'insulino résistance." Thesis, Reims, 2017. http://www.theses.fr/2017REIMS031/document.
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Longtemps considérée comme un simple support mécanique, la matrice extracellulaire (MEC) est un élément majeur dans le maintien de l’homéostasie. Ainsi l’élastine, principal constituant de la MEC des gros vaisseaux élastiques, est dégradée au cours du vieillissement, produisant ainsi des peptides d’élastine bioactifs (PE). Plusieurs études ont démontré l'implication des PE en physiopathologies tels que l’invasion tumorale, l’athérosclérose ou l’insulino-résistance (IRes). Ces effets s’expliquent par l’activation du complexe récepteur de l’élastine (CRE), composé par : une sous-unité extracellulaire liant les PE (EBP, elastin binding protein), la cathepsine A (dont le rôle reste inconnu), et la neuraminidase 1 (induisant la signalisation intracellulaire). L'IRes décrite, pourrait être associée à l’activité de désialylation de la neuraminidase-1 sur les chaines de N-glycosylation (Ng-c) du récepteur de l’insuline (RI). Sur la base de cette hypothèse, notre objectif a donc été de confirmer ce mécanisme et ses conséquences in silico (sur le RI), in vitro (pré-adipocytes 3T3-L1) et in vivo (aorte de souris). Nous montrons ainsi in vitro que les PE provoquent un dysfonctionnement de l’autophosphorylation du RI se répercutant sur plusieurs processus cellulaires comme l’entrée du glucose ou encore la différenciation adipocytaire. In silico, nous montrons pour la première fois le rôle des acides sialiques sur le comportement des Ng-c d'une part et sur le RI d'autre part. Enfin, in vivo, cette interaction CRE / IR engendre une hypertension artérielle par une diminution de la vasorelaxation des cellules endothélialesOften considered as a simple mechanical support, the extracellular matrix (ECM) is a major element of homeostasis regulation. Thus, elastin, the main constituent of large elastic vessels, is degraded during aging, producing bioactive elastin-derived-peptides (EDP). Several studies have demonstrated the EDP effects in physiopathologies such as tumor invasion, atherosclerosis, or insulin resistance (IRes) development. Those effects are explained by the activation of the elastin receptor complex (CRE), composed of: an extracellular subunit binding EDP (EBP, elastin binding protein), cathepsin A (its role is still unknown) and the sialidase neuraminidase-1 (Neu-1, involved in signaling pathway induction). Interestingly, the lab suggested that IRes may be induced by the desialylation of the N-glycan chains (Ng-c) on the insulin receptor (IR). The aim of this study was to confirm this hypothesis by demonstrating the consequence of desialylation on the IR in silico, on a 3T3-L1 pre-adipocyte cell in vitro, and on vascular complications in vivo. We show that EDP induce in vitro an impairment of IR autophosphorylation, affecting glucose uptake and adipocyte differentiation. In silico approach demonstrates the role of sialic acids on the behavior of Ng-c in the one hand and in other hand of IR. Finally, the IRes induced by ERC-IR interaction increase the vascular complication such as arterial hypertension by endothelial cell impairment. To conclude, Ng-c alteration would likely be responsible for structural changes in the IR at the origin of insulin resistance
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Guhmann, Pauline. "Délivrance orale d'insuline par double encapsulation : développement et évaluation de l'efficacité et de la sécurité des systèmes entériques et nanoparticulaires." Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-01071851.
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Actuellement, l'injection sous-cutanée d'insuline est le seul moyen pour les diabétiques de type 1 d'équilibrer leur glycémie. Les travaux de thèse entrent dans le cadre du projet ORAIL qui vise à développer un système de délivrance orale d'insuline basé sur la double encapsulation, et à valider l'efficacité et la sécurité de ce système in vitro dans des modèles d'épithélium intestinal, et in vivo chez le rat. Le vecteur pharmaceutique développé est composé d'une gélule contenant des nanoparticules (NPs) d'insuline formulées à partir d'acide (lactique-co-glycolique) par la méthode de double émulsion eau/huile/eau. Un premier objectif de la thèse a été d'évaluer chez le rat la gastrorésistance et l'entérosolubilité de la gélule sélectionnée pour l'encapsulation des NPs, par tomodensitométrie aux rayons X et par l'étude de la biodisponibilité de l'ibuprofène et de l'acétaminophène. Les résultats de ces travaux ont montré que la gélule est résistante en conditions gastriques et se dégrade au niveau de l'intestin. Un deuxième objectif a été de synthétiser des NPs d'insuline de taille croissante (100 à 800 nm), et d'évaluer l'internalisation de ces NPs et leur sécurité dans des cultures de cellules Caco-2, et dans des co-cultures de cellules Caco-2 et HT29-MTX. Les résultats de ces travaux ont montré que les NPs sont internalisées de manière dose et temps-dépendante, et que la taille de NPs permettant une internalisation optimale est de 400 nm après 4h d'incubation. Des études mécanistiques ont suggéré l'implication de mécanismes cavéoline-dépendants dans l'internalisation des NPs. Aucune toxicité des NPs n'a été observée quels que soient les paramètres étudiés (viabilité et mort cellulaire, augmentation de perméabilité, production de mucus, sécrétion de cytokines pro-inflammatoires). Dans une dernière partie de notre travail, nous avons montré que l'administration intraduodénale de NPs d'insuline de 200 et 400 nm à des rats diabétiques permettait une diminution significative de leur glycémie sans altération morphologique de leur paroi intestinale, données confortant nos résultats in vitro. Notre vecteur basé sur la double encapsulation semble donc être un système prometteur pour l'administration orale d'insuline. Le vecteur complet doit cependant être évalué in vivo chez le rat.
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Saget, Sarah. "Impact de différents régimes durant la lactation sur le développement de pathologies cardio-métaboliques chez des souris RCIU." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS118.
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Le Retard de Croissance Intra-Utérin (RCIU) est associé à un risque accru de développer des pathologies cardio-métaboliques à long terme. De plus, des études suggèrent que la nutrition en période post-natale précoce pourrait moduler l’apparition de ces maladies. Afin d’étudier les mécanismes impliqués dans la programmation de ces pathologies, le laboratoire a développé un modèle de souris nées avec un RCIU induit par un régime hypo-protéique de la mère et dont la nutrition durant la lactation a été modulée en normalisant les portées afin d’induire une surnutrition, une nutrition normale ou une restriction alimentaire. La restriction durant la lactation des souriceaux RCIU semble les protéger de l’apparition de pathologies cardio-métaboliques. A l’inverse, la nutrition normale ou la surnutrition durant la lactation des souriceaux RCIU induit un surpoids dès l’âge de 1 mois, puis une résistance à l’insuline, une accumulation de lipides au niveau hépatique et une hypertension artérielle avec l’âge. La résistance à l’insuline est associée à une altération de la phosphorylation d’AKT dans le foie qui pourrait être favorisée par la diminution permanente des taux d’AKT. Cette baisse a été associée à une dérégulation au niveau de la marque d’histone stimulatrice H3K4me3. En outre, une augmentation de PTEN, l’inhibiteur d’AKT, pourrait aussi être impliquée via des mécanismes épigénétiques : une diminution de l’H3K4me3 a été associée des taux plus faibles de certains miARNs, dont le miARN19a qui cible PTEN de manière privilégiée. L’importance de ce miARN est en cours d’étude dans une cohorte humaineIntra-Uterine Growth Retardation (IUGR) is associated with increased risk of cardio-metabolic diseases. Furthermore, previous studies also indicated that changing nutrition during the early post-natal period could worsen pathologies later on. In order to study mechanisms involved in programming of these pathologies, our laboratory developed a mouse model of IUGR- induced by feeding pregnant mice with an isocaloric/ low-protein diet - and whose nutrition during lactation was modulated by normalizing litter sizes to induce overfeeding, normal feeding or restriction. Restriction during lactation can protect IUGR mice from the development of cardio-metabolic pathologies even in aged mice. In contrast, both normal feeding or overfeeding during lactation exacerbate weight gain by 1 month of age onward, and induce an insulin resistance, a steatosis and an arterial hypertension with age. Molecular alterations of AKT phosphorylation in liver of mice were observed before the appearance of insulin resistance. Interestingly, this could be promoted by the permanent decrease in AKT protein levels that is associated with a decrease in the positive H3K4me3 histone mark in Akt promoter. Furthermore, an alteration in H3K4me3 levels was also observed in the promoter of microRNA17-92a cluster gene. miR-19a, a member of this cluster, is known to regulate PTEN translation, an AKT inhibitor. In agreement, post-transcriptional regulation of PTEN seems to be altered in adult IUGR-N and IUGR-O male mice. Currently, importance of this microRNA is studied in a human cohort
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Guarilha, Alessandra Lia Gasparetti. "Transdução do sinal da insulina em animais expostos ao frio : o papel do cross-talk entre o receptor 'beta' 3 - adrenergico e o receptor de insulina em tecido adiposo marrom." [s.n.], 2004. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310365.
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Orientador: Licio Augusto VellosoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-04T02:29:02Z (GMT). No. of bitstreams: 1 Guarilha_AlessandraLiaGasparetti_D.pdf: 7883483 bytes, checksum: cefd0ee77fd363b470280f9b8a380ff9 (MD5) Previous issue date: 2004
Resumo: A exposição de animais homeotérmicos ao mo é utilizada como um método reprodutível para se obter um modelo animal de hipoinsulinemiaacompanhada por elevada mobilização periférica de glicose. No presente estudo, avaliaram-se as etapas iniciais e intermediárias da via de sinalização da insulina em tecidos periféricos de ratos expostos ao mo. Avaliou-se ainda, a comunicação intracelular entre o receptor (33-adrenérgicoe as vias de sinalização da insulina em tecido adiposo marrom de ratos expostos ao mo e tratados, ou não, com compostos agonista ou antagonista (33-adrenérgicos.A exposição de ratos ao mo promoveu a redução da secreção de insulina, acompanhada de um elevado clearance de glicose e maior captação de glicose por tecido muscular esquelético, adiposo branco e adiposo marrom. Tais fenômenos foram acompanhados por inibição da ativação da maior parte dos componentes da via de sinalização da insulina em tecido muscular esquelético e adiposo branco; por estimulação da maior parte dos componentes da via de sinalização da insulina em tecido adiposo marrom; e por efeitos variados (estímulo, inibição e não-modulação) de componentes da via de sinalização da insulina em figado. Por fim, este estudo demonstrou que a exposição ao mo ativa a sinalização (33-adrenérgicaem tecido adiposo marrom. Tal ativação leva à modulação da atividade de vários componentes da via de sinalização da insulina neste tecido. Entretanto, fatores independentes da sinalização (33-adrenérgica parecem contribuir para a complexa regulação do sinal da insulina obseIVada em tecido adiposo marrom de ratos expostos ao mo. Em conclusão, o presente estudo revelou alguns dos intrincados mecanismos pelos quais a exposição ao mo controla a atividade da insulina em animais homeotérmicos, podendo favorecer a identificação de potenciais alvos para a ação terapêutica em doenças onde a resistência à insulina desempenha papel central
Abstract: Cold exposure provides a reproducible model of improved glucose turnover accompanied by reduced blood levels of insulin. In the present study, the initial and intermediate steps of the insulin-signaling pathway in peripheral tissues of rats exposed to cold environment were evaluated. Also, the intracellular connection between insulin and ~3-adrenergic signaling in brown adipose tissue of cold exposed rats treated, or not, with ~3-adrenergic agonist or antagonist compounds were evaluated. During cold exposure, insulin secretion was significantly impaired, while whole body glucose clearance rates were significantly improved. This was accompanied by an increased glucose uptake by skeletal muscle, white adipose tissue and brown adipose tissue. These phenomena were paralleled by an apparent molecular resistance to insulin in skeletal muscle and white adipose tissue; by improved molecular response to insulin in brown adipose tissue; and by ambiguous effects (stimulation, inhibition and not modulation) of regulation of the insulin-signaling pathway in liver. Finally, cold exposure activated the ~3-adrenergic signaling in brown adipose tissue. It leads to modulation of activity of several components of the insulin signal transduction pathway in this tissue. However, ~3-adrenergic receptor independent mechanisms seem to contribute to the complex regulation of the insulin signaling observed in brown adipose tissue of rats exposed to cold. In conclusion, the present study revealed some of the complex mechanisms that participate in the cold-exposure-induced control of the insulin action in homeothermic animals. These results may favour the identification of novel potential targets for therapeutics in diabetes and related disorders
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
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Maffeis, Laura <1981>. "Correlation between insulin resistance and treatment-resistant acne." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5654/.
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Physiologically during puberty and adolescence, when juvenile acne usually appears, the response to a glucose load is increased if compared to the one observed in adult and at pre-pubertal age, while insulin sensitivity is reduced. Insulin is a hormone that acts at different levels along the axis which controls the sex hormones. It increases the release of LH and FSH by pituitary gland, stimulates the synthesis of androgens in the gonads and stimulates the synthesis of androgenic precursors in adrenal glands. Finally, it acts in the liver by inhibiting the synthesis of Sex Hormone Binding Globulin (SHBG). Insulin is also able to act directly on the production of sebum and amplify the effects of Iinsulin Growth Factor-1 in the skin, inhibiting the synthesis of its binding protein (IGF Binding Protein-1).
In female subjects with acne and Polycystic Ovary Syndrome (PCOS) insulin resistance is a well known pathogenetic factor, while the relationship between acne and insulin resistance has been poorly investigated in males so far.
The purpose of this study is to investigate the correlation between insulin resistance and acne in young males who do not respond to common therapies. Clinical and biochemical parameters of glucose, lipid metabolism, androgens and IGF-1 were evaluated. Insulin resistance was estimated by Homeostasis Model assessment (HOMA-IR) and Oral Glucose Tolerance Test was also performed. We found that subjects with acne had higher Sistolic and Diastolic Blood Pressure, Waist/Hip Ratio, Waist Circumference, 120' OGTT serum insulin and serum IGF-1 and lower HDL-cholesterol than subjects of comparable age and gender without acne.
The results thus obtained confirmed what other authors have recently reported about a metabolic imbalance in young males with acne. Furthermore, these results support the hypothesis that insulin resistance might play an important role in the pathogenesis of treatment-resistant acne in males.
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Mezghenna, Karima. "No synthase neuronale pancréatique et musculaire dans la pathogénie des états prédiabétiques." Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON13503.
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Le diabète de type 2, défini par une hyperglycémie chronique, résulte d'un déficit de la sécrétion d'insuline et d'une insulinorésistance. Durant le prédiabète qui précède la maladie, la cellule ß pancréatique est capable d'établir une hyperactivité sécrétoire compensatrice de l'insulinorésistance. Les NO synthases neuronales (nNOS) pancréatique et musculaire contrôlent respectivement la sécrétion d'insuline induite par le glucose dans la cellule ß et la force contractile, la captation et l'utilisation du glucose dans les myocytes. Dans le modèle génétique du rat obèse Zucker fa/fa mimant l'état prédiabétique associant un hyperinsulinisme et une insulinorésistance, nous avons retrouvé au niveau de la cellule ß une forte augmentation du complexe entre la nNOS et son inhibiteur endogène PIN (Protein Inhibitor of Neuronal NOS) au niveau des granules de sécrétion d'insuline. Ce complexe, grâce à une interaction accrue avec la myosine V, participe à l'hyperactivité sécrétoire de la cellule ß pancréatique. En effet, des molécules inhibant spécifiquement l'interaction nNOS-PIN permettent de rétablir, chez le rat fa/fa, une sécrétion d'insuline normale. Au niveau musculaire, nous avons observé, dans ce modèle animal, une diminution d'expression de la nNOS sans variation du taux d'ARNm, traduisant une protéolyse accrue de la protéine. L'inhibition de la dégradation protéasomale permet de restaurer l'expression et l'activité catalytique de la nNOS dans le muscle squelettique. Cette perte de fonctionnalité de l'enzyme participerait à l'installation de l'insulinorésistance. Ces travaux ont permis de valider la nNOS comme une cible potentielle pour la prévention du diabète de type 2Type 2 diabetes is a chronic disorder defined by chronic hyperglycemia resulting from a deficiency of insulin secretion and an insulin resistance in peripheral tissues and liver. A long lasting silent phase, called prediabetes, precedes the disease and in which pancreatic ß cell is able to improve insulin secretion to compensate for the insulin resistance. The pancreatic and muscular neuronal nitric oxide synthases (nNOS) control respectively glucose-induced insulin secretion in pancreatic ß cell and glucose uptake and utilization in myocytes. In the genetic model of obese Zucker fa/fa rat mimicking the prediabetic state characterized by hyperinsulinemia and insulin resistance, we found a high increase in the amount of the complex between nNOS and its endogenous inhibitor PIN (Protein Inhibitor of Neuronal NOS) at the level of insulin secretory granules within the ß cell. This complex, through an increased interaction with myosin V, participates in the secretory hyperactivity of the pancreatic ß cell, observed in this model of prediabetes. Indeed, molecules that specifically inhibit nNOS-PIN interaction allow to restore a normal insulin secretion in fa/fa rat. In skeletal muscle of this model, we observed a decreased expression of nNOS protein with no change in mRNA levels, suggesting an increased proteolysis of the protein. Inhibition of proteasomal degradation restores the expression and the catalytic activity of nNOS in skeletal muscle. Thus, this loss of functionality of the enzyme could participate in the installation of insulin resistance. This work therefore validated nNOS as a potential target for the prevention of type 2 diabetes
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Walker, Adrian Bernard. "The effect of insulin on resistance artery function in insulin-resistant states." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312450.
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Leturque, Armelle. "Adaptations du métabolisme glucidique pendant la gestation chez la ratte." Paris 7, 1985. http://www.theses.fr/1985PA077060.
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Durant la gestation, des modifications physiologiques et métaboliques importantes interviennent dans le compartiment maternel liées à l'apparition de novo des foetus et des placentas. Le foetus consomme, en tant que substrat énergétique essentiel, une quantité croissante du glucose. Quant au placenta, il contrôle le transfert de glucose au foetus et secrète des hormones favorisant la production d'insuline par le pancréas maternel. Les adaptations du métabolisme glucidique maternel seront donc nombreuses. Le but de notre travail a été de définir au cours de la gestation chez la ratte les mécanismes par lesquels l'homéostasie glucidique est maintenue face à une dépense énergétique intense et de quantifier les besoins en glucose de chaque tissu. Nous avons aussi défini et quantifié la résistance à l'insuline qui s'établit pendant la gestation et nous nous sommes demandés quels étaient les tissus et les mécanismes impliqués. Chez la ratte une étude de l'évolution de la glycémie au cours de la gestation mise en parallèle avec l'évolution du poids du conceptus montre 1) qu'à 14 jours de gestation une hypogly¬cémie post-absorptive est observée alors que le conceptus repré¬sente seulement 4 % du poids de la mère, 2) que durant la dernière semaine de gestation la glycémie diminue légèrement alors que le conceptus est en phase exponentielle de croissance. Nous en avons conclu que l'hypoglycémie de la gestation n'était pas due à une consommation importante de glucose par le conceptus.
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Blond, Emilie. "Mécanisme de l'insulino-résistance lors de la modulation in vivo et in vitro par l'acide nicotinique et les polyphénols." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10169.
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L'insulino-résistance est un des mécanismes physiopathologiques associé au diabète de type II et à l'obésité. Améliorer la compréhension de ce mécanisme est nécessaire pour essayer de limiter l'extension de ces maladies considérées à l'heure actuelle comme de véritables épidémies. Une des causes de l'insulino-résistance réside dans l'accumulation intrahépatique et intramusculaire de lipides due à la rupture de la balance entre oxydation mitochondriale et lipogenèse de novo, perturbant la signalisation insulinique à l'origine de l'insulino-résistance. Connaître les facteurs induisant la modification de cette balance et la manière dont ceux-ci la déséquilibrent permettrait de prévenir l'insulino-résistance hépatique et musculaire. Nous avons souhaité approfondir, grâce à des études in vivo et in vitro, le rôle de l'acide nicotinique, agent hypolypémiant, des polyphénols, micronutriments présents dans les fruits et légumes et du fructose, molécule lipogénique. Ces composés agiraient comme modulateurs de la résistance à l'insuline et comme inducteurs du déséquilibre entre oxydation mitochondriale et lipogenèse de novo. Après avoir mis au point deux améliorations techniques (stabilité des solutions de [6,6-²H2]-glucose utilisées pour la mesure de la sensibilité à l'insuline et validation des mesures de dépenses énergétiques d'un nouveau calorimètre), nous avons montré que l'acide nicotinique est capable d'améliorer le profil lipidique plasmatique, tout en induisant une insulino-résistance hépatique dans une population d'hommes présentant une dyslipidémie mixte. Cette insulino-résistance, confirmée dans un modèle cellulaire d'hépatome humain, est reliée à l'inhibition d'une des enzymes « clés » de la lipogenèse de novo, la diacylglycérol acétyltransférase (DGAT). Cette inhibition enzymatique diminue les concentrations plasmatiques en triglycérides et induit une augmentation d'intermédiaires lipidiques à l'origine de l'insulino-résistance. Nous avons également mis en évidence le rôle insulinosensibilisateur d'un extrait de polyphénols de raisins rouges, lors d'un stress métabolique induit par la consommation de fructose dans une population de sujets à risque génétique de défaut d'oxydation mitochondriale. Cet effet insulino-sensibilisateur est dû à l'augmentation de l'activité et de la biogenèse mitochondriales réduisant l'effet lipogénique du fructose. Ces résultats montrent l'importance du lien entre rupture de la balance lipogenèse de novo oxydation lipidique et impact sur l'insulino-sensibilité. L'acide nicotinique est impliqué dans l'induction d'une insulino-résistance hépatique par inhibition de la DGAT, enzyme clé de la lipogenèse de novo. Les polyphénols sont impliqués dans l'augmentation de la sensibilité à l'insuline par amélioration de la fonctionnalité et de la biogenèse mitochondriales en réponse à une augmentation de la lipogenèse induite par le fructose
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Capetini, Vinícius Cooper. "Efeito da suplementação com zinco na evolução da resistência à insulina induzida por dieta hiperlipídica em camundongos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-10082016-154401/.
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O aumento da prevalência do diabete melito do tipo 2 (DM2) é intenso e implica ampla busca pela prevenção e tratamento da doença. Estudos têm mostrado a participação do zinco na síntese, secreção e via de sinalização da insulina e sobre o controle glicêmico. Este trabalho objetivou analisar o mecanismo de ação do zinco no controle da secreção de insulina e no controle glicêmico, de modo a entender se a suplementação com o zinco previne ou retarda a manifestação do DM2. O projeto foi aprovado pela CEUA-ICB (USP). Camundongos machos C57BL/6 foram divididos em 4 grupos experimentais: dieta controle (NFD); dieta controle suplementada com ZnCl2 (NFDZ); dieta hiperlipídica (HFD); e dieta hiperlipídica suplementada com ZnCl2 (HFDZ). A massa corporal, a ingestão de ração e água e a glicemia foram acompanhados semanalmente. Testes intraperitoneais de tolerância à glicose (ipGTT) e à insulina (ipITT) foram realizados na 14ª semana de tratamento. Completado as 15 semanas de tratamento a glicemia, a insulinemia e a zincemia foram analisadas, sendo aplicados os testes de HOMA-IR e HOMA-β. Em ilhotas pancreáticas isoladas foi analisada a secreção estática de insulina em diferentes concentrações de glicose. O teste de captação e metabolismo de glicose foi feito no músculo sóleo e a análise do conteúdo das proteínas AKT e GSK3-β foi feita no músculo sóleo e no fígado. Os dados (média±SEM) foram analisados por Two-way ANOVA com pós-teste Bonferoni ou por teste t de Student (P 0,05). A suplementação com zinco melhorou a disfunção glicêmica induzida por dieta hiperlipídica, sem no entanto afetar a resistência à insulina ou a secreção de insulina por ilhotas isoladas.The increase in prevalence of type 2 diabetes mellitus (DM2) is intense and implies broad quest for prevention and treatment of disease. Studies have shown the participation of zinc in the synthesis, secretion and signaling pathway of insulin and the glucose control. This study aimed to analyze the mechanism of action of zinc in the control of insulin secretion and glucose control in order to understand whether supplementation with zinc prevents or delays the manifestation of DM2. The project was approved by CEUA-ICB (USP). Male mice C57BL/6 were divided en 4 groups: control diet (NFD); control diet supplemented with ZnCl2 (NFDZ); high fat diet (HFD); and high fat diet supplemented with ZnCl2 (HFDZ). Body weight, feed intake and water and the glucose levels were monitored weekly. Intraperitoneal glucose tolerance test (ipGTT) and insulin (ipITT) were performed at the 14th week of treatment. Completing the 15 weeks of the treatment glycemia, insulinemia and zincemia were analyzed, being applied HOMA-IR and HOMA-β tests. In isolated islets was assessed the static insulin secretion at different glucose concentrations. The uptake and glucose metabolism test was done in the soleus muscle and the content analysis of the AKT and GSK3-β protein was made in the soleus muscle and liver. The data (mean ± SEM) were analyzed by two-way ANOVA with Bonferoni post-test or Student\'s t test (P < 0,05). Zinc supplementation improves glucose dysfunction induced by high fat diet, without nonetheless affecting insulin resistance and insulin secretion by isolated islets.
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Hagihara, Graziela Neves. "Resposta à angiotensina II em artérias mesentéricas de resistência na obesidade: participação das MAPKs." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-18092012-095317/.
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A angiotensina II (AngII) pode ativar as vias de sinalização das proteínas quinases ativadas por mitógenos (MAPKs). Investigamos o papel da obesidade e das MAPKs na resposta à AngII em ratos obesos por injeção de glutamato monossódico (Ob). Artérias mesentéricas de resistência com endotélio intacto e não as artérias sem endotélio, isoladas de Ob, respondem menos à AngII. As respostas à noradrenalina e ao cloreto de potássio estavam inalteradas. Aumento da expressão do receptor AT2 (AT2R), da óxido nítrico sintase (eNOS) e da ERK1/2 podem estar envolvidos na menor resposta pois a inibição do AT2R, da eNOS e da ERK1/2 corrigiram-na. A maior ativação da ERK1/2 nos Ob levou à maior ativação da eNOS e maior geração de NO, diminuindo a resposta à Ang II. Concluímos que na obesidade, a resposta contrátil à Ang II é menor, como possível mecanismo adaptativo frente ao aumento da ativação do sistema renina-angiotensina. Esse mecanismo envolve a participação do endotélio com maior liberação de NO, aumento do número de AT2R, e da fosforilação da eNOS e da ERK1/2.Angiotensin II (AngII) can activate mitogen-activated protein kinases (MAPKs) pathways. We investigated the role of obesity and MAPKs in AngII response in monosodium glutamate-induced obese rats (Ob). Endothelium-intact but not endothelium-denuded mesenteric resistance arteries isolated from Ob exhibited a lower response to AngII. The response to nordrenaline and potassium chloride were unaltered. Increased expression of AT2 receptor, nitric oxide synthase (eNOS) and ERK1/2 might be involved in the reduced response since inhibition of AT2R, eNOS and ERK1/2 corrected it. Increased activation of ERK 1/2 in Ob might activate eNOS, generating more NO and vasodilation that contributed to reduce the contraction to AngII. We concluded that, in obesity, the lower response to AngII might be an adaptive mechanism against the increased activation of the renin-angiotensin system. This mechanism involves the participation of the endothelium through a greater release of NO, increased AT2R, eNOS and ERK1/2 expressions.
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Zecchin, Henrique Gottardello. "Transmissão do sinal de insulina e acetilcolina na aorta de modelos animais e resistencia a insulina." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311235.
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Orientador: Mario Jose Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A resistência seletiva à insulina através da via IRS/PI3-K/Akt/eNOS associada à ativação normal ou exacerbada da via de crescimento MAPK tem sido proposta como um possível elo entre situações de resistência à insulina e doença cardiovascular. Inicialmente demonstramos que animais com resistência à insulina e doença cardiovascular (o rato espontaneamente hipertenso, SHR) apresentam menor ativação da via IRS/PI3-K/Akt/eNOS e hiperativação/hiperexpressão da via da MAPK na aorta torácica, enquanto a ativação normal da via IRS/PI3-K/Akt/eNOS pode proteger o animal obeso, resistente à insulina e que não apresenta doença cardiovascular. Posteriormente, outras vias estimulatórias do crescimento celular, como a via JAK/STAT, foram estudadas no vaso de outro modelo animal de resistência à insulina e doença cardiovascular - o rato com obesidade induzida por dieta. Este modelo demonstrou que a redução da ativação da via PI3-K/Akt/eNOS ocorre em paralelo à hiperativação das vias da MAPK e JAK/STAT, e isso pode desempenhar função importante da patogênese da doença cardiovascular neste estado patológico. Em outro estudo foi demonstrado pela primeira vez que a acetilcolina pode ativar a eNOS de maneira cálcio-independente, através da via IRS/PI3-K/Akt utilizando para isso uma tirosina quinase intracelular, a JAK2. Em ratos com obesidade induzida por dieta, resistentes à insulina e com disfunção endotelial, foi demonstrado que há resistência na via da PI3-K/Akt/eNOS tanto em resposta à insulina quanto à acetilcolina, em decorrência de maior fosforilação inibitória do IRS-1 e da redução dos níveis teciduais da eNOS. Assim, o desequilíbrio entre a ativação reduzida da via IRS/PI3-K/Akt/eNOS e a maior ativação das vias de crescimento (MAPK e JAK/STAT) pode contribuir para o desenvolvimento de doença cardiovascular em estados de resistência à insulina
Abstract: The actions of acetylcholine on endothelium are mainly mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study we show that acetylcholine induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is detected. In addition, acetylcholine induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK1/2). The pharmacological blockade of JAK2 or PI 3-kinase reduced acetylcholine-stimulated eNOS phosphorylation, NOS activity and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3- kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by acetylcholine in vessels. Moreover, we demonstrate that, in aorta of obese rats (high-fat diet), there is an impairment in insulin- and acetylcholinestimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/MAP kinase pathway. These results suggest that in aorta of obese rats, there is not only insulin resistance, but also acetylcholine resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
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Lalli, Cristina Alba. "Efeito da rosiglitazona e da lovastatina na resistencia insulinica da dieta hiperlipidica." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311224.
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Orientador: Mario Jose Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A insulina é o principal hormônio anabólico, que atua através da ativação de transportadores, regulação de enzimas e expressão de genes que codificam enzimas envolvidas na captação e armazenamento de substratos. Para exercer suas ações, a insulina emprega duas vias principais de sinalização intracelular: a via da PI 3-quinase e a via da MAPK. A regulação da ação do hormônio se faz por meio de vários mecanismos. O modelo animal de dieta hiperlipídica apresenta alterações metabólicas e de sinalização semelhantes aos encontrados na resistência insulínica de humanos com obesidade induzida por dieta. O objetivo de nosso trabalho foi estudar em ratos alimentados com dieta hiperlipídica, etapas da sinalização insulínica e também algumas vias de regulação da sinalização, após o uso de duas drogas: a rosiglitazona, uma tiazolidinediona usada para o tratamento do diabetes melito tipo 2 como sensibilizadora de insulina e a lovastatina, droga inibidora da HMGCoA redutase, que diminui a síntese de colesterol, mas que também tem apresentado efeito de aumentar a sensibilidade à insulina, tanto em modelos animais como em humanos. Ratos alimentados com dieta hiperlipídica por quatro semanas e tratados na última semana com as drogas, isoladamente, foram submetidos à extração de tecidos hepático e muscular e os fragmentos obtidos foram submetidos à análise de concentração protéica ou de grau de fosforilação de proteínas através de técnicas de imunoprecipitação e immunoblotting. A sensibilidade à insulina foi avaliada pelo teste de tolerância à insulina e cálculo da constante de decaimento da glicose (Kitt). No estudo. da rosiglitazona, foi observada diminuição significativa da sensibilidade à insulina expressa por diminuição no Kitt, nos animais que receberam a dieta e recuperação da sensibilidade após o uso da droga. A fosforilação do IRS-l, associação do substrato com a enzima PI3K e a ativação da Akt no tecido hepático e muscular também se mostraram diminuídas pela dieta e recuperadas com o uso da rosiglitazona. O estudo da lovastatina demonstrou efeito positivo da droga sobre a sensibilidade insulínica, revertendo a resistência induzida pela dieta hiperlipídica, expressa por valor de Kitt semelhante ao dos animais controle. Na via de sinalização da PI3K: fosforilação do IR e do IRS-I, associação do IRS-l à PI3k e ativação da Akt, tanto no tecido hepático como muscular, a lovastatina reverteu as alterações da dieta, com recuperação a valores semelhantes aos do grupo controle. Também nas vias de regulação, a dieta induziu maior fosforilação do IR em serina, maior fosforila do IRS-I em serina307, maior atividade da JNK e da proteína fosfatase PTPIB e menor ativação do IKB, efeitos que podem explicar a resistência desse modelo. A lovastatina reverteu todas essas alterações. Concluindo, a rosiglitazona reverteu as alterações causadas pela dieta hiperlipídica sobre as etapas iniciais da sinalização insulínica na via da PI3K. A lovastatina recuperou as alterações induzidas pela dieta hiperlipídica na transmissão do sinal insulínico, agindo sobre as vias de regulação da sinalização: ação da PTPIB, fosforilação do IR e do IRS-l em serina induzidos pela JNK e PTPIB e ativação da via inflamatória
Abstract: Insulin is the major anabolic hormone and acts through transporter activation, enzymes regulation and gene expression. This hormone uses' two main signaling pathways: the PI3K pathway, involved in its metabolic effects and the MAPK pathway, responsible for cell growth and differentiation. There are many mechanisms of regulation of insulin signaling. The use of a high- fat diet is a known model of insulin resistance with metabolic and signaling changes similar to those of human insulin resistance syndrome observed in diet induced obesity. Rosiglitazone is an agent of the class of thiazolidinediones, insulin-sensitizing agents whose effects are mainly due to the activation of PP ARy and are used to treat type 2 diabetes. Lovastatin is one of a class of a class of cholesterol synthesis inhibitors; recent studies have shown that this agent might have relevant effects on insulin resistance in both animal models and humans. The aim of this study was to evaluate the effects of two different drugs independent1y, rosiglitazone and lovastatin, on insulin signaling in liver and muscle of rats fed on a hígh-fat diet. We used four week old male Wistar rats, fed on a high- fat diet during four weeks and treated with rosiglitazone or lovastatin during the last week, compared to rats fed on standard chow. Fragments of liver and muscle tis sues were extracted from anesthetized animaIs and protein concentrations and phosphorylation degree were studied through immunoprecipitation and immunoblotting techniques. Insulin sensitivity was evaluated by insulin tolerance test and calculation of the disappearance rate constant (KitD. We observed that high-fat fed diet rats presented a significant decrease in Kitt compared to control rats. The animaIs that were fed with the high-fat diet and were treated with either one ofthe drugs presented a reversal ofthis effect. In the study of rosiglitazone, the high-fat model demonstrated a decrease in the IRS-I phosphorylation, IRS-l/PI3K association and activation of Akt and rosiglitazone administration resulted in the reversion of all the effects in liver and muscle. In addition to the effect on insulin sensitivity, the use of lovastatin was also associated with an increase in insulin-induced IR tyrosine phosphorylation and, in parallel, a decrease in IR serine phosphorylation and association with PTPIB. Our data also show that lovastatin treatment was associated with an increase in the insulin-stimulated IR/IRS-l/PI3KJ Akt pathway in the liver and musc1e of high-fat fed rats, in parallel with a decrease in the inflammatory pathway (JNK and IKKI3/IKB/NFKB) related to insulin resistance. In conclusion, rosiglitazone and lovastatin improved the altera_s in insulin signaling pathways presented by the high-fat model of insulin resistance
Doutorado
Clinica Medica
Doutor em Clínica Médica
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Fonseca, Eveline Aparecida Isquierdo. "Influência da obesidade e da resistência à insulina sobre o desenvolvimento tumoral: efeito da metformina." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-25032010-152338/.
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A influência da obesidade e da resistência à insulina (induzidas em ratos por injeção de glutamato monossódico em neonatos) sobre o desenvolvimento tumoral (5x105 células do tumor de Walker-256) e os efeitos da metformina (300mg/kg, v.o., 15 dias) nessa condição foram investigados. Na 16ª semana de vida, inocularam-se as células e iniciou-se o tratamento. Após 15 dias de tratamento, caracterizou-se a obesidade e a analisou-se o crescimento tumoral. O desenvolvimento tumoral e a caquexia foram maiores nos obesos. A metformina reduziu o desenvolvimento do tumor, mas não a caquexia. Apesar da metformina não ter melhorado a sensibilidade à insulina, corrigiu a dislipidemia, reduziu a peroxidação lipídica e as gorduras periepididimal e retroperitoneal. Conclui-se que a obesidade aumenta o desenvolvimento tumoral e que a metformina é eficaz em diminui-lo. O mecanismo envolvido parece não depender da melhora da sensibilidade à insulinaThe influence of obesity and insulin resistance (induced in rats by monosodium glutamate in neonates) on tumor development (5x105 Walker-256 tumor cells) and the effect of metformin (300mg/kg, by gavage, for 15 d) on it. On the 16th week, tumor cells were subcutaneously injected and the treatment started. On the 18th week, the obesity was characterized and the tumor was evaluated. The tumor development and the cachexia were higher in obese rats. The tumor development was reduced by metformin, but not cachexia. Although metformin did not improve insulin sensitivity it did correct the dislypidemia, reduced the periepididimal and retroperitoneal adipose tissues and lipid peroxidation. In conclusion obesity increases tumor development and metformin is able to reduce it. The reduction occurred independently of the correction of insulin resistance
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Pere, Marie-Christine. "Adaptations du metabolisme hepatique chez la lapine en fin de gestation." Paris 6, 1987. http://www.theses.fr/1987PA066575.
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Lemos, Christine Marinho de. "Efeito do PD 153035, um inibidor tirosina quinase, na sinalização da insulina e metabolismo da glicose." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313435.
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Orientador: Mario Jose Abdalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Estudos recentes demonstraram que tratamentos prolongados com drogas inibidoras da atividade tirosina quinase (TKI) poderiam agir favoravelmente não só controlando crescimento e replicação celular, como também funções fisiológicas responsáveis por manter a homeostase da glicose. Porém, os efeitos diretos de PD 153035, um TKI, na regulação das etapas iniciais da ação da insulina não são conhecidos. A insulina, ao se ligar à subunidade a de seu receptor heterotetramérico, dá início a uma série de ações imediatas e tardias, metabólicas e promotoras de crescimento .Tais eventos ocorrem através da estimulação da subunidade ß transmembrana do receptor, que autofosforila e ativa a fosforilação de substratos endógenos intracelulares, conhecidos como substratos do receptor de insulina ou IRSs. Os principais substratos do receptor de insulina são o IRS-1 e IRS-2, que quando fosforilados em tirosina se ligam e ativam proteínas com porção SH2, como a PI 3-quinase. A ativação destas proteínas desencadeia a ativação de suas serinas-quinases importantes que são a AKT e as ERKs (1/2), que são essenciais, respectivamente, para os efeitos metabólicos e de controle gênico do homônio. No presente estudo investigamos o efeito do tratamento com PD 153035, por 7 dias, na sensibilidade e sinalização da insulina em fígado, musculo e tecido adiposo de ratos Wistar. Foi investigado o grau de fosforilação em tirosina do receptor de insulina, dos substratos 1 e 2 do receptor ( IRS-1 e IRS-2 ), a associação deles com a enzima PI 3-quinase, o grau de fosforilação em serina/treonina da AKT, a fosforilação das ERKs (1/2), da p70s6k, da AMPK, da JNK e I?Ba nos três tecidos. Nenhuma diferença nos níveis glicêmicos foi observado durante o GTT entre os grupos tratado com PD 153035 e controle. As taxas de desaparecimento de glicose plasmática estavam altas nos animais tratados. No fígado de ratos tratados com PD 153035, observamos um aumento da fosforilação em tirosina do IR, IRS-1 e do IRS-2 e um aumento da associação desses substratos com a PI 3-quinase. Porém uma diminuição significativa da fosforilação da AKT e da p70s6k foi observada, sem alteração no grau de fosforilação das ERKS (1/2). Não foi observado diferença significativa no grau de fosforilação da JNK, porém os animais tratados apresentaram uma redução significativa nos níveis de I?Ba . O grau de fosforilação da AMPK mostrou-se aumentado nos animais tratados. Quando estudamos o tecido muscular, após estímulo agudo com insulina observamos uma diminuição significativa no grau de fosforilação do receptor de insulina nos animais tratados com PD 153035. Entretanto, nesses animais, pudemos observar após estímulo agudo com insulina, que a fosforilção em tirosina do IRS-1 aumentou significativamente. O aumento da fosforilação do IRS-1 foi acompanhada pelo aumento na associação IRS-1/ PI 3-quinase e pelo aumento no grau de fosforilação da AKT e da p70s6k. a. O grau de fosforilação da AMPK mostrou-se aumentado nos animais tratados. Não foi observada alteração no grau de fosforilação das ERKs (1/2) neste tecido. Foi observado uma redução do grau de fosforilação das serinas quinases JNK e I??a no músculo dos animais tratados. Os animais que receberam tratamento crônico com PD 153035 por 7 dias apresentaram uma redução da adiposidade visceral, bem como uma perda de peso em relação ao grupo controle. Observamos nesses animais uma redução significativa no grau de fosforilação do IR e do IRS-1 no tecido adiposo. A associação IRS-1/PI 3-quinase mostrou uma redução significativa. A fosforilação da AKT e da P70s6k mostrou-se significativamente reduzida nos animais tratados. Entretanto observamos um aumento significativo da fosforilação do IRS-2 após estímulo insulínico agudo, porém acompanhado pela redução significativa na associação IRS-2/PI 3-quinase. Não observamos diferença nos níveis de fosforilação das ERKs. Observamos que o grau de fosforilação da proteína AMPK aumentou significativamente no ratos que receberam tratamento com PD 153035. Foi observado uma redução significativa do grau de fosforilação da JNK e I??a no tecido adiposo dos animais tratados. Sumariamente, o tratamento com PD 153035 por 7 dias aumentou a fosforilação em tirosina do IR, IRS-1 e IRS-2 no fígado, apesar da fosforilação da AKT apresentar-se reduzida neste tecido. No músculo dos animais tratados com PD 153035 observamos que a droga melhora a sinalização da insulina, provavelmente pela redução da atividade das serinas quinases JNK, IKKß e mTOR. No tecido adiposo a droga induziu resistência à insulina, acompanhada de redução no ganho de peso e redução da adiposidade visceral, possivelmente pelo aumento da secreção de adiponectina pelos adipócitos. Em conclusão, os resultados do nosso estudo demonstram que o tratamento com PD 153035 aumentou a sensibilidade à insulina, por aumento da adiponectina, aumento da AMPK em fígado, músculo e adiposo, e aumentada via IRS/PI3K/AKT em músculo
Abstract: It has been recently demonstrated that long-term treatment with some of tyrosine kinase inhibitor (TKI) drugs, might favorably act at steps in controlling not only cell growth and replication, but also physiological functions responsible for maintaining glucose homeostasis. However, the direct effects of PD 153035, a TKI, in the regulation of the early steps of insulin action are not known. Insulin initiates its growth and metabolic promoting effects by biding to its receptor at the plasma membrane, which has tyrosine-kinase activity, and is able to autophosphorylates and phosphorylates cytoplasmatic proteins called insulin receptor substrates (IRSs). The main substrates of insulin receptor are IRS-1 and IRS-2, which when phosphorylated in tyrosine bind and activate several proteins, including phosphatidylinositol (PI) 3-kinase. These initial steps lead to the activation of two serine/threonine kinases ¿ AKT and ERK family (1/2) of MAPK. In the present study, we investigated the effect of treatment with PD 153035, for 7 days, on insulin sensitivity and insulin signaling in liver, muscle and adipose tissue of Wistar rats. It was investigated the tyrosine phosphorylation of IR, IRS-1 and IRS-2, their association with PI 3-kinase, and Akt serine/threonie phosphorylation , ERKs (1/2) phosphorylation, p70s6k, AMPK, JNK and ???a phosphorylation, in the three tissues. No differences in fasting plasma glucose levels were observed in animals treated with PD 153035. Plasma glucose disappearance rates were higher in treated animals In the liver of rats treated with PD 153035, we observed an increased IR, IRS-1 and IRS-2 tyrosine phosphorilation and an increased association of these substracs with PI 3-quinase. However a significant decrease of AKT and of the p70s6k phosphorylation was observed too, without alteration in ERKs phosphorylation levels (1/2). No significant difference was observed in JNk phosphorylation levels, however ??? showed a reduced phosphorylation in the liver of these animals. AMPK showed a significant increased phosphorylation in treated animals. When we studied muscle, insulin-induced IR tyrosine phosphorylation showed significantly reduced in these animals, however treating rats with PD153035 significantly increased the insulin-induced IRS-1 phosphorylation in the muscle. The increased phosphorylation of IRS-1 was accompanied by increase in IRS-1/PI3-kinase association and Akt and p70s6k phosphorylation were higher in treated animals after insulin stimulation. AMPK showed a significant increased phosphorylation in treated animals. There was no significant changes in ERKs (/2) phosphorylation in this tissue. Reduced phosphorylation of serine-kinases as c-jun N terminal (Jnk) and I?kß was observed. The animals that received chronic treatment with PD 153035 for 7 days had presented a reduction in visceral fat mass, as well as a loss of weight, regarding the control group We observed in these animals a significant decreased IR and IRS-1 tyrosine phosphorylation in the adipose tissue. The association IRS-1/PI3-kinase showed a significant reduction. AKT and P70s6K phosphorylation showed significantly decreased in treated animals. However we observe a significant increased phosphorylarion of insulin-induced IRS-2 phosphorylation, but the association IRS-2/PI 3-kinase showed a significant reduction. We did not observe any difference in phosphorylation levels of ERKs (1/ 2). AMPK phosphorylarion increased significantly in animals that received treatment with PD 153035. Reduced phosphorylation of JNK and Ikkßa was observed in adipose tissue of treated animals. In summary, our results demonstrated that in 7 days of treatment with PD 153035 increased tyrosine phosphorylation of IR/IRS-1/IRS-2 in the liver were observed, in spite of AKT phosphorylation had decreased in this tissue. In muscle of animals treated with PD 153035 we observed that the drug had improved the insulin signalling, probably by reduction of the serine kinase activity JNK, ???ß and mTOR. In the adipose tissue, the drug induced insulin resistance, accompanied of visceral fat mass reduction as well as a loss of weight, probably due to an increased adiponectin secretion by fat cels. In conclusion, the results of our study demonstrate that the treatment with PD 153035 increased the insulin sensibility, by increased levels of adiponectin, increased AMPK in liver, muscle and adipose tissue, and increased IRS/PI3K/AKT pathway in muscle
Mestrado
Ciencias Basicas
Mestre em Clinica Medica
25
Al-Naser, Al Zekri Huda M. "Oligo/amenorrhoea : endocrine profiles, ovarian ultrasound, insulin resistan and anthropometric factors; relationships between insulin resistance and ovarian function." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360284.
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Pereira, Renato Felipe. "Estudo dos mecanismos envolvidos no desenvolvimento de resistência à insulina em ratos com lesão periapical /." Araçatuba, 2018. http://hdl.handle.net/11449/180228.
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Orientador: Doris Hissako SumidaBanca: João Cesar Bedran de Castro
Banca: Fabio Santos de Lira
Banca: José Antunes Rodrigues
Banca: Sérgio Eduardo de Andrade Perez
Resumo: Nos últimos anos, a relação entre infecções orais e desordens sistêmicas tem se consolidado como área de grande interesse na comunidade cientifica médica e odontológica. A lesão periapical (LP) é caracterizada como uma inflamação oral e está associada ao aumento da quantidade de citocinas pró-inflamatórias que possivelmente induzem resistência insulínica (RI). A RI é definida como a incapacidade dos tecidos periféricos em responder adequadamente às concentrações fisiológicas deste hormônio, no entanto, os mecanismos que causam RI não são totalmente compreendidos. Estudos anteriores do nosso laboratório observaram que a LP promove aumento das concentrações plasmáticas de TNF-α, prejuízos na transdução do sinal insulínico e redução do conteúdo de GLUT4 na membrana plasmática em tecido muscular esquelético, indicando uma relação entre LP e RI. Tais achados evidenciam a necessidade de realizar mais estudos para verificar os mecanismos envolvidos nestas alterações. O presente estudo, conduzido em ratos com LP, teve como objetivos: 1) calcular o índice HOMA-IR a partir dos concentrações plasmáticas de glicose e insulina 2) avaliar conteúdo total das proteínas inflamatórias (JNK, IKKα/ e TNF-) no músculo gastrocnêmio (MG) e o grau de fosforilação de JNK e IKKα/ no mesmo tecido; 3) verificar a presença de macrófagos infiltrados por meio da detecção da proteína F4/80 em MG; 4) quantificar a expressão de fatores de transcrição envolvidos com a diferenciação de linfócitos no baço (T-... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: In the last few years, the relationship between oral infections and systemic disorders has been consolidated as an issue of great interest in the medical and dental scientific community. The periapical lesion (PL) is characterized as an oral inflammation and is associated with an increase in the levels of pro-inflammatory cytokines that possibly induce insulin resistance (IR). IR is defined as the inability of peripheral tissues to respond adequately to the physiological concentrations of this hormone, however, mechanisms that cause IR are not fully understood. Previous studies performed by our laboratory have found that PL promotes an increase in plasma TNF-α concentrations, impairment of insulin signal transduction, and reduction of plasma membrane GLUT4 content in skeletal muscle tissue, indicating a relationship between PL and IR. These findings highlight the need for further studies to verify the mechanisms involved in these changes. The present study was conducted in rats with PL and aimed: 1) to calculate the HOMA-IR index from the plasma glucose and insulin levels 2) to evaluate the total content of the inflammatory proteins (JNK, IKKα/β and TNF-α) in the gastrocnemius muscle (GM) and the JNK and IKKα/β phosphorylation status in the same tissue; 3) to verify the presence of infiltrated macrophages by F4/80 protein detection of in GM; 4) to quantify the expression of transcription factors involved in the lymphocytes differentiation into spleen (T-bet, GATA3 and FOXP3);... (Complete abstract click electronic access below)
Doutor
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Silva, Patrícia Ebersbach. "Efeito do tabagismo passivo e do exercício físico associado sobre a expressão de transportador de glicose GLUT4 em músculos de ratos /." Presidente Prudente : [s.n.], 2009. http://hdl.handle.net/11449/87339.
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Orientador: Patrícia Monteiro SeraphimBanca: Ubiratan Fabres Machado
Banca: Ercy Mara Cipulo Ramos
Resumo: O tabagismo altera o metabolismo celular em vários aspectos e evidências apontam que este pode desencadear um quadro de resistência à insulina e, em longo prazo, Diabetes tipo 2. Dentre as alterações metabólicas mais importantes associadas à resistência à insulina, encontra-se a alteração na quantidade de transportador de glicose GLUT4 disponível na membrana plasmática de tecido muscular e tecido adiposo. No entanto, a atividade física aparece como um dos fatores que poderia modificar o risco dos indivíduos desenvolverem resistência insulínica e/ou diabetes, uma vez que pode aumentar a expressão da proteína e do RNAm do transportador de glicose GLUT4, estimulando o transporte de glicose por uma via independente da via de sinalização da insulina. Dentro deste contexto, este trabalho teve por objetivo avaliar o efeito do tabagismo e de atividade física moderada associada sobre a sensibilidade à insulina em músculos de ratos, através da quantificação de proteína e do RNAm do transportador de glicose GLUT4. Para a realização deste estudo foram utilizados ratos Wistar, divididos em 4 grupos: (CS) grupo controle, (CE) controle exercitado, (FS) fumante sedentário e (FE) fumante submetido a exercício físico. Os grupos FS e FE foram submetidos à combustão dee4 cigarros/vez, 30 minutos, 2x/dia, durante 60 dias. Os grupos CE e FE executaram protocolo de exercício em esteira rolante, 60 dias, 60 minutos por sessão... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Cigarette smoking changes the cellular metabolism in many aspects and evidences suggest that it is related to insulin resistance and type 2 diabetes. Within the metabolic alterations associated to insulin resistance we can mention disturbs on GLUT4 content in plasma membrane of muscle e adipose tissue. However, physical activity appears as a factor that could modify the risk for these pathologies, increasing GLUT4 expression and stimulating glucose transport, in an independent-pathway of insulin signaling. In this context, this study aimed to evaluate the effect of smoking and moderated physical activity on insulin sensitivity in muscle of rats, by quantifying GLUT4 protein and mRNA. For this study, it was used Wistar rats divided into 4 groups: control (CS), control submitted to an exercise protocol (CE), sedentary smoker (FS) and smoker submitted to an exercise protocol (FE). The FS and FE groups were submitted to cigarette smoke exposition, 4 cigarettes/30 min./twice a day for 60 days. Groups CE and FE performed running on a treadmill for 60 days during 60 minutes per session... (Complete abstract click electronic access below)
Mestre
28
Calegari, Vivian Cristine. "Papel da proteina SOCS3 sobre a modulação do sinal intracelular da angiotensina II e sobre o cross-talk entre a sinalização da angiotensina II e da insulina em tecido cardiaco de ratos." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310364.
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Orientador: Licio Augusto VellosoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O hormônio angiotensina II (ANGII) através de seu receptor AT1 é capaz de ativar a via de sinalização JAK/STAT. Estudos demonstram que esta via encontra-se hiper-ativada durante o desenvolvimento da hipertensão. Os mecanismos pelos quais esta via é regulada pela ANGII ainda não foram totalmente elucidados. Relatos demonstram que hormônios, citocinas e fatores de crescimento que transduzem seus sinais através da via JAK/STAT, acabam por induzir a expressão de proteínas da família SOCS e que estas, por sua vez, promovem a regulação do sinal de seus indutores. Estudos epidemiológicos demonstram que a hipertensão é um dos mais importantes fatores de risco para o desenvolvimento da resistência à insulina (RI). Embora seja conhecido que a ANGII apresenta importante papel no desenvolvimento da hipertensão e da RI, uma vez que a inibição de sua ação, não somente reduz a pressão sanguínea como também melhora a sensibilidade à insulina em indivíduos hipertensos e resistentes à insulina, muito pouco é conhecido sobre os mecanismos moleculares pelos quais este hormônio pode causar RI. No presente estudo, examinamos o papel da ANGII sobre os mecanismos de ativação e regulação da via JAK/STAT em coração de ratos Wistar adultos (RWA) e em cardiomiócitos ventriculares isolados de ratos neonatos (CVIN). Nossos resultados revelaram que, após a ligação da ANGII ao receptor AT1, ocorre ativação de JAK2 e STAT1 e, subsequentemente, a expressão de SOCS3 é induzida. Verificamos ainda que a ativação da via JAK/STAT e a expressão de SOCS3 são dependentes da ativação de AT1 pela ANGII e que a expressão de c-jun pode ser induzida também pelo receptor AT2. Além disso, observamos que SOCS3 pode participar do mecanismo de desensibilização ou refratariedade do sinal da ANGII através da via JAK/STAT como demonstrado pelo seu bloqueio com oligonucleotídeo antisense contra SOCS3 (AS SOCS3). Também investigamos se a proteína SOCS3, induzida por ANGII, pode participar do cros-talk molecular entre o sinal da ANGII e da insulina. Observamos que o tratamento com ANGII causa queda significativa na atividade de proteínas da via PI 3-K/AKT da insulina e que SOCS3, induzida por ANGII, associa-se a IR, IRS1 e IRS2. O uso de AS SOCS3 restaura os níveis de fosforilação em tirosina de IRS1 e IRS2 induzidos pela insulina, aumenta a associação entre IRS1 e IRS2 com PI 3-K, e a subseqüente atividade desta enzima e da proteína AKT e leva a um aumento na translocação de GLUT4 para a membrana celular. O presente estudo demonstra, pela primeira vez, que o hormônio ANGII é capaz de induzir a expressão de uma proteína supressora da sinalização das citocinas, SOCS3, e que esta proteína, além de participar do controle das ações fisiológicas de seu indutor, também participa do cros-talk negativo entre o sinal de dois hormônios, ANGII e insulina, podendo se constituir, desta forma, em mais um mecanismo de interconexão entre hipertensão arterial e RI e/ou diabetes mellitus tipo II
Abstract: Intracellular interactions between different signaling systems may function as mechanisms for enhancing or counter-regulating hormone action. The hormone angiotensin II (ANGII) is involved in the development of both, hypertension and insulin resistance. Several studies demonstrate that in signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study we demonstrate that ANGII is able to activate the JAK/STAT pathway and, subsequently, the expression of SOCS3. SOCS3 is constitutively expressed at a low level in the heart of rats and neonatal rat ventricular myocytes. ANGII, at a physiological concentration, enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide against SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-jun expression after repetitive infusions of the hormone. We also demonstrate the interaction of ANGII-induced SOCS3 with the insulin signaling pathway in cardiac tissue in vivo and in isolated cell system. ANGII-induced SOCS3 interacts with the IR, JAK2, IRS1 and IRS2. The inhibition of SOCS-3 expression by antisense oligonucleotide partially restores the ANGII-induced inhibition of insulin-induced IR, IRS- 1 and IRS-2 tyrosine phosphorylation, IRS1 and IRS2 association with p85- phosphatidylinositol 3-quinase and AKT [Ser473] serine phosphorylation. Moreover, the inhibition of SOCS3 expression partially reverses ANGII- induced inhibition of insulinstimulated GLUT-4 translocation to the cell membrane. Thus, ANGII-induced SOCS3 in rat heart and neonatal rat ventricular myocytes may actively participate in the control of the ANGII signaling, and also, as a late event, in the negative cross-talk between ANGII and insulin signaling pathways
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
29
Roman, Erika Anne de Freitas Robles 1979. "Ativação da via de sinalização AMPK/Acetil-CoA carboxilase no hipotalamo de ratos expostos a baixa temperatura." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310691.
Full textAbstract:
Orientadores: Marcio Alberto Torsoni, Licio Augusto Velloso.Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A exposição de animais homeotérmicos ao frio leva a uma poderosa ativação da sinalização anorexigênica, acompanhada por resistência molecular e funcional à inibição da alimentação induzida pela insulina. Evidências recentes sugerem que a AMPK participa do controle da saciedade e da adiposidade, dependente de nutriente. O objetivo do presente estudo foi avaliar o efeito da exposição ao frio sobre a ativação molecular da sinalização da AMPK em hipotálamo de ratos. Immunoblotting demonstrou que a exposição ao frio por si é suficiente para induzir, em um modelo tempo dependente, a ativação molecular da serina/treonina quinase, proteína quinase ativada por AMP (AMPK) e a inativação da acetil-CoA carboxilase (ACC). Estes fenômenos moleculares foram acompanhados pela resistência à inativação da AMPK e pela ativação da ACC, dependentes de nutrientes. Além disso, a exposição ao frio levou a uma inibição parcial da resposta anorexigênica induzida pela alimentação, a qual foi acompanhada pela resistência à supressão da alimentação induzida pela insulina. Finalmente, a exposição ao frio prejudicou significativamente a inibição da AMPK, induzida pela insulina, através de um mecanismo dependente do ¿cross-talk¿ molecular entre fosfatidilinositol-3(PI3)-quinase/Akt e AMPK. Como conclusão, a hiperfagia durante a exposição ao frio resulta, pelo menos em parte, da resistência hipotalâmica à sinalização anorexigênica dependente de nutrientes e insulina
Abstract: The exposure of homeothermic animals to a cold environment leads to a powerful activation of orexigenic signalling which is accompanied by molecular and functional resistance to insulin-induced inhibition of feeding. Recent evidence suggests that AMPK participates in nutrient-dependent control of satiety and adiposity. The objective of the present study was to evaluate the effect of cold exposure upon the molecular activation of AMPK signalling in the hypothalamus of rats. Immunoblotting demonstrated that cold exposure per se is sufficient for inducing, on a time-dependent basis, the molecular activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) and inactivation of the acetyl-CoA carboxylase (ACC). These molecular phenomena were accompanied by resistance to nutrient-induced inactivation of AMPK and activation of ACC. Moreover, cold-exposure led to a partial inhibition of a feeding-induced anorexigenic response, which was paralleled by resistance to insulin-induced suppression of feeding. Finally, cold exposure significantly impaired insulin-induced inhibition of AMPK through a mechanism dependent on the molecular cross-talk between phosphatidylinositol-3(PI3)-kinase/Akt and AMPK. In conclusion, increased feeding during cold exposure results, at least in part, from resistance to insulin¿ and nutrient-dependent anorexigenic signalling in the hypothalamus
Mestrado
Ciencias Basicas
Mestre em Clinica Medica
30
Oliveira, Alexandre Gabarra de 1980. "Efeito do exercício físico agudo e crônico na expressão e ativação do TLR4 em roedores." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311238.
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Orientador: Mario José Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Reumo: Evidências recentes têm apontado para estreita correlação entre resistência à insulina, inflamação e obesidade. Nesse contexto, o toll-like receptor 4 (TLR4) parece exercer papel importante, pois sua ativação leva a aumentos na fosforilação de I?B kinase (IKK'beta') e c-Jun NH2-terminal kinase (JNK) e na expressão de citocinas inflamatórias como o fator de necrose tumoral alfa (TNF- ?), substâncias capazes de atenuar a sensibilidade à insulina.. Recentemente, nosso laboratório demonstrou que animais com TLR4 não funcional ficam protegidos da resistência à insulina e do ganho de peso, induzidos por dieta hiperlipídica, sugerindo papel de destaque do TLR4 na interface entre sistema imune inato e metabolismo energético. Por outro lado, o exercício físico pode melhorar a sensibilidade à insulina e a inflamação na obesidade, entretanto os mecanismos são pouco compreendidos. A relação entre TLR4 e exercício físico é um tópico ainda pouco investigado, no entanto há indícios de que o exercício físico possa levar à redução na sua expressão gênica. Assim buscamos analisar o efeito do exercício físico sobre a expressão e ativação do TLR4 e de suas consequências sobre a sinalização e sensibilidade à insulina em ratos obesos. O presente estudo demonstrou que apenas o exercício crônico foi capaz de reduzir a expressão de RNA mensageiro e de proteína do TLR4 em músculo, fígado e tecido adiposo. Contudo, tanto o exercício crônico quanto o agudo atenuaram a sinalização do TLR4 nesses tecidos, como evidenciado pela redução da fosforilação de JNK e IKK'beta'. Observamos também importante redução nos níveis circulantes de lipopolissacarídeo (LPS) nos dois protocolos de exercício, e menores níveis de ácidos graxos livres (AGL) apenas no exercício crônico. Em paralelo, demonstramos melhora na fosforilação em tirosina do IR'beta' e do IRS-1 e da Akt em serina após ambos os protocolos. Dessa forma, podemos concluir que o exercício físico promoveu importante atenuação sobre a sinalização do TLR4 em músculo, fígado e tecido adiposo; possivelmente mediada pela redução dos níveis de LPS circulante, que resultou em melhora na sinalização e sensibilidade à insulina em animais com obesidade induzida por dieta hiperlipídica. Esses dados promoveram considerável progresso no entendimento dos eventos moleculares que ligam o exercício físico com a melhora na inflamação e na resistência à insulina
Abstract: Recent evidences have suggested a strong correlation among insulin resistance, inflammation and obesity. In this context, the toll-like receptor 4 (TLR4) seems to play an important role in the development of insulin resistance, since the activation of this receptor increases I?B kinase (IKK'beta') and c-Jun NH2-terminal kinase (JNK)activity and pro-inflammatory cytokines expression such as tumor necrosis factor-alpha (TNF-?), substance known by its negative effects over insulin sensitivity. Previous results from our laboratory demonstrated that mice with loss-of-function mutation in TLR4 are protected from both weight gain and insulin resistance induced by high-fat diet, suggesting an important role of TLR4 in the link between the innate immune system and energy metabolism. In parallel, life style interventions involving exercise clearly improve insulin sensitivity, and possibly inflammation, in obese individuals, yet the mechanisms for these effects are not well understood. There is evidence that exercise leads to decreased gene expression of TLR4, however the relationship between TLR4 and exercise is still poorly investigated. Thus we aimed to analyze the effect of physical exercise on TLR4 expression and activation in obese rats and its consequences in insulin signaling and sensitivity. The present study demonstrated that chronic exercise was able to reduce the TLR4 expression of both mRNA and protein in muscle, liver and adipose tissue. However, the acute and chronic exercise blunted the TLR4 signaling in these tissues, as evidenced by reducing phosphorylation levels of JNK and IKK'beta'. We also observed a significant reduction in lipopolysaccharide (LPS) circulating levels in both exercise protocols and lower levels of free-fat acids (FFA) only in the chronic exercise. In parallel, we demonstrated improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation after both exercise protocols. Thus, we concluded that physical exercise promotes a significant attenuation of the TLR4 signaling pathway in muscle, liver and adipose tissue; possibly by reducing LPS circulating levels, that resulted in an improved insulin signaling and sensitivity diet-induced obese animals. These data provided considerable progress in our understanding of molecular events that link exercise with to an improvement in inflammation and insulin resistance
Doutorado
Clinica Medica
Doutor em Clínica Médica
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Silva, Patrícia Ebersbach [UNESP]. "Efeito do tabagismo passivo e do exercício físico associado sobre a expressão de transportador de glicose GLUT4 em músculos de ratos." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/87339.
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silva_pe_me_prud.pdf: 747809 bytes, checksum: dc9c919c8866b8929f30a2b3dbe33ab8 (MD5)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O tabagismo altera o metabolismo celular em vários aspectos e evidências apontam que este pode desencadear um quadro de resistência à insulina e, em longo prazo, Diabetes tipo 2. Dentre as alterações metabólicas mais importantes associadas à resistência à insulina, encontra-se a alteração na quantidade de transportador de glicose GLUT4 disponível na membrana plasmática de tecido muscular e tecido adiposo. No entanto, a atividade física aparece como um dos fatores que poderia modificar o risco dos indivíduos desenvolverem resistência insulínica e/ou diabetes, uma vez que pode aumentar a expressão da proteína e do RNAm do transportador de glicose GLUT4, estimulando o transporte de glicose por uma via independente da via de sinalização da insulina. Dentro deste contexto, este trabalho teve por objetivo avaliar o efeito do tabagismo e de atividade física moderada associada sobre a sensibilidade à insulina em músculos de ratos, através da quantificação de proteína e do RNAm do transportador de glicose GLUT4. Para a realização deste estudo foram utilizados ratos Wistar, divididos em 4 grupos: (CS) grupo controle, (CE) controle exercitado, (FS) fumante sedentário e (FE) fumante submetido a exercício físico. Os grupos FS e FE foram submetidos à combustão dee4 cigarros/vez, 30 minutos, 2x/dia, durante 60 dias. Os grupos CE e FE executaram protocolo de exercício em esteira rolante, 60 dias, 60 minutos por sessão...
Cigarette smoking changes the cellular metabolism in many aspects and evidences suggest that it is related to insulin resistance and type 2 diabetes. Within the metabolic alterations associated to insulin resistance we can mention disturbs on GLUT4 content in plasma membrane of muscle e adipose tissue. However, physical activity appears as a factor that could modify the risk for these pathologies, increasing GLUT4 expression and stimulating glucose transport, in an independent-pathway of insulin signaling. In this context, this study aimed to evaluate the effect of smoking and moderated physical activity on insulin sensitivity in muscle of rats, by quantifying GLUT4 protein and mRNA. For this study, it was used Wistar rats divided into 4 groups: control (CS), control submitted to an exercise protocol (CE), sedentary smoker (FS) and smoker submitted to an exercise protocol (FE). The FS and FE groups were submitted to cigarette smoke exposition, 4 cigarettes/30 min./twice a day for 60 days. Groups CE and FE performed running on a treadmill for 60 days during 60 minutes per session... (Complete abstract click electronic access below)
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Endre, Tomas. "The hypertension-prone man a study on the pathogenesis of hypertension with regard to insulin sensitivity /." Lund : Dept. of Medicine, Lund University, University Hospital MAS, 1997. http://books.google.com/books?id=3UlsAAAAMAAJ.
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Svanfeldt, Monika. "Perioperative nutrition and insulin resistance /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-637-9/.
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Isaksson, Bengt. "Insulin resistance in pancreatic cancer /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-493-3/.
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Berends, Lindsey Matara. "Developmental programming of insulin resistance." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648433.
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Ali, Salmin. "GLUT 4 and Insulin Resistance." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1409746939.
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Collison, Mary Williamson. "Insulin signalling in insulin resistance and cardiovascular disease syndromes." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366184.
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Bassil, Fares. "Multiple system atrophy : a translational approach Characterization of the insulin/IGF-1 signaling pathway." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0131/document.
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Ce travail porte sur des approches translationnelles dans les synucléinopathies notamment l’atrophie multisystématisée (AMS). Au-delà de leur rôle dans la régulation du glucose, l’insulin et l’insulin like growth factor-1 (IGF-1) ont des propriétés neurotrophiques. Des études ont montrées que la signalisation de l’insuline/IGF-1 est altérée dans la maladie d'Alzheimer et des données suggèrent l’altération de l’insuline/IGF-1 dans la maladie de Parkinson (MP) et l’AMS. Nous avons mis en évidence une résistance à l’insuline dans les neurones des patients MP et AMS ainsi que dans les oligodendrocytes chez les patients AMS.Mon travail a également consisté à cibler la troncation de l’α-synuclein (α-syn) comme cible thérapeutique. Nous avons démontré dans un modèle murin d’AMS que la diminution de l’α-syn tronquée permettait de réduire l’agrégation d’α-syn et la dégénérescence des neurones dopaminergiques.Enfin, nous avons étudié l’implication dans l’AMS des métalloprotéinases matricielles (MMP), des enzymes impliquées dans remodelage de la matrice, la démyélinisation, la troncation de l’α-syn et la perméabilité de la barrière hémato-encéphalique. Ce travail nous a permis de montrer une augmentation de l’expression et de l’activité de MMPs chez les patients AMS. Nous avons également montré que les cellules gliales sont la source de cette augmentation et que la MMP-2 est retrouvée dans les agrégats des patients AMS.Nous montrons ici de caractéristiques distinctes de l’AMS comme des altérations qui se produisent dans les oligodendrocytes. Nous présentons aussi VX-765 comme un candidat prometteur pour ralentir la progression de la pathologie dans un contexte de synucléinopathieThis work focused on translational approaches in synucleinopathies and more specifically in multiple system atrophy (MSA). Beyond their role in glucose homeostasis, insulin/IGF-1 are neurotrophic factors in the brain. Studies have shown altered insulin/IGF-1 signalling in Alzheimer’s disease and data suggest impaired insulin signaling/IGF-1 in Parkinson's disease (PD) and MSA. The aim of my work was to characterize insulin/IGF-1 signalling in MSA and PD brain tissue. Both groups showed neuronal insulin resistance. Oligodendrocytes in MSA patients were also insulin resistant.In line with the translational approach, we also targeted α-synuclein (α-syn) truncation pharmacologically in MSA transgenic mice, which led to reduced α-syn aggregation and the protection of dopaminergic neurons.We also assessed the activity and distribution of matrix metalloproteinases (MMPs) in the brain of MSA patients compared to healthy controls. MMPs are involved in the remodelling of the extracellular matrix, demyelination, α-syn truncation and blood brain barrier permeability. We showed altered expression and activity of MMPs in two distinct structures in MSA brains. We were also able to show that glial cells were the source of increased MMPs and show a unique expression of MMPs in α-syn aggregates of MSA patients compared to PD, evidence that might hint at a mechanism that is differently altered between PD and MSA.We here show distinct pathological features of MSA such as key alterations occurring in oligodendrocytes, further supporting MSA as a primary oligodendrogliopathy. We also present VX-765 as a candidate drug for disease modification in synucleinopathies
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Stuart, Charles A., Mary E. A. Howell, Brian M. Cartwright, Melanie P. McCurry, Michelle L. Lee, Michael W. Ramsey, and Michael H. Stone. "Insulin Resistance and Muscle Insulin Receptor Substrate-1 Serine Hyperphosphorylation." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/4117.
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Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin-responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate-1 (IRS-1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS-1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS-1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS-1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS-1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c-Jun N-terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS-1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS-1 diminishes the transmission of the insulin signal and thereby decreases the insulin-stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS-1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss.
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Rafacho, Alex. "Avaliação dos efeitos de diferentes concentrações de dexametasona sobre parametros fisiologicos de ilhotas pancreaticas." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314398.
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Orientador: Jose Roberto BosqueiroTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A resistência à insulina (RI) é uma condição que exige maiores níveis de insulina circulante e que normalmente são providenciados pelo aumento da função e população de células ß. A RI pode ser observada a partir de diversos modelos experimentais em roedores tais como os modelos transgênicos, de gravidez, submetidos às dietas hiperlipídicas e hipercalóricas e a partir de infusão venosa de glicose. Estes modelos têm sido úteis para a compreensão dos mecanismos compensatórios observados durante a RI. Os glicocorticóides são amplamente utilizados na indução farmacológica da RI em modelos animais e em seres humanos, com fins científicos. A ativação da sinalização da insulina e das proteínas reguladoras do ciclo celular é crucial para a função e crescimento das células ß adultas. No presente trabalho, apresentamos modelos para investigação da função e crescimento de células ß pancreáticas in vivo a partir da administração diária de três concentrações distintas de dexametasona (DEX) (0,1, 0,5 e 1,0 mg/kg, peso corpóreo, intraperitoneal - DEX 0.1, DEX 0.5 e DEX 1.0, respectivamente) por 5 dias consecutivos. A sensibilidade periférica à glicose e à insulina, parâmetros de secreção de insulina e histomorfométricos foram investigados. A análise dos níveis de proteínas relacionados à função e crescimento de células ß foi realizada por Western blotting. O tratamento com DEX induziu RI de maneira dose- dependente. Aumento da secreção de insulina em resposta à glicose foi observado tanto in vivo quanto ex vivo nos três grupos tratados com DEX. Ratos DEX 1.0, que apresentam hiperglicemia moderada e marcante hiperinsulinemia, exibiram aumento de 5,1 vezes na proliferação além de hipertrofia de células ß, com aumento significativo na massa de células ß comparado aos ratos CTL. Os ratos DEX 0.5, hiperinsulinêmicos, porém normoglicêmicos, também apresentaram aumento significante de 3,6 vezes na proliferação e modesta hipertrofia de células ß. Entretanto, os ratos DEX 0.1, que desenvolveram o menor grau de RI, compensaram à demanda de insulina apenas com aumento da função de células ß. Nenhuma alteração da freqüência de morte celular foi observada nas células ß dos três grupos DEX comparados ao grupo CTL. Foi observada ativação da via IRS-2/PI3- K/Akt/p70S6K, bem como da proteína retinoblastoma nas ilhotas do grupo DEX 1.0 e, em menor grau, no grupo DEX 0.5 quando comparados com as ilhotas do grupo CTL. Assim, aumentando a concentração de dexametasona induzem-se três graus de requerimento de insulina in vivo, servindo como modelo para investigação de alterações compensatórias em células ß. O aumento da demanda de insulina é compensado por aumento da função das células ß (em todos os GRUPOS DEX) e por hiperplasia e hipertrofia de células ß nos GRUPOS DEX 1.0 e DEX 0.5. Baseado nos presentes resultados concluímos que o aumento dos níveis circulantes de insulina parece ser o maior estímulo para proliferação e hipertrofia das células de células ß observado na RI induzida pela dexametasona.
Abstract: Insulin resistance (IR) is a condition that demand increased levels of circulating insulin that are normally provided by increase of ß-cell function and mass. The IR can be observed in several experimental rodent models such as transgenic, pregnancy, high-fat or high-caloric diet and from glucose infusion model. These models have aided in elucidating the compensatory mechanisms observed during the IR. The glucocorticoids are widely used to induce the pharmacological IR in animal models and in humans, with scientific purpose. Activation of insulin signaling and cell cycle proteins are crucial to the function and growth of adult ß-cells. At the present study, we showed models to investigation of pancreatic ß-cell function and growth in vivo from the daily administration of three different dexamethasone (DEX) concentration (0.1, 0.5 e 1.0 mg/kg, body weight, intraperitoneal - DEX 0.1, DEX 0.5 and DEX 1.0, respectively) for 5 consecutive days. The peripheral sensibility to glucose and insulin, insulin secretion and histomorphometrical parameters were investigated. The analyses of proteins related to ß -cell function and growth were done by Western blotting. DEX treatment induced IR in a dose-dependent manner. Incease of glucose-stimulated insulin secretion was observed in vivo as well as ex vivo in the three DEX groups. DEX 1.0 rats, that present moderate hyperglicemya and marked hyperinsulinemia, ehibited a 5.1-fold increase in ß-cell proliferation besides hypertrophy, with significant increase of ß -cell mass compared to CTL rats. DEX 0.5 rats, that are hiperinsulinemic and normoglicemic, also exhibited a significant 3.6-fold increase in ß-cell proliferation as well as ß -cell hypertophy. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only ß -cell function. No alteration in cell death frequency was noted in ß -cells from the three DEX groups compared to CTL group. Activation of IRS-2/PI3-K/Akt/p70S6K pathway as well as the retinoblastoma protein in islets from DEX 1.0 and, in lesser extend, in DEX 0.5 group was observed compared to islets from CTL group. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory beta-cell alterations. The increased insulin demand is compensated by increase of ß-cell function (in all DEX groups) and ß -cell hyperplasia and hypertrophy in DEX 0.5 and DEX 1.0 groups. Based on the present results we concluded that the augmented levels of circulating insulin seem to be the major stimulus for ß-cell proliferation and hypertrophy observed in dexamethasone-induced insulin resistance.
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular
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Barber, Collin. "SIRT3: Molecular Signaling in Insulin Resistance." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/315823.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Post-translational modification of intracellular proteins through acetylation is recognized as an important regulatory mechanism of cellular energy homeostasis. Specific proteins called sirtuins deacetylate other mitochondrial proteins involved in glucose and lipid metabolism, activating them in metabolic processes. SIRT3 is a sirtuin of particular interest as it is found exclusively in mitochondria and has been shown to affect a variety of cellular metabolic processes. The activity of this enzyme is related to cellular insulin sensitivity. This study attempted to identify the relationship between insulin sensitivity and change in amount of SIRT3 following a bout of exercise in non-diabetic individuals. We find a moderate inverse correlation between insulin sensitivity and increase in SIRT3 abundance following exercise. This suggests that this protein may not be involved directly in cells’ ability to regulate energy homeostasis or that it may act through another mechanism not investigated in this study.
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Borer, Katharine Elizabeth. "Laminitis and insulin resistance in ponies." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572136.
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Aksentijević, Dunja. "Myocardial insulin resistance in experimental uraemia." Thesis, University of Hull, 2008. http://hydra.hull.ac.uk/resources/hull:5757.
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Cardiac complications are a major cause of death in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) is a significant contributing factor to uraemic cardiomyopathy and results in significant molecular, cellular and metabolic remodelling. Progression of LVH leads to the development of insulin resistance, a feature common to CKD and heart failure, further jeopardising survival of the uraemic heart. The aim of this thesis was to investigate the effect of uraemia on cardiac physiology, function and metabolism. Specifically, the aim of the study was to examine the cellular mechanisms underlying the development of myocardial insulin resistance in uraemia. The experimental model was induced surgically via a two-stage 5/6 nephrectomy in adult male Sprague-Dawley rats over three, six weeks or nine weeks. An integrated experimental approach combining in vivo and ex vivo methods was used to characterize the morphology and physiology of the experimental model, examine myocardial function and energy provision; assess alterations in myocardial protein expression and determine potential mechanism involved in the development of insulin resistance. Uraemic animals exhibited impaired renal function (creatinine 69±2 vs. 40±2 uM n=41; p<0.05), cardiac hypertrophy (dry heart weight: tibia length 0.5±0.01 vs. 0.4±0.01 g/cm; n=30; p<0.05), impaired glucose tolerance, hyperinsulinaemia, anaemia and hypertension. In perfused hearts, uraemia caused a limited response of the uraemic heart to an increase in workload, demonstrated by cardiac dysfunction and metabolic adaptation. This profile was exacerbated in the presence of insulin. In vivo studies highlighted that insulin sensitivity was reduced in uraemic animals (HOMA-IR 1.27±0.3 vs. 0.58±0.1; n=8 p<0.02) and declined progressively with renal dysfunction. LV tissue from the uraemic model showed an increase in myocardial GLUT4 and normal insulin mediated translocation mechanism. In conclusion, uraemic animals exhibited a reduction in insulin sensitivity, glucose intolerance and hyperinsulinaemia, indicating onset of insulin resistance after 6 weeks of uraemia. Profile of myocardial GLUT4 expression and response to insulin stimulation suggested that insulin resistance is not a consequence of impaired translocation. The lack of overt metabolic remodelling suggests a compensatory phase of left ventricular hypertrophy.
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Lo, Kin Yui Alice. "Transcriptional regulation of adipose insulin resistance." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/71466.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2012.Page 168 blank. Cataloged from PDF version of thesis.
Includes bibliographical references (p. 155-167).
Insulin resistance is a condition that underlies type 2 diabetes and various cardiovascular diseases. It is highly associated with obesity, making it a pressing medical problem in face of the obesity epidemic. The obesity association also makes adipose tissue the target of interest for ongoing research. Previous work on adipose insulin resistance has largely been focused on deciphering the signaling defects and abnormal adipokine secretion profiles. There is increasing awareness that transcriptional control is a source of dysregulation as well as an avenue of therapeutic intervention for insulin resistance. However, knowledge of transcriptional regulation and dysregulation of adipose insulin resistance remains fragmentary. Here, we present a genome-wide perspective on transcriptional regulation of adipocyte biology and adipose insulin resistance. We made use of the latest high-throughput sequencing technology to interrogate different aspects of transcriptional regulation, namely, histone modifications, protein-DNA interactions, and chromatin accessibility in adipocytes. In combination with the transcriptional outcomes measured by microarray and RNA-sequencing, we (1) characterized a largely unknown histone modification, H3K56 acetylation, in human adipocytes, and (2) set up four diverse in vitro insulin resistance models in mouse adipocytes and analyzed them in parallel with mouse adipose tissues from diet-induced obese mice. In both cases, through computational analysis of the experimentally identified cis-regulatory regions, we identified existing and novel trans-regulators responsible for adipose transcriptional regulation. Furthermore, by comprehensive pathway analysis of the in vitro models and mouse models, we identified aspects of in vivo adipose insulin resistance that are captured by the different in vitro models. Taken together, our studies present a systems view on adipose transcriptional regulation, which provides a wealth of novel resources for gaining insights into adipose biology and insulin resistance.
by Kin Yui Alice Lo.
Ph.D.
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Raab, R. Michael. "Genomic analysis of hepatic insulin resistance." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33762.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2006.Includes bibliographical references (leaves 159-191).
Type II Diabetes mellitus is a genetically complex disease characterized by insulin resistance in peripheral tissues, which results in simultaneous hyperglycemia and hyperinsulinemia. Because of the prevalence of type II diabetes, many researchers are investigating the genetics of glucose homeostasis, however, traditional mapping techniques have not been successful in determining all of the genes that regulate glycemia. To complement these efforts, we used DNA microarrays to find differentially expressed genes and combinatorial siRNA screening to investigate the effects of hepatic gene transcription during periods of high and low glucose production. This strategy provides a new approach to studying the molecular mechanisms of disease pathogenesis. Our investigations focused on discovering new genes that influence hepatic metabolism and glucose production. Hepatocytes help maintain whole body glycemia by providing glucose and other substrates during non-feeding periods. DNA microarrays containing 17,000 unique gene probes were used to study hepatic gene transcription during normal, insulin resistant, and fasting states in C57/BL/6J mice. We analyzed this data set using a combination of statistical and multivariate techniques to determine 41 different, genes that are differentially expressed and highly discriminatory of the treatment groups.
(cont.) Hepatocytes perform many physiological roles, thus to investigate which genes from the microarray analysis affected hepatic metabolism, we developed combinatorial RNA-interference (RNAi) based gene silencing techniques. Using combinatorial siRNA screening, we silenced genes that were over-expressed within the microarray data set to study loss of function effects on hepatic metabolism, which was quantified by measuring intracellular metabolite concentrations in relevant metabolic pathways. Based upon the metabolite dependent clustering of experimental and control samples using Fisher Discriminant Analysis, four of the silenced genes had a significant effect on key metabolites involved in hepatic glucose output. Of these four genes, three were shown to influence hepatic glucose output in our primary cell model.
by R. Michael Raab.
Ph.D.
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Tewari, Nilanjana. "Mechanisms underlying obesity-related insulin resistance." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/34081/.
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This thesis investigates the effect of body composition on insulin resistance and the impact of supplementation with nutritional support or carbohydrate treatment. Insulin resistance occurs as a response to a number of stressors, including surgery. However, the mechanism underlying the development of insulin resistance is as yet unclear. Adipose tissue distribution appears to play a role in the development of insulin resistance and obesity-related complications. In obese and non-obese patients undergoing open abdominal surgery who received preoperative carbohydrate or placebo, there was a significant fall in perioperative insulin sensitivity and changes in the expression of genes relating to carbohydrate and fat oxidation. There was no influence of perioperative carbohydrate or obesity on change in insulin sensitivity. Patients undergoing neoadjuvant chemotherapy for oesophageal cancer underwent pre and post chemotherapy assessment of insulin sensitivity and body composition. There was a significant reduction in insulin sensitivity despite minimal change in body composition and adequate nutritional intake. These studies have provided further information about the optimal methods for assessment of insulin sensitivity and body composition as well as an insight into mechanisms underlying the association between body composition and insulin sensitivity.
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Malik, Muhammad Omar. "Insulin resistance, ethnicity and cardiovascular risk." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6517/.
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Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality. The literature supports a series of established risk factors for CVD: age, gender, family history of CVD, ethnicity (un-modifiable); and high blood pressure, blood cholesterol, TGs, LDL, diabetes, pre-diabetes, obesity, smoking, physical inactivity, stress and unhealthy diet (modifiable). High blood pressure (hypertension) shares many of these risk factors. However, much of the variance/risk in both conditions cannot be explained. This has led to a search for novel risk factors, including insulin resistance and subclinical inflammation, the significance of which at present are controversial, particularly in relation to hypertension. There are also ethnic differences in the incidence, prevalence, risk factors and progression of cardiovascular disease. In some populations CVD occurs at an earlier age and progresses more rapidly. In this thesis I worked on two datasets in relation to hypertension, cardiovascular disease and their risk factors: (i) the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) study (chapters 2, 3, 5 and 6); and (ii) routinely-collected national data in Scotland via the SDRN (Scottish Diabetes Research Network) and SCI-Diabetes (chapter 2 and 7). Work on data from the RISC cohort focused on the relation between clamp-measured insulin sensitivity (its unique feature), inflammatory markers and hypertension; the SDRN work addressed ethnic differences in relation to diabetes and CVD. The first study (Chapter 3) examined the importance of insulin sensitivity/resistance in the development of hypertension and change in blood pressure over three years of follow-up in the healthy European (EU) RISC population. Systolic BP (SBP) was higher at baseline in insulin resistant (IR) women. There was no difference in BP in relation to IR in men. After adjustment for age, BMI, baseline BP and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not men, and SBP over time did not increase in insulin sensitive women. The second study (Chapter 4) was a systematic review of the relationships between two markers of low grade inflammation (IL-6 and CRP) and BP/hypertension, considering the roles of adiposity and insulin resistance. The systematic review showed evidence of considerable variation in the relationships amongst low grade inflammation, adiposity, insulin resistance and the development of hypertension. There appeared to be a positive association in the literature between CRP and DBP in younger individuals, although none of the studies were adjusted for insulin sensitivity determined by clamp technique. This association was further explored using RISC study data in Chapter 5 with stratification by sex and adjusting for clamp-derived insulin sensitivity. The third study (Chapter 5) examined the relationship of inflammatory markers with the development of hypertension and change in blood pressure over three years in the same healthy European population and whether any relationship was independent of clamp-measured insulin sensitivity (IS). High sensitivity C reactive protein (hsCRP) predicted prospective change in diastolic BP independent of insulin sensitivity and BMI whereas IL-6 had no relation with BP (both systolic and diastolic) or the incidence of hypertension. The fourth study (Chapter 6) evaluated all available predictors of BP rise over time (both systolic and diastolic) in a healthy EU population; moreover the significance of different predictors was examined within subgroups defined by age and sex. This analysis showed that baseline BP was the principal determinant of follow-up BP in all age and sex groups. Obesity was the second most important predictor (BMI in adults aged 30-44 years; percent change in BMI in middle age people aged 45-60 years). Lifestyle factors influenced BP via their effect on BMI. People who maintained their BMI during the three year follow-up did not exhibit a rise in BP (whether systolic or diastolic). Other important predictors identified in this analysis were insulin sensitivity in middle aged women and hsCRP in adult men. The fifth study (chapter 7) evaluated the role of ethnicity in the development of cardiovascular disease in people with type 2 diabetes living in Scotland. Over a follow-up of seven years, Pakistani people had increased risk of CVD and Chinese people had decreased risk of CVD as compared to White population. Pakistanis had an increased risk of CVD at a younger age independent of other conventional risk factors. In summary, insulin sensitivity and inflammation influence blood pressure, but their role is not generalised across different age and sex groups. BMI and change in BMI are important predictors of follow-up BP in adults and middle age healthy people, supporting a role for maintenance of BMI in preserving cardiovascular health. In addition to the known ethnic differences in the development of diabetes, I identified ethnic differences in the development of CVD.
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Nowak, Christoph. "Insulin Resistance : Causes, biomarkers and consequences." Doctoral thesis, Uppsala universitet, Molekylär epidemiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316891.
Full textAbstract:
The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors. The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality. In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk. In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.
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Morin-Papunen, L. (Laure). "Insulin resistance in polycystic ovary syndrome." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514257405.
Full textAbstract:
Abstract
The polycystic ovary syndrome, described first as the association
of bilateral polycystic ovaries and amenorrhoea, oligomenorrhoea,
hirsutism and obesity, was later shown to be a complex metabolic syndrome.
The first purpose of this study was to investigate the occurrence
of hyperinsulinaemia and the severity of insulin resistance and
glucose tolerance disorders in polycystic ovary syndrome by means of
the oral glucose tolerance test and the euglycaemic hyperinsulinaemic
clamp. The next goal was to investigate whether women with polycystic
ovary syndrome would benefit from insulin-sensitising drugs, and
in particular to compare the effects of metformin and a contraceptive
pill containing ethinyl oestradiol and cyproterone acetate. Altogether,
81 women with polycystic ovary syndrome and 34 healthy control subjects
were involved in the study.
Marked impairment of insulin sensitivity in obese subjects
with polycystic ovary syndrome, including a decrease of both cellular
oxidative and non-oxidative utilisation of glucose, and a slight non-significant
decrease of insulin sensitivity in non-obese subjects was observed.
Both non-obese and obese subjects with polycystic ovary syndrome
exhibited increased abdominal obesity compared with the controls,
confirming the fact that obesity, in particular abdominal obesity,
is an important contributor in the development of insulin resistance
in this syndrome.
Metformin alleviated hyperandrogenism by essentially decreasing
ovarian, but not adrenal androgen secretion. The improvement of
hyperandrogenism and ovarian function seemed to be mediated by the
improvement of hyperinsulinaemia, which resulted itself from subtle
improvements in both hepatic insulin extraction and insulin sensitivity.
Metformin decreased abdominal obesity and the release of free fatty
acids from adipose tissue, and improved ovarian cyclicity and fertility.
The transient decrease in serum leptin levels observed may have
some role in the improvement of ovarian function. The contraceptive
pill significantly improved hyperandrogenism and hirsutism, and
it slightly affected glucose metabolism. Thus, it could be the treatment
of choice in women with hirsutism problems and no fertility hopes.
Metformin could be the drug of choice for women with polycystic
ovary syndrome who wish to conceive. Because of its beneficial metabolic
effects, the value of metformin in reducing the risk of cardiovascular
diseases in polycystic ovary syndrome needs to be further studied.
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Ortiz, Josiane Noveti Morais. "Adiponectina, TNF-'alfa' e IL-6 em pacientes portadores de obesidade grave : relação com a sensibilidade a insulina e com a tolerancia a glicose." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311987.
Full textAbstract:
Orientador: Sarah Monte AlegreDissertação (mestrado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-11T07:51:04Z (GMT). No. of bitstreams: 1 Ortiz_JosianeNovetiMorais_M.pdf: 1470071 bytes, checksum: 08c02e85220eefda78e3311ccc0a0153 (MD5) Previous issue date: 2007
Resumo: A obesidade é uma doença cuja prevalência vem aumentando de forma global em todas as faixas etárias, raças e em ambos os sexos, e está associada a altas taxas de morbidade e mortalidade. Obesos desenvolvem também hiperinsulinemia e resistência à insulina, o que pode levar ao aparecimento de diabetes tipo 2 (DM). Recentemente foi demonstrado que o tecido adiposo, mais que um local de acúmulo de reservas energéticas, desempenha papel de um verdadeiro órgão secretor de moléculas sinalizadoras (adipocinas) que atuam em diversos locais do organismo. O acúmulo de tecido adiposo causado pela obesidade acarreta um aumento da produção de adipocinas, como o Fator de Necrose Tumoral Alfa (TNF-a) e a Interleucina-6 (IL-6), que ao estimular a produção de proteínas de fase aguda pelo fígado, conduzem a um estado inflamatório subclínico, associado ao surgimento das comorbidades presentes na obesidade. A adiponectina, produzida pelo tecido adiposo, ao contrário, exerce um papel protetor, diminuindo a resistência à insulina, porém encontra-se paradoxalmente diminuída em obesos. Ajudar a entender as interações existentes entre obesidade, adipocinas e resistência à insulina, avaliando concentrações séricas de adiponectina, TNF-a, IL-6, Proteína C-reativa (CRP) em pacientes obesos graves com (IT) ou sem (NT) intolerância à glicose, bem como em controles, antes e após infusão de insulina, é o objetivo deste trabalho. Para tanto, 32 indivíduos obesos (15 NT, 11 IT e 6 DM; IMC=50,2±2,2; 48,3±2,2 e 51,0±3,0Kg/m2) e 9 indivíduos eutróficos (CT=22,3±0,6Kg/m2) classificados a partir de teste oral de tolerância à glicose, pareados por idade e sexo, realizaram clamp euglicêmico hiperinsulinêmico (180 min; infusão de insulina - 40µU/min·m2). Adiponectina, TNF-a, IL-6, e CRP foram dosados em jejum e aos 180 minutos do clamp. Antes do início do estudo foi realizada bioimpedância elétrica (BIA) para determinação da composição corporal. Os pacientes obesos eram resistentes à insulina (sensibilidade à insulina ou ¿M¿: NT=28,5±3,4 IT=23,3±1,6 e DM=16,8±3,4; todos p<0,001 vs. CT=52,5±2,7 µmol/min/KgMM). As concentrações basais de TNF-a, IL-6 e CRP eram similares entre os subgrupos de obesos, maiores que nos controles (todos p<0.01) e relacionadas independentemente ao IMC e/ou à % gordura corporal. As concentrações basais de adiponectina eram menores nos obesos (NT=7,5±1,4; IT=5,6±0,9; DM=3,3±0,7 vs. CT=11,6±1,4 µg/ml) e direta e independentemente relacionadas à sensibilidade à insulina e inversamente com as medidas de adiposidade, glicemia e insulinemia. A infusão de insulina diminuiu a adiponectinemia nos obesos independentemente do grau de tolerância à glicose (p =0,009) e exerceu pouco efeito sobre as demais citocinas. Portanto, as concentrações circulantes elevadas de TNF-a, IL-6 e CRP em pacientes com obesidade grau III não dependem do grau de tolerância à glicose e não se modificam sob infusão aguda de insulina. As concentrações circulantes de adiponectina encontram-se diminuídas, variando de acordo com o grau de tolerância à glicose, e sofrem ação inibitória da insulina. A hiperinsulinemia presente nos pacientes obesos pode contribuir para diminuir a adiponectinemia acarretando um aumento ainda maior da resistência à insulina e da conseqüente hiperinsulinemia
Abstract: Obesity is associated with a cluster of metabolic alterations such as insulin resistance, hypertension, and dyslipidemia and with a low-grade systemic inflammation, which is presumed to play a role in the development of insulin resistance, cardiovascular disease (CVD) and type 2 diabetes mellitus (DM). Adipocytokines or adipokines are synthesized by adipose tissue, released into the circulation and may act as signaling molecules. High circulating levels of Tumor Necrosis Factor-Alpha (TNF-a) and Interleukin-6 (IL-6) in adipose tissue have been demonstrated in obesity. Adiponectin, abundantly expressed in white adipose tissue, seems to play a protective role against atherosclerosis and insulin resistance but is decreased in obesity. The role of insulin sensitivity and insulin levels on the modulation of adiponectin concentrations in humans remains unclear. Aim: to evaluate the acute insulin effect on circulating adiponectin, TNF-a, IL-6 and C-reactive protein (CRP) and their relationship with insulin resistance in normal subjects and in class III obese subjects with normal (NGT) or impaired glucose tolerance (IGT). Methods: 32 obese, 15 NGT, 11 IGT and 6 DM subjects (BMI=50.2±2.2; 48.3±2.2 and 51.0±3.0Kg/m2) and 9 lean subjects (CT 22.3±0.6Kg/m2) received an OGTT and a 3h-euglycemic clamp (insulin infusion - 40µU/min·m2). Adiponectin, TNF-a, IL-6 and CRP were assayed at fasting and at 180min of insulin infusion. BIA was performed before the study to assess body composition. Results: Obese patients were insulin resistant (M:NGT=28.5±3.4; IGT=23.3±1.6 and DM=16.8±3.4; all p<0.001 vs. CT=52.5±2.7 µmol/KgFFM·min). Fasting TNF-a IL-6 and CRP were similar among obese subgroups, higher than CT (p<0.01) and related to BMI and/or fat mass. Adiponectin was lower in obese (NGT=7.55±1.26; IGT=5.55±0.95; DM=3.31±0.75 vs. CT=11.56±1.37 µg/ml) and directly and independently related to M after adjustment for waist, fat mass and BMI (p<0.001). Insulin infusion lowered adiponectin only in obese subjects and little affected the other cytokines. Discussion: In severely obese subjects, TNF-a, IL-6 and CRP are increased independently of glucose tolerance status, and are not affected in the short-term by insulin. Adiponectin levels are decreased in these subjects, according to the glucose tolerance degree, and are downregulated by insulin infusion. More importantly, the persistent hyperinsulinemia can contribute to reduce the adiponectin expression, contributing to further insulin resistance and hyperinsulinemia
Mestrado
Ciencias Basicas
Mestre em Clinica Medica