Rozprawy doktorskie: „Insulin signaling-Resistance”

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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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Nyman, Elin. "Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes". Doctoral thesis, Linköpings universitet, Avdelningen för cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-104725.

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Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant. The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments. We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells. In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes – and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state – an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV).

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Franck, Niclas. "On the importance of fat cell size, location and signaling in insulin resistance". Doctoral thesis, Linköping : Linköping University, 2009. http://www.bibl.liu.se/liupubl/disp/disp2009/med1123s.pdf.

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Yamada, Chizumi. "Genetic inactivation of GIP signaling reverses aging-associated insulin resistance through body composition changes". Kyoto University, 2008. http://hdl.handle.net/2433/135794.

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Lee, Nina Louise. "The roles of diet and SirT3 levels in mediating signaling network changes in insulin resistance". Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/81674.

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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2013.
Title as it appears in MIT Commencement Exercises program, June 2013: Signaling network changes in high fat diet-induced insulin resistance Cataloged from PDF version of thesis.
Includes bibliographical references (p. 73-80).
The goal of my research is to understand the mechanism by which high fat diets mediate insulin sensitivity and the role SirT3 plays in high fat diet-induced insulin resistance. Insulin resistance is defined as the inability of cells and tissues to respond properly to ordinary amounts of insulin and is a precursor to many metabolic diseases such as diabetes and cardiovascular disease. Obesity, brought on in large part by caloric excess from high fat diet feeding, is a major contributor to insulin resistance. The recent drastic increase in the prevalence of obesity makes it imperative that steps are taken to more effectively treat and cure obesity-linked diseases such as diabetes. To identify optimal therapeutic targets, it is crucial to first gain a mechanistic understanding of obesity-induced insulin resistance, and understand how specific changes in the signaling network affect insulin sensitivity. Previous work has demonstrated that levels of SirT3, a mitochondrial protein deacetylase, are diet dependent. Additionally, SirT3 expression levels have been shown to mediate insulin and glucose tolerance in animals in a diet-dependent manner. Perturbations in SirT3 levels also alter the levels of phosphorylation on several canonical insulin signaling proteins. In my research, I further investigated the link between SirT3, diet and insulin resistance from a signaling network perspective. Using mouse liver as a model system, I analyzed liver tissue from mice fed a normal diet (insulin sensitive) or mice fed a high fat diet, thus inducing insulin resistance. Quantification of phenotypic and network events in response to insulin and utilization of computational techniques revealed activated pathways and nodes mediating insulin response, some of which had not been previously associated with the canonical insulin signaling network. I extended the study to analyze the role SirT3 plays in diet-mediated insulin sensitivity by perturbing the level of SirT3 in mice on both normal chow and high fat diets. The results of this research are useful for designing more efficacious therapies to treat insulin resistance-induced diseases.
by Nina Louise Lee.
S.M.

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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 dépression
Insulin 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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Renström, Frida. "Fat cell insulin resistance : an experimental study focusing on molecular mechanisms in type 2 diabetes". Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1078.

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The aim of the present thesis was to further increase our understanding of mechanisms contributing to and maintaining cellular insulin resistance in type 2 diabetes (T2D). For this reason, the effects of high glucose and insulin levels on glucose transport capacity and insulin signaling, with emphasis on insulin receptor substrate 1 (IRS-1) were assessed in fat cells. Altered levels of IRS-1 have previously been observed in adipose tissue from insulin-resistant and T2D subjects. A high glucose level (≥15 mM) for 24 h exerted only a minor impairment on glucose transport capacity in human adipocytes, as opposed to rat adipocytes. However, when combined with a high insulin level (104 µU/ml), basal and insulin-stimulated glucose transport was significantly impaired in both human and rat adipocytes. This was associated with a depletion of IRS-1 and IRS-2 protein levels in rat adipocytes, as a result of post-translational changes and altered gene transcription, respectively. In human adipocytes was only IRS-1 protein levels reduced. The high glucose/high insulin setting achieved maximal impairment of glucose transport within 6 h. Subsequent incubations of rat adipocytes under physiological conditions could partially restore insulin sensitivity. Interestingly, in both human and rat fat cells, decreased levels of IRSs occurred after the establishment of impaired glucose transport, suggesting that the observed depletion of IRSs is a consequence rather than a cause of insulin resistance. Nonetheless, IRS depletion is likely to further aggravate insulin resistance. Tyrosine phosphorylation of IRS-1 upon insulin stimulation activates the signaling pathway that mediates glucose transport. Pre-treatment of human adipocytes with high glucose and insulin levels was not associated with any alterations in the total IRS-1 Tyr612 phosphorylation following 10 min insulin stimulation. However, a significant increase in basal Tyr612 phosphorylation was observed. Furthermore, a rise in basal IRS-1 Ser312 phosphorylation was found. This is associated with reduced IRS-1 function and is considered to target IRS-1 to degradation pathways, and thus could potentially explain the observed decrease in IRS-1 protein levels. Our results imply an enhanced activation of insulin’s negative-feedback control mechanism that inhibit IRS-1 function. This could potentially have contributed to the observed impairment of insulin action on glucose transport in these cells. Accordingly, we have also shown that the downstream activation of protein kinase B upon insulin-stimulation is significantly impaired in human adipocytes exposed to the high glucose/high insulin setting, indicating a defect in the signaling pathway mediating glucose transport. We also investigated whether there are humoral factors in the circulation of T2D patients that contribute to peripheral insulin resistance. Human adipocytes cultured for 24 h in medium supplemented with 25% serum from T2D subjects, as compared to serum from non-diabetic subjects, displayed significantly reduced insulin-stimulated glucose uptake capacity. The effect could neither be attributed to glucose, insulin, FFA, TNF-α or IL-6 levels in the serum, but other circulating factor(s) seem to be of importance. In conclusion, chronic conditions of elevated glucose and/or insulin levels all impair insulin action on glucose turnover, but to different extents. A clear distinction between rat and human fat cells in the response to these different milieus was also observed. Alterations in the function of the key insulin signaling protein IRS-1 might be involved in the mechanisms underlying the impaired glucose uptake capacity. IRS-1 reduction however, occurs after but probably aggravates the existing insulin resistance. The effects of high glucose and/or insulin levels may be of importance in T2D, but additional novel factors present in the circulation of T2D patients seem to contribute to cellular insulin resistance.

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Araújo, Michella Soares Coelho. "Obesidade e resistência à insulina induzida pela restrição crônica no consumo de sal em ratos Wistar: efeitos sobre o balanço energético, sistema renina-angiotensina (SRA) e sinalização da insulina". Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-15012007-134042/.

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A restrição de sal na dieta está associada com resistência à ação da insulina e obesidade. O mecanismo molecular pelo qual a dieta hipossódica (HO) pode induzir resistência à insulina e obesidade não está totalmente compreendido. O objetivo do presente estudo foi avaliar a influência da ingestão crônica de sal sobre o peso corporal (PC), sinalização da insulina no fígado, músculo e tecido adiposo branco (TAB) e sua associação com adiposidade e resistência à insulina. Com esta finalidade, ratos Wistar foram alimentados com dieta HO, normossódica (NR) ou hipersódica (HR) desde o desmame. O PC foi avaliado desde o desmame. Ao completarem 12 semanas de vida, foram avaliados pressão arterial, balanço energético, consumo de ração, glicemia, angiotensina II (ANGIO II) plasmática e perfil hormonal. A atividade motora espontânea foi estudada em ratos com 8 e 12 semanas. A sensibilidade à insulina foi analisada pelo índice de HOMA. A expressão da proteína desacopladora mitocondrial 1 (UPC-1) foi quantificada no tecido adiposo marrom (TAM) e o conteúdo de ANGIO II no TAM, TAB e hipotálamo. As etapas iniciais da sinalização da insulina foram avaliadas por imunoprecipitação e immunoblotting das proteínas envolvidas como o receptor da insulina (IR), substrato 1 e 2 do IR (IRS-1 e IRS-2), enzima fosfatidilinositol 3 quinase (PI-3q), proteína quinase B (Akt/PKB), ativação da proteína c-jun NH2-terminal quinase (JNK) e fosforilação em serina 307 do IRS-1. O PC no desmame foi semelhante entre os grupos de dieta. No entanto, na idade adulta os ratos em dieta HO apresentaram maior PC, adiposidade visceral, glicemia e insulinemia de jejum, concentração de ANGIO II plasmática e aumento do conteúdo de ANGIO II no TAM. Por outro lado, nestes mesmos animais a dieta HO diminuiu o consumo de ração, o gasto energético, a expressão da proteína UCP-1, adiponectina plasmática e o conteúdo de ANGIO II no TAB. A atividade motora não foi diferente entre os grupos estudados. A dieta HO diminuiu a via IR/PI-3q/Akt/Foxo1 de sinalização da insulina no fígado e músculo. Por outro lado, parte desta via (IRS-2/Akt/Foxo1) mostrou-se aumentada no TAB. No fígado e músculo houve um aumento da fosforilação da proteína JNK associada com maior fosforilação do IRS-1ser307 no grupo HO. Em conclusão, a restrição ou sobrecarga crônica de sal altera a evolução ponderal associada com modificações no balanço energético e no perfil hormonal na idade adulta. A resistência à insulina induzida pela dieta HO é tecido-específico e foi acompanhada por uma ativação da proteína JNK e um aumento da fosforilação dos resíduos de serina 307 do IRS-1.
Restriction of sodium chloride intake has been associated with insulin resistance (INS-R) and obesity. The molecular mechanisms by which the low salt diet (LSD) can induce INS-R and obesity have not yet been established.The aim of the present study was to evaluate the influences of salt intake on body weight (BW) and on insulin signaling in liver, muscle and white adipose tissue (WAT). Wistar rats were fed a LSD, normal (NSD), or high (HSD) salt diet since weaning. At 12 weeks of age, BW, blood pressure(BP),energy balance, food intake, plasma glucose and angiotesin II (ANGIO II), and hormonal profile were evaluated. Afterward, motor activity, HOMA index, uncoupling protein 1 expression (UCP-1) and tissue adipose ANGIO II content was determined. The early steps of insulin signaling (IR: insulin receptor, IRS-1 and IRS-2: IR substrate 1 and 2, PI-3K: phosphatidylinositol 3-kinase), Akt (protein kinase B) phosphorylation, JNK (c-jun NH2-terminal kinase) activation and IRS-1ser307 (serine 307 of IRS-1) phosphorylation were evaluated by immunoprecipitation and immunoblotting. LSD increased BW, visceral adiposity, blood glucose, insulin, leptin, plasma ANGIO II and its content in BAT. Otherwise, LSD decreased food intake, energy expenditure, UCP-1 expression, adiponectin and ANGIO II content in WAT. Motor activity was not influenced by the dietary salt content. In LSD, a decreasing in IR/PI-3K/Akt/Foxo1 was observed in liver and muscle and an increase in this pathway was showed in adipose tissue. JNK activity and IRS-1ser307 phosphorylation were higher in liver and muscle. In conclusion, LSD induced obesity and insulin resistance due to changes in energy expenditure, SRA and insulin signaling. The INS-R is tissuespecific and is accompanied by JNK activation and IRS-1ser307 phosphorylation.

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Steiler, Tatiana L. "Kinase cascades in the regulation of glucose homeostasis /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-201-2/.

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Schäfer, Alexander [Verfasser], Jerzy [Akademischer Betreuer] Adamski, Bernhard [Akademischer Betreuer] Küster i Marius [Akademischer Betreuer] Ueffing. "The Epoxyeicosatrienoic Acid Pathway Enhances Hepatic Insulin Signaling and Is Repressed In High Fat Diet Induced Hepatic Insulin Resistance : A proteomic study / Alexander Schäfer. Betreuer: Jerzy Adamski. Gutachter: Bernhard Küster ; Jerzy Adamski ; Marius Ueffing". München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1085023532/34.

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Matos, Mariana Aguiar de. "O efeito do treinamento intervalado de alta intensidade em componentes celulares e moleculares relacionados ? resist?ncia ? insulina em indiv?duos obesos". UFVJM, 2016. http://acervo.ufvjm.edu.br/jspui/handle/1/1337.

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Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG)
Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq)
Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES)
O excesso de gordura corporal caracter?stico da obesidade est? relacionado a diversas altera??es metab?licas, que incluem a resist?ncia ? insulina. Dentre as medidas n?o farmacol?gicas empregadas para a melhora da sensibilidade ? insulina est? o treinamento f?sico aer?bio, como o treinamento intervalado de alta intensidade (HIIT, do ingl?s high intensity interval training). Sendo assim, esse estudo avaliou os efeitos do HIIT em componentes bioqu?micos, celulares e moleculares relacionados ? resist?ncia ? insulina em obesos. Indiv?duos obesos sens?veis (n=9) e resistentes ? insulina (n=8) foram submetidos a 8 semanas de HIIT, em cicloerg?metro, realizado 3 vezes por semana, com intensidade e volume progressivos (8 a 12 est?mulos; 80 a 110% da pot?ncia m?xima). Amostras de sangue venoso e do m?sculo vasto lateral foram obtidas antes e ap?s o programa de HIIT. Ap?s o programa de treinamento houve aumento da sensibilidade ? insulina nos obesos resistentes ? insulina, mas n?o houve redu??o da massa de gordura. A concentra??o de citocinas no soro, o estresse oxidativo sist?mico e frequ?ncia das c?lulas imunes n?o foram modificadas ap?s o treinamento. No m?sculo esquel?tico, o HIIT promoveu aumento da fosforila??o do substrato do receptor de insulina (IRS) (Tyr612), da Akt (Ser473) e da prote?na quinase dependente de c?lcio/calmodulina (CAMKII) (Thr286), e aumento do conte?do da ?-hidroxiacil-CoA desidrogenase (?-HAD) e citocromo C oxidase (COX-IV). Houve ainda, redu??o da fosforila??o da quinase regulada por sinal extracelular (ERK1/2) nos obesos resistentes ? insulina. Conclu?mos que 8 semanas de HIIT promoveram melhora da sensibilidade ? insulina, modificou componentes da via de sinaliza??o da insulina e do metabolismo oxidativo no m?sculo esquel?tico. Essas altera??es ocorreram independentes de mudan?as na gordura corporal total e de par?metros inflamat?rios sist?micos.
Tese (Doutorado) ? Programa Multic?ntrico de P?s-Gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2016.
Obesity is characterized by excess of body fat, and its development can lead to a variety of metabolic disorders, including insulin resistance. Exercise is recognized as a non-pharmacological approach to increasing skeletal muscle insulin sensitivity, although the mechanisms are not elucidated. Additionally, the understanding of high intensity interval training (HIIT, high intensity interval training) treat insulin resistance is less understood. Therefore, this study evaluated the effects of HIIT on biochemical, molecular, and cellular markers related to insulin resistance in sedentary obese individuals. Sensitive (n=9) and insulin resistant (n=8) obese individuals (body mass index ? 30 kg/m-2) were engaged in 8 weeks of HIIT using a cycle ergometer. The HIIT was performed 3 times a week, and its intensity and volume progressively increased throughout the training period (from 8 to 12 stimuli; from 80 to 110% of the maximum power). Venous blood and the vastus lateralis muscle samples were obtained before and after the HIIT. HIIT enhanced insulin sensitivity in insulin-resistant obese individuals without changing body fat mass. Cytokine concentration in serum, blood oxidative stress, and frequency of some immune cells were not altered by HIIT. In skeletal muscle, HIIT increased the phosphorylation of insulin receptor substrate (IRS) (Tyr612), Akt (Ser473), and protein kinase dependent calcium/calmodulin (CaMKII) (Thr286). HIIT also increased the expression of ?-hydroxyacyl-CoA dehydrogenase (?-HAD) and cytochrome C oxidase (COX-IV). A reduction of the kinase phosphorylation of extracellular signal-regulated (ERK1/2) was only seen in obese insulin resistant individuals. The results show that 8 weeks of HIIT enhanced insulin sensitivity, modified components of the insulin-signaling pathway, and improved skeletal muscle oxidative metabolism. These changes were independent of alterations in body fat and inflammatory parameters.

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La, Bounty Paul Willoughby Darryn Scott. "The effects of heavy resistance exercise in combination with orally administered branched-chain amino acids or leucine on insulin signaling and Akt/mTOR pathway activity in active males". Waco, Tex. : Baylor University, 2007. http://hdl.handle.net/2104/5069.

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Marçal, Anderson Carlos. "Dieta normocalórica de ácidos graxos de cadeia média: Efeitos sobre a secreção de insulina, tecido adiposo e fígado de ratos jovens". reponame:Repositório Institucional da UFS, 2009. https://ri.ufs.br/handle/riufs/1040.

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A suplementação dietética com AGCM induz resistência à insulina, redução de peso ponderal e aumento da adiposidade em ratos Wistar. Adipócitos isolados apresentam reduzidas captação de glicose estimulada por insulina e atividade/fosforilação da proteína AMPK. A expressão protéica do IR no tecido hepático está aumentada em animais tratados com AGCM com redução do grau de fosforilação, enquanto que o grau de fosforilação da proteína AKT permaneceu semelhante entre os grupos. Ilhotas pancreáticas isoladas apresentam redução na secreção de insulina quando incubadas com altas concentrações de glicose, diminuição do conteúdo total de insulina, hipersensibilidade a leucina e/ou arginina e aumento do percentual de morte celular com diminuída expressão da proteína AKT_1 . Desta forma, utilização em longo prazo dessa estratégia nutricional pode interferir no crescimento normal do indivíduo, na sensibilidade à insulina e possívelmente, desenvolvimento e instalação do diabetes. _______________________________________________________________________________________ ABSTRACT: The introduction of MCFA into diet induces insulin resistance, reduced body weight gain, and increased adiposity in Wistar rats. Isolated adipocytes have reduced insulin induced glucose uptake and phosphorylation/activation of AMPK protein. The insulin receptor protein expression is increased in liver of MCFA fed rats accompanied by reduced tyrosine phosphorylation, with similar AKT serine phosphorylation. Isolated pancreatic islets had reduced glucose stimulated insulin secretion due to high glucose exposure and reduced insulin content; higher insulin secretion induced by leucine and arginine, and increased apoptosis with reduced AKT protein level. In these regard, the chronic ingestion of MCFA may interfere with normal body growth, with the insulin sensitivity and may participate with the development of diabetes.

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Moughaizel, Michelle. "Metabolic and cardiovascular effects of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway modulation : Study in the WHHL rabbit as an experimental model of high fructose high fat diet-induced metabolic syndrome". Thesis, Nantes, Ecole nationale vétérinaire, 2020. http://www.theses.fr/2020ONIR151F.

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Le syndrome métabolique (SMet) est caractérisé par la présence chez le même individu de plusieurs anomalies parmi les suivantes: une adiposité abdominale, une insulino-résistance (IR), une intolérance au glucose, une hypertension artérielle et une dyslipidémie. Des études ont révélé que la modulation de la voie de signalisation NO/GMPc dans le SMet peut exercer des effets métaboliques et cardiovasculaires protecteurs. Nous avons exploré, dans ce contexte, l'effet du mirabegron et du BAY 41-2272, deux molécules connues pour leur capacité à activer la voie NO-GMPc. Nous avons d'abord développé un modèle animal expérimental avec deux facteurs principaux du SMet, la dyslipidémie et l’IR. Nos résultats ont montré qu'après 12 semaines d'alimentation riche en fructose et en graisses (HFFD), le lapin Watanabe (WHHL), un modèle animal de dyslipidémie spontanée, présentait une intolérance au glucose, une IR (test HOMA-IR), une aggravation de la dyslipidémie et une diminution de la contractilité cardiaque (approche ex-vivo). Après 12 semaines de traitement, le mirabegron et le BAY 41-2272 ont prévenu le gain de poids et l’augmentation du taux de TG et ont amélioré la sensibilité à l'insuline, la fonction endothéliale des artères carotides et la fonction cardiaque (mirabegron). Ce travail a permis de mettre en place un modèle expérimental combinant la dyslipidémie et l’IR chez le lapin WHHL. De plus, les résultats ont montré que l'activation à long terme de la voie de signalisation NO-GMPc représente une approche pharmacologique prometteuse dans la gestion des complications métaboliques et cardiovasculaires associées au SMet
Metabolic syndrome (MetS) is characterized by abdominal adiposity, insulin resistance (IR), glucose intolerance, arterial hypertension and dyslipidemia. Experimental studies have revealed that modulation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway in MetS can exert protective metabolic and cardiovascular effects. In this regard, we explored the effect of mirabegron and BAY 41-2272, two molecules known for their ability to activate the NO-cGMP pathway. We first developed an experimental animal model with two main components of the MetS, dyslipidemia and IR. Our results showed that after 12 weeks of high-fructose high-fat diet (HFFD) feeding, the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of spontaneous dyslipidemia, exhibited glucose intolerance, IR (HOMA-IR test), an aggravation in dyslipidemia and a decrease in cardiac contractility (ex-vivo approach). Twelve weeks of mirabegron and BAY 41-2272 treatment prevented weight gain and the increase in TG levels and improved insulin sensitivity, carotid endothelial function, and cardiac function (mirabegron). We were able to develop an experimental model combining dyslipidemia and IR in the WHHL rabbit. Furthermore, our results showed that long-term activation of the NO-cGMP signaling pathway represents a promising pharmacological approach in the management of the MetS and its metabolic and cardiovascular consequences

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15

Sun, Zheng. "IMIDAZOLINE RECEPTORS IN INSULIN SIGNALING AND METABOLIC REGULATION". Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1157694260.

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16

Shi, Xiarong. "Mitochondrial Dysfunction and AKT Isoform-Specific Regulation in 3T3-L1 Adipocytes: A Dissertation". eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/505.

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Excess food consumption and/or lack of exercise have dramatically contributed to the prevalence of overweight (BMI≥25) and obesity (BMI≥30) in modern society. The obesity epidemic has been linked to the rise in type 2 diabetes. In recent years, evidence has pointed to a close association between mitochondrial dysfunction in white adipose tissue (WAT) and insulin resistance, a key feature of type 2 diabetes. In order to dissect the cause and effect relationship between WAT mitochondrial dysfunction and insulin resistance, we established an in vitro cell line system to investigate this issue. We artificially introduced mitochondrial dysfunction in 3T3-L1 adipocytes by depleting the mitochondrial transcription factor A (Tfam) during adipogenesis, without changing the overall adipocyte differentiation program. We found that these Tfam-depleted 3T3-L1 adipocytes showed symptoms of insulin resistance, evidenced by impaired insulin stimulated GLUT4 translocation and glucose uptake. This result suggested that mitochondrial dysfunction could be a primary contributor to insulin resistance in fat tissue. However, the exact mechanism underlying this finding remains unclear. As part of a comprehensive understanding of insulin signaling in fat cells, we also investigated the involvement of the endosomal protein WDFY2 in the regulation of Akt isoform-specific effect on glucose uptake. In 3T3-L1 adipocytes, both Akt1 and Akt2 isoforms are expressed, but only Akt2 plays an indispensible role in insulin-stimulated GLUT4 translocation and glucose uptake. Previous studies implied that endosomal proteins may take a part in determining Akt substrate specificity. Here we found that WDFY2 preferentially co-localized with Akt2 and that knockdown of WDFY2 inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes, suggesting that endosomes are involved in this regulation. The effect of WDFY2 knockdown on insulin-stimulated glucose uptake worked through the down-regulation of Akt2, but not Akt1, protein level. We concluded that, endosomal protein WDFY2, by preferentially interacting with Akt2, regulates insulin signaling in glucose uptake in 3T3-L1 adipocytes. Our findings may help to develop specific therapeutic interventions for treatment of insulin resistance and type 2 diabetes.

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17

Karlsson, Håkan K. R. "Insulin signaling and glucose transport in insulin resistant human skeletal muscle /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-469-4/.

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18

Liu, Danting. "RNASE L MEDIATES GLUCOSE HOMEOSTASIS THROUGH REGULATING THE INSULIN SIGNALING PATHWAY". Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1544627440336052.

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19

Shonesy, Brian Christopher Suppiramaniam Vishnu. "Insulin signaling and synaptic physiology insights into the pathogenesis of Alzeimer's disease /". Auburn, Ala, 2009. http://hdl.handle.net/10415/1772.

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20

Chriett, Sabrina. "Epigenetic regulations by insulin and histone deacetylase inhibitors of the insulin signaling pathway in muscle". Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1167/document.

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L’émergence et le développement des maladies métaboliques est sous le contrôle de multiples facteurs génétiques et environnementaux. Le diabète et la résistance à l’insuline sont des maladies métaboliques caractérisées par des défauts dans la sécrétion de l’insuline ou son utilisation périphérique, ou les deux. L’insuline est l’hormone clé de l’utilisation du glucose, et régule également transcriptionnellement et épigénétiquement l’expression des gènes.En travaillant sur le muscle, l’implication de l’épigénétique dans la régulation de l’expression des gènes de la voie de l’insuline a été mis en évidence. L’hexokinase 2 (HK2) est régulée par l’insuline et participe au métabolisme glucidique. Le rôle de l’épigénétique y est démontré avec l’augmentation de l’acétylation des histones autour du site d’initiation de la transcription (SIT) de HK2 et l’accumulation d’une isoforme permissive des histones, H2A.Z. Ces deux phénomènes sont le signe d’une transcription permissive.Nous avons ensuite étudié le rôle de l’acétylation des histones dans les régulations amenées par l’insuline dans les myotubes L6. Nous avons utilisé le butyrate, un inhibiteur des histones deacetylase (HDACi), dans un contexte d’insulino-résistance induite par une lipotoxicité. Le butyrate a en partie restauré la sensibilité à l’insuline visible au niveau des phosphorylations de la PKB (protein kinase B) et de la MAPK (Mitogen-activated protein kinase), inhibées par le traitement au palmitate. Le butyrate a augmenté l’expression de l’ARNm et de la protéine d’IRS1. La surexpression génique d’IRS1 est épigénétique-dépendante car liée à une augmentation de l’acétylation des histones au SIT d’IRS1.L’ensemble de ces résultats démontre l’existence d’un lien entre les modifications épigénétique et l’action de l’insuline. Cela suggère qu’une intervention pharmacologique sur la machinerie épigénétique pourrait être un moyen d’améliorer le métabolisme, et l’insulino-résistance
Diabetes and insulin resistance are metabolic diseases characterized by altered glucose homeostasis due to defects in insulin secretion, insulin action in peripheral organs, or both. Insulin is the key hormone for glucose utilization and regulates gene expression via transcriptional and epigenetic regulations.We determined the epigenetic implications in the regulation of expression of insulin signaling pathway genes. Hexokinase 2 (HK2) is known to be upregulated by insulin and directs glucose into the glycolytic pathway. In L6 myotubes, we demonstrated that insulin-induced HK2 gene expression rely on epigenetic changes on the HK2 gene, including an increase in histone acetylation around the transcriptional start site (TSS) of the gene and an increase in the incorporation of the histone H2A.Z isoform – a histone variant of transcriptionally active chromatin. Both are epigenetic modifications compatible with increased gene expression.To elucidate the role of histone acetylation in the regulation of insulin signaling and insulin-dependent transcriptional responses in L6 myotubes, we investigated the effects of butyrate, an histone deacetylase inhibitor (HDACi), in a model of insulin resistance induced by lipotoxicity. Butyrate partly alleviated palmitate-induced insulin resistance by ameliorating insulin-induced PKB (protein kinase B) and MAPK (Mitogen-activated protein kinase) phosphorylations, downregulated with exposure to palmitate. Butyrate induced an upregulation of IRS1 gene and protein expression. The transcriptional upregulation of IRS1 was proven to be epigenetically regulated, with butyrate promoting increased histone acetylation around the TSS of the IRS1 gene.These results support the idea of the existence of a link between epigenetic modifications and insulin action. Pharmacological targeting of the epigenetic machinery might be a new approach to improve metabolism, especially in the insulin resistant condition.Key words: Muscle, insulin resistance, epigenetic, chromatin, histone acetylation, histone deacetylase inhibitor (HDACi), butyrate, palmitate

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21

Druwe, Ingrid Leal. "The Role of Arsenite in the Induction of C-Reactive Protein and Aberrant Insulin Signaling". Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/247276.

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Metabolic syndrome affects approximately 25% of the US population and increases risk for the development of cardiovascular disease, as well as, and Type 2 diabetes. Inorganic arsenite exposure has been associated with cardiovascular disease, insulin resistance and Type 2 diabetes. The mechanisms by which arsenic increases these health risks has not been fully elucidated. In this report we show two pathways by which arsenite may contribute to metabolic syndrome. First through induction of C-Reactive Protein (CRP) and secondly through inhibition of insulin stimulated glucose uptake. CRP is a clinical marker for metabolic syndrome and a predictive clinical marker for cardiovascular disease and type 2 diabetes. Treatment of HepG2 cells with arsenite resulted in elevated CRP production and secretion. In addition, treatment of FvB mice with 100 ppb sodium arsenite via drinking water for six months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-3), a mouse kidney cell line, were stimulated with CRP, which resulted in activation of NFkappaB. Pretreatment with Y27632, a Rho kinase inhibitor, prior to CRP stimulation attenuated NFkappaB activation. Additionally, L6 myocytes, an insulin responsive cell line, exposed to arsenite for 4 or 7 days showed decreased insulin-stimulated glucose uptake but no decrease in AKT activation. In addition, we found that ERK activity decreased, while p38 MAPK activity increased, in response to prolonged arsenite treatment. These data support the epidemiological evidence that chronic exposure to low physiologically relevant levels of arsenite can contribute to insulin resistance and type 2 diabetes. These data provide a novel pathway by which arsenic can contribute to metabolic syndrome, cardiovascular disease, insulin resistance and type 2 diabetes.

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22

Gao, Hui. "Estrogen signaling in metabolic disease : a functional genomics approach /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-974-2/.

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23

Shi, Xiarong. "Mitochondrial Dysfunction and AKT Isoform-Specific Regulation in 3T3-L1 Adipocytes: A Dissertation". eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/505.

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Excess food consumption and/or lack of exercise have dramatically contributed to the prevalence of overweight (BMI≥25) and obesity (BMI≥30) in modern society. The obesity epidemic has been linked to the rise in type 2 diabetes. In recent years, evidence has pointed to a close association between mitochondrial dysfunction in white adipose tissue (WAT) and insulin resistance, a key feature of type 2 diabetes. In order to dissect the cause and effect relationship between WAT mitochondrial dysfunction and insulin resistance, we established an in vitro cell line system to investigate this issue. We artificially introduced mitochondrial dysfunction in 3T3-L1 adipocytes by depleting the mitochondrial transcription factor A (Tfam) during adipogenesis, without changing the overall adipocyte differentiation program. We found that these Tfam-depleted 3T3-L1 adipocytes showed symptoms of insulin resistance, evidenced by impaired insulin stimulated GLUT4 translocation and glucose uptake. This result suggested that mitochondrial dysfunction could be a primary contributor to insulin resistance in fat tissue. However, the exact mechanism underlying this finding remains unclear. As part of a comprehensive understanding of insulin signaling in fat cells, we also investigated the involvement of the endosomal protein WDFY2 in the regulation of Akt isoform-specific effect on glucose uptake. In 3T3-L1 adipocytes, both Akt1 and Akt2 isoforms are expressed, but only Akt2 plays an indispensible role in insulin-stimulated GLUT4 translocation and glucose uptake. Previous studies implied that endosomal proteins may take a part in determining Akt substrate specificity. Here we found that WDFY2 preferentially co-localized with Akt2 and that knockdown of WDFY2 inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes, suggesting that endosomes are involved in this regulation. The effect of WDFY2 knockdown on insulin-stimulated glucose uptake worked through the down-regulation of Akt2, but not Akt1, protein level. We concluded that, endosomal protein WDFY2, by preferentially interacting with Akt2, regulates insulin signaling in glucose uptake in 3T3-L1 adipocytes. Our findings may help to develop specific therapeutic interventions for treatment of insulin resistance and type 2 diabetes.

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24

Fang, Youjia. "The Novel Role of Interleukin-1 Receptor-Associated Kinase 1 in the Signaling Process Controlling Innate Immunity and Inflammation". Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/32331.

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Obesity-induced chronic inflammation plays a key role in the pathogenesis of insulin resistance and the metabolic syndrome. Proinflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signaling transduction. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a serine/threonine kinase functioning in Toll-like Receptor signaling pathways, and plays an important role in inflammation and immune response. In our studies, we demonstrated that IRAK-1 is involved with the negative regulation of PI3K-Akt dependent signaling pathway induced by insulin and TLR 2&4 agonists. Out data also indicate that IRAK-1 can interact with IRS-1 protein both in vivo and in vitro. The binding sites for the IRAK1-IRS1 biochemical interaction are IRS-1â s PH domain and IRAK-1â s proline-rich LWPPPP motif. Our studies also indicate that IRAK-1 is involved with the negative regulation of glycogen synthesis through inhibiting PI3K-Akt signaling pathway and thus releasing GSK3Î²â s inhibitory effect on glycogen synthase. Moreover, our studies also suggest that IRAK-1 is involved in the activation of transcription factors CREB and ATF-1 by stimulating CREB-Ser133 and ATF-1 phosphorylation. CREB transcription factor family induces genes involved in cellular metabolism, gene transcription, cell cycle regulation, cell survival, as well as growth factor and cytokine genes. That may partially explain our finding that IRAK-1 may be also involved with cell proliferation and survival pathway.
Master of Science

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25

Frazier, Hilaree N. "Exploring the Role of Insulin Receptor Signaling in Hippocampal Learning and Memory, Neuronal Calcium Dysregulation, and Glucose Metabolism". UKnowledge, 2019. https://uknowledge.uky.edu/pharmacol_etds/32.

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In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the importance of insulin and its related actions in the brain are robustly supported, the distinct mechanisms and pathways that mediate these effects remain unclear. To address this, I conducted a series of experiments exploring the impact of insulin on memory and learning in two models: primary hippocampal cell cultures and the Fisher 344 animal model of aging. These studies attempted to identify relationships between insulin receptor signaling, neuronal gene expression, glucose metabolism, and calcium homeostasis in the hippocampus using either expression of a constitutively active human insulin receptor or administration of intranasal insulin. The following dissertation summarizes this work and provides valuable insights into the potential pathways mediating these relationships. Of note, intranasal studies reported that insulin is able to significantly alter gene expression patterns in the hippocampus of both young and aged rats following chronic, repeated exposure to the ligand. In cell culture, constitutive insulin signaling correlated with significantly elevated neuronal glucose uptake and utilization, as well as with significant alterations in the overall expression and localization of the neuron-specific glucose transporter 3. Interestingly, continued activity of the insulin receptor did not appear to alter voltage-gated calcium channels in hippocampal neurons despite prior evidence of the ligand’s role in other calcium-related processes. The results reported in this manuscript suggest that in the brain, insulin may be involved in a myriad of complex and dynamic events dependent on numerous variables, such as age, length of the exposure, and/or the insulin formulation used. Nevertheless, this work highlights the validity of using insulin to ameliorate age-related cognitive decline and supports the need for further studies exploring alternative approaches to enhance insulin receptor signaling in the brain.

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26

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 synucléinopathie
This 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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27

Helsley, Robert N. "THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE". UKnowledge, 2016. http://uknowledge.uky.edu/pharmacol_etds/14.

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Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. The work herein identified several widely used pharmaceutical agents and endocrine disrupting chemicals as PXR-selective agonists such as drugs involved in HIV therapy and phthalates/phthalate substitutes, respectively. We investigated the role of amprenavir, an HIV protease inhibitor, and tributyl citrate, a phthalate substitute, on PXR-dependent alterations in lipoprotein metabolism. Acute exposure with either xenobiotic in mice elicited increases in the proatherogenic LDL-cholesterol levels in a PXR-dependent manner. PXR activation significantly induced expression of genes involved in intestinal lipid metabolism. Further, we went on to identify the intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), as a direct PXR-target gene. PXR activation also stimulated cholesterol uptake in both murine and human intestinal cells. Moreover, we provide evidence that the microsomal triglyceride transfer protein (MTP) may be a direct PXR-target gene. Taken together, these findings provide critical mechanistic insight into the role of xenobiotic-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of xenobiotics on CVD risk in humans. In addition to PXR signaling, we investigated the role of IκB kinase β (IKKβ), a central coordinator of inflammation, in adipocyte progenitor cells. Targeting IKKβ in adipose progenitor cells resulted in decreased high fat diet (HFD)-elicited adipogenesis, while protecting mice from inflammation and associated insulin resistance. Consistently, we discovered that IKKβ inhibition by antisense oligonucleotides ablated HFD-induced adiposity, while protecting mice against associated metabolic disorders. In conclusion, targeting IKKβ with antisense therapy may present as a novel therapeutic approach to combat obesity and metabolic dysfunctions.

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28

Young, James L. "Innate Immunity in Type 2 Diabetes Pathogenesis: Role of the Lipopolysaccharide Signaling Cascade: A Dissertation". eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/400.

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Once seen as a disease of wealthy nations, type 2 diabetes mellitus is now showing unprecedented growth throughout the world, fueling increases in microvascular and macrovascular complications. A compelling and growing body of evidence suggests that glucose intolerance and insulin resistance, hallmarks of the diabetic patient, may be driven by chronic inflammation. In particular, a predominance of visceral fat has been associated with enhanced inflammatory cytokine secretion that may contribute to enhanced risk of diabetes and comorbid cardiovascular disease in these individuals. As a function of its potency and wide environmental and biological distribution, we hypothesized that bacterial lipopolysaccharide (LPS, also known as endotoxin) may promote adipose inflammation and concomitant metabolic dysfunction. Indeed, expression of the LPS receptor CD14 is enhanced on visceral adipocytes of ob/ob mice, paralleling enhanced IL-6 secretion ex vivo. Furthermore, rosiglitazonefed ob/obmice demonstrated a reduction in CD14 that coordinated with diminished IL-6 secretion, suggesting a basis for the touted anti-inflammatory effects of this commonly employed type 2 diabetes medication. Mice deficient in components of the LPS signaling cascade, namely CD14, TLR4, and MyD88, yielded adipocytes with markedly attenuated IL-6 secretion, corroborating the central importance of LPS in adipocyte inflammation and supporting the role of this signaling pathway in depot-specific inflammation. Despite the prominent role of LPS signaling in adipocyte inflammation, CD14-, TLR4-, and MyD88-deficient mice failed to show resistance to diet induced obesity. Surprisingly, cd14-/- and tlr4-/- mice had marked glucose intolerance without alteration in total weight or adipose accumulation. In contrast, myd88-/- mice revealed minor glucose intolerance only with high fat diet challenge at an advanced age despite being overtly obese. In cd14-/- and tlr4-/-, but not myd88-/-, mice, an exaggerated rebound to hypoglycemia was associated with enhanced norepinephrine secretion, which could be abrogated by the adrenergic β-blocker propranolol. The overlay of these mouse models reveals a divergence of phenotypes that demonstrate LPS signaling disruption may lead to glucose intolerance and insulin resistance in part due to enhanced sympathoadrenal tone, uncovering an essential role of innate immunity in physiological stress and its impact upon glucose homeostasis.

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29

Juan, Yu Cheng, i 阮裕程. "Effect of diet-induced insulin resistance on brain insulin signaling pathway and glucose uptake". Thesis, 2009. http://ndltd.ncl.edu.tw/handle/34082862400673047854.

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碩士
長庚大學
生物醫學研究所
97
Environmental factors and changes in lifestyle are considered the major contributors in the global epidemic of metabolic syndrome. Metabolic syndrome is characterized by a group of risk factors in a person. These include: insulin resistance or glucose intolerance, central obesity, dyslipidemia (high triglycerides and low HDL cholesterol), and hypertension. People with metabolic syndrome are at increased risk of cardiovascular diseases and type 2 diabetes. Insulin and its receptor have both recently been identified in the central nervous system (CNS); the biological function of insulin on the CNS includes maintenance of normal neuron function, regulation of food intake, inhibition of hepatic gluconeogenesis, and its influence on reproduction and cognition. The present study aims to investigate the role of different diet components in peripheral insulin resistance and examine the effects of diet components on brain glucose uptake and insulin signaling. Male Sprague-Dawley rats were fed chow diet, high fat diet, high fructose diet, high cholesterol diet, high cholesterol diet + 10% fructose in drinking water for 12 weeks. Blood pressure and plasma lipid levels were significantly increased in the four experimental groups as compared to the control group. Under euglycermic hyperinsulinemic (EHC) condition, the glucose infusion rate (GIR) was dramatically reduced in HFat, HC, and HCF rats- suggesting development of insulin resistance in these animals. Cerebral CuZnSOD protein levels were markedly elevated in HFat、HFru groups compared to the control rats. In addition, the p-eNOS levels under EHC condition leads to dephosphorylation of eNOS .This study suggests an association between dietary factors with the development of peripheral insulin resistance. However, there seem to be less of an effect CNS.

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30

Yeh, Tung-Chen, i 葉同成. "Caffeine intake improves fructose-induced hypertension and insulin resistance by enhancing central insulin signaling". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/247ck8.

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博士
國立中山大學
生物科學系研究所
102
Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and the formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure (BP). Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing BP in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, HOMA-IR, and triglyceride levels and increased the serum dHDL level in fructose-fed rats but not in control rats. Caffeine treatment resulted in recovery of the fructose-induced decrease in nitric oxide (NO) production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1S307) and reversed AktS473 and neuronal NO synthase (nNOS) phosphorylation. Likewise, caffeine was able to improve insulin sensitivity and decrease the insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and the expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance IRS1-phosphatidylinositol 3-kinase-Akt-nNOS signaling to decrease BP by abolishing superoxide production in the NTS.

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31

Kim, Jeong-Ho. "Molecular mechanism of insulin resistance : role of mTOR signaling pathways /". 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3314819.

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Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008.
Source: Dissertation Abstracts International, Volume: 69-05, Section: B, page: 2715. Adviser: Andrew Belmont. Includes bibliographical references (leaves 137-149) Available on microfilm from Pro Quest Information and Learning.

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Federico, Lisa Marie. "Mechanistic link between intestinal insulin signaling and lipoprotein metabolism in a model of insulin resistance". 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=95136&T=F.

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Norouzi, S. "The role of zinc and the Zip7 transporter in disease processes associated with IR in skeletal muscle". Thesis, 2019. https://eprints.utas.edu.au/34263/1/Norouzi_whole_thesis.pdf.

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Zinc is a critical metal ion that has wide-ranging effects on cellular function. It is required for growth and development, immunity, and metabolism, and is therefore, vital for life. Disturbances in zinc homeostasis lead to various disease states including cancer, neurological disorders and diabetes. Recent studies have highlighted the dynamic role of zinc as an insulin mimetic and a cellular second messenger that controls many processes associated with insulin signalling and other downstream pathways that are amendable to glycaemic control. Therefore, mechanisms that contribute to the decompartmentalization of zinc and dysfunctional zinc transporter mechanisms, including zinc signalling are associated with metabolic disease. As zinc cannot pass through biological membranes unassisted, cellular zinc storage, release and distribution are controlled by a family of proteins: zinc transporters and metallothioneins. Increasing evidence suggests that dysregulation of these proteins might act as key causative or promoting factors in several chronic pathologies such as insulin resistance and type 2 diabetes. Of these, emerging research has highlighted a role for several zinc transporters in the initiation of zinc signalling events in cells that lead to metabolic processes associated with maintaining insulin sensitivity and thus glycaemic homeostasis. One principle zinc transporter, Zip7 is emerging as a ‘gate-keeper’ of zinc flux from intracellular organelles including the Golgi apparatus and endoplasmic reticulum. Recent studies have identified that this transporter facilitates the mobilisation of intracellular zinc flux into the cytosol and the subsequent zinc-mediated activation of cell signalling molecules involved in glucose homeostasis. However, the mechanisms whereby zinc and Zip7 achieve glucose control is not known. The present study evaluated the insulin-like effects of zinc on cell signalling pathways associated with controlling glucose homeostasis. Initially, key molecules involved in controlling glucose metabolism including tyrosine, PRSA40, Akt, ERK1/2, SHP-2, GSK-3β and p38, and the physiological response of glucose oxidation were analysed in the presence of zinc treatment in mouse and human skeletal muscle cells. Insulin and zinc treatment independently led to the phosphorylation of these proteins over a 60-minute time course in both mouse and human skeletal muscle cells and was concomitant with an increase in glucose oxidation. Similarly, utilising a commercially available protein array that contains several key proteins implicated in insulin signalling pathways we identified that zinc could active the phosphorylation of p38, ERK1/2 and GSK-3β in human and ERK1/2 and GSK-3β in mouse skeletal muscle cells. Glucose oxidation assays were performed on skeletal muscle cells treated with insulin, zinc, or a combination of both and resulted in a significant induction of glucose consumption in mouse and human skeletal muscle cells when treated with zinc alone. Insulin, as expected, increased glucose oxidation in mouse and human skeletal muscle cells, however the combination of zinc and insulin did not augment glucose consumption in these cells. Given that we did not observe an additive effect of insulin and zinc treatment together on glucose oxidation, we sought to determine whether a functional insulin receptor is required to facilitate zinc activation of pAkt. We utilised mouse C2C12 skeletal muscle cells treated with an insulin receptor tyrosine kinase inhibitor (HNMPA-(AM)3) in the presence of insulin or zinc. We observed that HNMPA-(AM)3 was sufficient to inhibit insulin-induced pAkt. Similarly, we identified that HNMPA-(AM)3 inhibited zinc-induced pAkt and suggests that zinc potentially acts through the insulin signalling pathway. Previous studies have identified that Zip7 controls cell signalling pathways associated with glycaemic control in skeletal muscle cells. It was suggested that dysfunctional cell signalling processes in disease states such as insulin resistance and type 2 diabetes might be due to aberrant Zip7 expression and/or function. Accordingly, we initially set out to determine the role of Zip7 in an insulin-resistant cell culture model. Initially we tested the ability of glucose to regulate Zip7 protein levels. We found that 25 mM of glucose treatment of C2C12 mouse skeletal muscle cells significantly increased Zip7 protein levels. We also determined that Zip7 (and Glut4) were significantly reduced in insulin resistant skeletal muscle cells through inhibition of insulin receptor signalling and palmitate-induced insulin resistance. These studies suggest that Zip7 plays an important role in maintaining cell signalling processes associated with glucose control. We next focused our studies to determine if the expression of Zip7 changed in a mouse model of obesity. We found that Zip7 and the glucose transporter, Glut4 was reduced in obese mice fed a high fat diet. From the above studies we established a Zip7 overexpression cell culture model to test the ability of this transporter to regulate genes implicated in glucose homeostasis. These studies were based on previous work which identified that a reduction in Zip7 in skeletal muscle cells led to several changes in genes associated with insulin signalling and glycaemic control. Accordingly, utilising an insulin signalling pathway array that contained 84 genes involved in insulin signalling, we identified that overexpression of Zip7 in mouse C2C12 skeletal muscle cells led to significant changes in Akt3, Dok2, Fos, Hras, Kras, Nos2, Pck2, and Pparg. In these studies, we demonstrated that zinc acts as an insulin mimetic, activating key molecules implicated in cell signalling to maintain glucose homeostasis in mouse and human skeletal muscle cells. Similarly, these studies demonstrated that Zip7 is involved in processes associated with insulin signalling and glucose control in skeletal muscle. This study also raises the possibility that zinc transporters could provide novel utility to be targeted experimentally and in a clinical setting to treat patients with insulin resistance and thus introduce a new class of drug target with utility for diabetes pharmacotherapy.

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Tzeng, Chung-Yuh, i 曾崇育. "The study of hypoglycemic effect of electroacupuncture by reducing insulin resistance in chronic steroid induced insulin resistance rats and signaling pathways associated with hypoglycemic activity of ST 36 electroacupuncture". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/62714443948862441271.

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博士
國立清華大學
分子醫學研究所
104
This study is designed to evaluate the treatment effect of electroacupuncture (EA) in chronic steroid induced insulin resistant rat model. An alternative therapy is explored to reduce the chronic steroid induced insulin resistance.The aim of this study is to determine (1) if EA treatment can produce hypoglycemic effect and (2) inhibit the development of glucocorticoid-altered insulin sensitivity in chronic status and to (3) explore the mechanisms of EA by assaying plasma FFAs and proteins of insulin signal pathway. Intravenous glucose tolerance test (IVGTT) and insulin challenge test (ICT) were applied to evaluate the effect of EA on steroid induced insulin resistance (SIIR) rats. Finally, this study evaluates proteins of insulin signaling pathway to investigate the mechanisms by which EA improves the insulin resistance of SIIR rats. We hypothesized that electroacupuncture can produce a hypoglycemic effect in chronic steroid induced insulin resistance diabetes rat model. A diabetes rat model was created by using clinical-like dose dexamethasone, 1 mg/kg, i.p. once a day chronic to induce insulin resistance for 5 days. Then the steroid induced insulin resistant (SIIR) rats were randomly divided into SIIR+EA group and SIIR group. Plasma glucose, insulin challenge test (ICT) and intravenous glucose tolerance test (ivGTT) were used to test the change of plasma glucose levels between SIIR+EA group and SIIR group. The plasma free fatty acids (FFA) and related proteins of the insulin signaling pathway, such as IRS-1 and GLUT4 were also checked to explore the effect of EA on recovering insulin sensitivity of SIIR rats. The results showed that EA could decrease the FFA level and increase insulin sensitivity in SIIR rats. Further clinical studies are needed to determine whether EA can be an alternative and effective treatment for patients for whom chronic usage of dexamethasone is needed by reducing insulin resistance. Data on expression of all genes in a biological sample can be achieved in one experiment using the microarray method, the results of which can be analyzed to determine the potential pathways involved in a given process and identify potential therapeutic targets. Then the microarray analysis experiment was done to explore the possible signaling pathway related to hypoglycemic effect induced by the EA. Previous animal studies have reported a hypoglycemic effect of EA and suggested that the mechanisms are closely related to intracellular signaling pathways. The aim of this study was to screen potential for intracellular signaling pathways that are upregulated by EA at bilateral ST36 in rats with diabetes using microarray analysis. Streptozotocin (STZ) - induced diabetic rats were randomly assigned to experimental (EA, n=8) or control (non-EA, n=8) groups. Plasma glucose levels were measured at baseline, 30 and 60 minutes, and microarray analysis was performed on samples of the gastrocnemius muscle. Relative to baseline values, EA significantly reduced plasma levels of glucose at 30 and 60 minutes. The microarray pathway analysis showed that cell adhesion molecules and type 1 DM gene sets were both upregulated in EA versus non-EA groups (p<0.05). Cell adhesion molecules might be related to the hypoglycemic effect induced by EA in rats with STZ-induced type I diabetes. Future research will be required to examine the involvement of related intracellular signaling pathways.

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Hui, Lee Chia, i 李家慧. "A Possible Role of Betel-quid Chewing in Insulin Resistance and Endothelial Dysfunction-Effects of Arecoline on Insulin Signaling in Human Endothelial Cells". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/49795764307618922237.

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碩士
國防醫學院
牙醫科學研究所
101
Background : Betel nut is the most widely used addictive substance in the world , and betel quid chewing is a common oral habit in South Asia and Taiwan. Being a major alkaloid in betel nut , arecoline has long been considered a potential carcinogen. Several reports showed that arecoline can increase reactive oxygen species (ROS) to produce cytotoxicity and genotoxicity . Recent reports indicate that betel quid chewing also increase the risk of atherosclerosis and diabetes. However, the detail mechanism remains unknown. Most recently, arecoline have diabetogenic potential on adipocytes that may result in insulin resistance and diabetes at least in part via the obstruction of insulin signaling and the blockage of lipid storage. In this study, we try to investigate the possible mechanisms of arecoline induced insulin resistance and endothelial dysfunction. Methods : Human dermal microvascular endothelial cell (HMEC-1) were treated in different arecoline concentrations and tested the ROS levels and the expression of adhesion molecules, insulin signaling pathways and cell adhesion function. Then N-acetylcysteine (NAC) and Rosiglitazone were added to exam the effect on arecoline-induced endothelial dysfunction. Results : Our data showed that the ROS levels and adhesion molecules (ICAM-1, VCAM-1) significantly increased after arecoline treatment and along with increased adhesion ability between HMEC-1 and monocyte. The results also revealed that increased phosphorylation of JNK then downregulated insulin signaling pathways through IRS-1 and AKT after arecoline treatment. With the use of reducing agent NAC and Rosiglitazone in the arecoline-induced endothelial cell dysfunction, these cell dysfunctions and downstream signalings were found to be diminished and recovered. Conclusions : Our present study explore the influence of betel nut extract - arecoline on insulin signaling and endothelial dysfunction and partially explain the increased risk of insulin resistance and cardiovascular disease from betel nut chewing . In addition, our data showed Rosiglitazone reduced arecoline-induced endothelial dysfunction and insulin resistance including of reducing ICAM-1 and VCAM-1 expression and monocyte adhesion by modulating the JNK-IRS-1-PI3K/AKT signaling pathway in endothelial cells.

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Juo, Shih-Ting, i 卓詩婷. "Ursolic Acid and Oleanolic Acid Suppresses Tumor Necrosis Factor-α Induced Insulin Resistance by Reduced Foxo1 signaling in 3T3-L1 Adipocytes". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/2cbt35.

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Jideonwo, Victoria N. "Novel roles of sterol regulatory element-binding protein-1 in liver". Diss., 2016. http://hdl.handle.net/1805/10461.

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Indiana University-Purdue University Indianapolis (IUPUI)
Sterol Regulatory Element Binding Protein-1 (SREBP-1) is a conserved transcription factor of the basic helix-loop-helix leucine zipper family (bHLH-Zip) that primarily regulates glycolytic and lipogenic enzymes such as L-pyruvate kinase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and mitochondrial glycerol-3-phosphate acyltransferase 1. SREBP-1c activity is higher in the liver of human obese patients, as well as ob/ob and db/db mouse models of obesity and type 2 diabetes, underscoring the role of this transcription factor as a contributor to hepatic steatosis and insulin resistance. Nonetheless, SREBP-1 deficient ob/ob mice, do not display improved glycemia despite a significant decrease in hepatic lipid accumulation, suggesting that SREBP-1 might play a role at regulating carbohydrate metabolism. By silencing SREBP-1 in the liver of normal and type 2 diabetes db/db mice, we showed that indeed, SREBP-1 is needed for appropriate regulation of glycogen synthesis and gluconeogenesis enzyme gene expression. Depleting SREBP-1 activity more than 90%, resulted in a significant loss of glycogen deposition and increased expression of Pck1 and G6pc. Hence, the benefits of reducing de novo lipogenesis in db/db mice were offset by the negative impact on gluconeogenesis and glycogen synthesis. Some studies had also indicated that SREBP-1 regulates the insulin signaling pathway, through regulation of IRS2 and a subunit of the PI3K complex, p55g. To gain insight on the consequences of silencing SREBP-1 on insulin sensitivity, we analyzed the insulin signaling and mTOR pathways, as both are interconnected through feedback mechanisms. These studies suggest that SREBP-1 regulates S6K1, a downstream effector of mTORC1, and a key molecule to activate the synthesis of protein. Furthermore, these analyses revealed that depletion of SREBP-1 leads to reduced insulin sensitivity. Overall, our data indicates that SREBP-1 regulates pathways important for the fed state, including lipogenesis, glycogen and protein synthesis, while inhibiting gluconeogenesis. Therefore, SREBP-1 coordinates multiple aspects of the anabolic response in response to nutrient abundance. These results are in agreement with emerging studies showing that SREBP-1 regulates a complex network of genes to coordinate metabolic responses needed for cell survival and growth, including fatty acid metabolism; phagocytosis and membrane biosynthesis; insulin signaling; and cell proliferation.

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Xu, Yanjun. "Regulation of Drosophila melanogaster body fat storage by store-operated calcium entry". Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E5A-7.

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Lee, Andrew. "Characterizing the Role of a Novel F-actin Binding Protein in IRS1/PI3K Signaling and Glucose Uptake". Thesis, 2009. http://hdl.handle.net/1807/30127.

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Studies show that insulin induced activation and assembly of insulin receptor substrate-1 (IRS1) and phosphatidylinositol-3-kinase (PI3K), within remodelled actin structures is critical for GLUT4 translocation to the cell surface in muscle cells. This study identifies the F-actin binding protein, nexilin, as a novel IRS1 binding partner. Insulin stimulates nexilin to dissociate from IRS1 and interact with actin. Nexilin knockdown has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, but does enhance insulin-stimulated IRS1-PI3K interaction, increasing PIP3 formation, PKB activation and glucose uptake. This study also shows that nexilin overexpression may have an inhibitory effect on PKB phosphorylation and glucose uptake in adipocytes. These findings suggest nexilin is a negative regulator of IRS1 action on PI3K and insulin-stimulated dissociation of IRS1-nexilin allows the formation of IRS1-PI3K complexes in cytoskeletal-membrane compartments. Nexilin also specifically associates with the PH domain of IRS1, and not IRS2, suggesting a mechanism for signaling specificity of these isoforms.

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Tsai, Julie. "Intracellular Signaling Pathways Regulating Hepatic Apolipoprotein B100 Production: Roles of Mitogen-activated Protein Kinases (MAPKs) and Inhibitor of NFkappaB Kinase (IKK)-NFkappaB". Thesis, 2009. http://hdl.handle.net/1807/19239.

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Apolipoprotein B100 (apoB), the structural protein component of triglyceride-rich very low density lipoprotein (VLDL) and atherogenic low density lipoprotein, is considered an important risk indicator of atherosclerosis. In insulin resistant states, hepatic overproduction of apoB leads to metabolic dyslipidemia, characterized by high circulating VLDL and hypertriglyceridemia. Since the mitogen-activated protein kinases (MAPKs) and the inhibitor of NFkappaB kinase (IKK)-NFkappaB cascades are perturbed in insulin resistance, we hypothesized that the MAPKs (ERK, p38 and JNK) and the IKK-NFkappaB pathways regulate hepatic apoB output. We modulated these pathways in HepG2, a human hepatoma cell line, and primary hamster hepatocytes using chemical inhibitors and protein overexpression. ApoB synthesis and secretion were examined by metabolic pulse labeling. HepG2 is typically defective in secreting apoB as large VLDL particles and secretes smaller triglyceride-poor apoB-particles. Under continuous pulse labeling, ERK inhibition not only increased apoB secretion, it enabled HepG2 to secrete VLDL-sized particles in the presence of exogenous fatty acid (oleate). Concomitant with the increased apoB-particle size, ERK inhibition raised intracellular triglyceride level and diacylglycerol acyltransferase (DGAT) 1 and DGAT2 mRNA levels. Conversely, ERK activation decreased VLDL-apoB secretion from primary hepatocytes. In contrast to ERK, p38 or JNK inhibition decreased apoB secretion without affecting apoB-particle size from oleate-treated HepG2 cells. JNK inhibition also modulated apoB levels in primary hamster hepatocytes. Interestingly, the development of diet-induced hepatic insulin resistance was associated with decreased ERK, and enhanced p38 and NFkappaB activities. Thus we investigated the role of the NFkappaB pathway in regulating hepatic apoB production. IKK inhibition decreased and IKK overexpression increased apoB levels by modulating apoB mRNA translation and protein stability. IKK inhibition also suppressed hepatic apoB overproduction in an insulin resistance model, the fructose-fed hamster. Altogether, our results suggest that among the MAPK cascades, the MEK-ERK pathway is crucial in regulating apoB-lipoprotein assembly, possibly by modulating lipid availability to newly-synthesized apoB. The inflammatory IKK-NFkappaB cascade is also involved in regulating apoB synthesis and secretion. We postulate that dysregulation in the MAPK or NFkappaB cascades in insulin resistant and inflammatory states may contribute to hepatic apoB overproduction, and the common phenotype of hypertriglyceridemia and dyslipidemia.

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Chowdhury, Kawshik K. "The effect of voluntary exercise, with/without antioxidants, on meal-induced insulin sensitization (MIS) in health and in prediabetes AND The study of cellular signaling pathways associated with MIS in skeletal muscle". 2012. http://hdl.handle.net/1993/8117.

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Background: The augmented whole body glucose uptake response to insulin during the postprandial state is described as meal-induced sensitization (MIS). MIS occurs when the presence of food in the upper gastrointestinal tract (GIT) activates two feeding signals (activation of hepatic parasympathetic nerves and elevation of hepatic glutathione level), and causes insulin to release hepatic insulin sensitizing substance (HISS), which stimulates glucose uptake in peripheral tissues. The impairment of HISS release results in the absence of meal-induced insulin sensitization (AMIS), causing progression to a cluster of metabolic, vascular, and cardiac dysfunction, which we refer to as components of the AMIS syndrome. Objectives: The objective of my doctoral research was to study the manipulation of the HISS-pathway, in age- and diet-induced AMIS models, with exercise ± antioxidants. Also, in a separate project I studied the signaling pathways involved with the HISS action in skeletal muscle. Methods: The 7-day voluntary running was used as exercise intervention to manipulate the HISS pathway in healthy and prediabetic rats. The interaction of an antioxidant cocktail, SAMEC (S-adenosylmethionine + vitamin E + vitamin C), with the effects of exercise on postprandial insulin response was studied. Moreover, in the signaling studies the insulin and 5'-adenosine monophosphate activated protein kinase (AMPK) pathways were examined to test their possible involvement with the HISS action in skeletal muscle. Results: Voluntary running-wheel exercise for 7 days increases the postprandial glucose uptake response to insulin in health and in prediabetes through enhancement/restoration of HISS action. Supplementation with SAMEC during 7 days of exercise does not either harm or add benefits to the positive effects of exercise on insulin sensitivity. Finally, the signaling studies indicate that HISS increases the rate of glycogen synthesis in muscle through an insulin/AMPK-independent pathway.

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TRIANI, FRANCESCA. "Impairment of insulin signaling cascade favors the development of Alzheimer disease pathology by altering APP processing in the brain". Doctoral thesis, 2018. http://hdl.handle.net/11573/1212434.

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Brain insulin resistance is associated with an increased Aβ production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favouring brain insulin resistance development. Furthermore, reported a negative association between BVR-A protein levels/activation and BACE1 protein levels in the parietal cortex of aged beagles (an animal model of AD), thus suggesting a possible interaction. Therefore, we aimed to demonstrate that BVR-A impairment is a molecular bridge linking brain insulin resistance with increased Aβ production. Age-associated changes of BVR-A, BACE1, insulin signalling cascade and APP processing were evaluated in the parietal cortex of beagles and experiments to confirm the hypothesized mechanism(s) have been performed in vitro in HEK293APPswe cells. Our results show that BVR-A impairment occurs early with age and is associated with brain insulin resistance. Furthermore, we demonstrate that BVR-A impairment favours CK1-mediated Ser phosphorylation of BACE1 (known to mediate BACE1 recycling to plasma membrane) along with increased Aβ production in the parietal cortex, with age. Overall, our results suggest that the impairment of BVR-A is an early molecular event contributing to both (I) the onset of brain insulin resistance and (II) the increased Aβ production observed in AD. We, therefore, suggest that by targeting BVR-A activity it could be possible to delay the onset of brain insulin resistance along with an improved regulation of the APP processing.
Impairment of biliverdin reductase-A (BVR-A) is an early event leading to brain insulin resistance in AD. Intranasal insulin (INI) administration is under evaluation as a strategy to alleviate brain insulin resistance; however, the molecular mechanisms underlying INI beneficial effects are still unclear. We show that INI improves insulin signalling activation in the hippocampus and cortex of adult and aged 3×Tg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation and Aβ oligomers in brain, along with improved cognitive functions. The role of BVR-A was strengthened by showing that cells lacking BVR-A: (i) develop insulin resistance if treated with insulin; and (ii) can be recovered from insulin resistance only if treated with a BVR-A-mimetic peptide. These novel findings shed light on the mechanisms underlying INI treatment effects and suggest BVR-A as potential therapeutic target to prevent brain insulin resistance in AD.

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Marques, Filipa Carvalhal. "Mechanisms of aging: neuronal orchestration of stress resistance and protein homeostasis in the nematode Caenorhabditis elegans". Doctoral thesis, 2016. http://hdl.handle.net/10316/29393.

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Tese de doutoramento em Ciências da Saúde, no ramo de Ciências Biomédicas, apresentada à Faculdade de Medicina da Universidade de Coimbra
O envelhecimento é um processo complexo que ocorre em todos os organismos, da levedura ao Homem. Apesar de um século de pesquisa e discussão científica, os factores subjacentes à progressão do envelhecimento permanecem por clarificar. Mas os ângulos sob os quais este processo é visto sofreram grandes mudanças com o tempo. As primeiras teorias sugeriam que o envelhecimento decorre da acumulação estocástica de danos nas macromoléculas, levando ao mal funcionamento dos organismos e, por fim, à morte dos mesmos. Esta área de investigação foi radicalmente transformada nas últimas décadas por uma série de estudos pioneiros em diferentes modelos animais que mostraram claramente que o envelhecimento pode ser alterado através da manipulação de várias vias metabólicas e genéticas. Estas descobertas sugeriram que o nível de protecção de um organismo contra danos estocásticos pode ser regulado e, consequentemente, também o período de vida durante o qual o mesmo permanece saudável. No entanto, à medida que o conhecimento acerca destes mecanismos foi maturando, tornou-se evidente que a duração de vida, a resistência a stress e a homeostase proteica, aspectos que são regulados pelas vias que regulam o envelhecimento, podem ser desacopladas sem se influenciarem mutuamente. Mais recentemente, o processo de envelhecimento revelou possuir um nível adicional de complexidade quando se mostrou que pode ser coordenado por diferentes tecidos ao nível do organismo. Neste trabalho, o nosso interesse focou-se nos princípios subjacentes à orquestração do envelhecimento ao nível do organismo, bem como na dissociação entre duração de vida, resistência a stress e homeostase proteica. De modo a abordar estes temas, usámos o nemátode Caenorhabditis elegans (C. elegans), modelo animal que oferece inúmeras vantagens no estudo do envelhecimento. Começámos por investigar os mecanismos de comunicação entre tecidos que regulam a heat shock response (HSR) a nível do organismo no modelo C. elegans, procurando, mais concretamente, esclarecer que receptores neuronais estão envolvidos neste mecanismo de sinalização e em que neurónios desempenham a sua função. Para responder a estas questões, empregámos nemátodes geneticamente modificados que apresentam hipersensibilidade a RNA de interferência (RNAi) no tecido nervoso e identificámos um presumível receptor acoplado a proteínas G (GPCR) como sendo um componente-chave deste mecanismo. Este gene, a que atribuímos o nome gtr-1, é expresso em neurónios quimiosensoriais e desempenha um papel fundamental na indução de genes que codificam proteínas de heat shock nos tecidos somáticos após exposição a temperaturas elevadas, apesar de não ser necessário à percepção de calor. Surpreendentemente, o knockdown do gtr-1 através de RNAi tem um efeito protector em nemátodes que expressam nos músculos Aβ3-42 (um péptido com tendência agregativa associado à doença de Alzheimer), mas não influencia a duração de vida, a resistência a outros stresses ou funções associadas ao desenvolvimento. Na segunda parte deste trabalho pretendemos fazer uma caracterização mais detalhada dos elementos downstream à via de sinalização da insulina/IGF-1 (IIS) que estão directamente envolvidos na regulação da toxicidade proteica em C. elegans. Com este objectivo, procurámos genes previamente citados na literatura como reguladores da homeostase proteica e identificámos o tor-2 como sendo regulado ao nível da transcrição pela via IIS. Nesta tese mostramos que a expressão do tor-2 é induzida após a supressão desta via pelos factores de transcrição DAF-16 e SKN-1. Este gene revelou-se importante na resistência a temperaturas elevadas mas não na regulação do tempo de vida do animal ou na resistência a outros tipos de stress tais como exposição a bactérias patogénicas ou a radiação UV. Curiosamente, o tor-2 parece ser importante no combate à toxicidade proteica em neurónios, onde se mostrou anteriormente que este gene é expresso, ao passo que o seu knockdown protege os nemátodes que expressam proteínas agregativas tóxicas nos músculos. Este estudo oferece novas ideias: (1) que os neurónios quimiosensoriais desempenham um papel importante nos mecanismos que regulam a HSR no nemátode; (2) que o tempo de vida e a resistência a heat shock são separáveis; (3) consolida o conceito emergente de que a habilidade para responder o calor existe em detrimento da manutenção da proteostase; e (4) sugere que a homeostase proteica pode ser diferencialmente regulada de tecido para tecido por um único gene.
Aging is a complex process that occurs in organisms ranging from yeast to humans. The factors underlying the progression of aging still elude us, despite a century of scientific inquiry and discussion. Nevertheless, the angles from which aging was perceived have greatly changed over time. Early theories suggested that aging results from the accumulation of stochastic damage to macromolecules, leading to organismal malfunction and ultimately death. The field was however revolutionized over the last decades by a series of pioneering studies carried out in model organisms that showed that aging can actually be altered by the modification of several metabolic and genetic pathways. These findings suggested that the level of protection against stochastic damage can be regulated and, hence, the length of time an organism remains healthy. However, as the knowledge on these mechanisms matured, it became evident that lifespan, stress resistance, and protein homeostasis (proteostasis), aspects that are regulated by the aging-modulating pathways, can be uncoupled without influencing one another. The aging process revealed another level of complexity when it was shown to be coordinated by different tissues in an organismal-fashion. In this work, we were interested in the principles underlying the orchestration of aging at the organismal level, as well as in the uncoupling between lifespan, stress resistance, and proteostasis. To address these questions, we employed the nematode Caenorhabditis elegans (C. elegans), which offers key advantages in the study of aging. We started by focusing on the inter-tissue communication mechanisms that regulate the heat shock response (HSR) at the organismal level in C. elegans and attempted to clarify which neuronal receptors are required for this signaling mechanism and in which neurons they function. To answer these questions, we employed worms that were engineered to exhibit RNA interference (RNAi) hypersensitivity in neurons and identified a putative G protein-coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 (gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knockdown of gtr-1 by RNAi protected worms expressing the Alzheimer's-disease-linked aggregative peptide Aβ3-42 in their body-wall muscles from protein toxicity (proteotoxicity) but had no effect on lifespan, resistance to other stresses, or developmental functions. In the second part, we aimed at better characterizing the insulin/IGF-1 signaling (IIS)-downstream components involved in the direct regulation of protein toxicity (proteotoxicity) in the C. elegans model. For this, we searched for genes that are known regulators of proteostasis and identified tor-2 as a transcriptional target of the IIS pathway. Here we show that tor-2 is upregulated upon suppression of the IIS by both DAF-16 and SKN-1transcription factors. This gene is important for the resistance to heat shock but has no role in the determination of lifespan or in the resistance to other acute stresses such as exposure to pathogenic bacteria or to UV radiation. Interestingly, tor-2 seems to be important to counteract proteotoxicity in neurons, previously shown to be its main site of expression, whereas its knockdown protects worms that express toxic, aggregative-proteins in their body-wall muscles. In this work we provide several novel insights: (1) we show that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism; (2) that lifespan and heat stress resistance are separable; (3) we strengthen the emerging notion that the ability to respond to heat comes at the expense of proteostasis; and (4) suggest that proteostasis can be differentially regulated in a tissue-specific manner by a sole gene.
FCT - SFRH/BD/70502/2010

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