Дисертації з теми "Insulin resistance diabete"
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1
Capetini, Vinícius Cooper. "Efeito da suplementação com zinco na evolução da resistência à insulina induzida por dieta hiperlipídica em camundongos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-10082016-154401/.
Анотація:
O aumento da prevalência do diabete melito do tipo 2 (DM2) é intenso e implica ampla busca pela prevenção e tratamento da doença. Estudos têm mostrado a participação do zinco na síntese, secreção e via de sinalização da insulina e sobre o controle glicêmico. Este trabalho objetivou analisar o mecanismo de ação do zinco no controle da secreção de insulina e no controle glicêmico, de modo a entender se a suplementação com o zinco previne ou retarda a manifestação do DM2. O projeto foi aprovado pela CEUA-ICB (USP). Camundongos machos C57BL/6 foram divididos em 4 grupos experimentais: dieta controle (NFD); dieta controle suplementada com ZnCl2 (NFDZ); dieta hiperlipídica (HFD); e dieta hiperlipídica suplementada com ZnCl2 (HFDZ). A massa corporal, a ingestão de ração e água e a glicemia foram acompanhados semanalmente. Testes intraperitoneais de tolerância à glicose (ipGTT) e à insulina (ipITT) foram realizados na 14ª semana de tratamento. Completado as 15 semanas de tratamento a glicemia, a insulinemia e a zincemia foram analisadas, sendo aplicados os testes de HOMA-IR e HOMA-β. Em ilhotas pancreáticas isoladas foi analisada a secreção estática de insulina em diferentes concentrações de glicose. O teste de captação e metabolismo de glicose foi feito no músculo sóleo e a análise do conteúdo das proteínas AKT e GSK3-β foi feita no músculo sóleo e no fígado. Os dados (média±SEM) foram analisados por Two-way ANOVA com pós-teste Bonferoni ou por teste t de Student (P 0,05). A suplementação com zinco melhorou a disfunção glicêmica induzida por dieta hiperlipídica, sem no entanto afetar a resistência à insulina ou a secreção de insulina por ilhotas isoladas.The increase in prevalence of type 2 diabetes mellitus (DM2) is intense and implies broad quest for prevention and treatment of disease. Studies have shown the participation of zinc in the synthesis, secretion and signaling pathway of insulin and the glucose control. This study aimed to analyze the mechanism of action of zinc in the control of insulin secretion and glucose control in order to understand whether supplementation with zinc prevents or delays the manifestation of DM2. The project was approved by CEUA-ICB (USP). Male mice C57BL/6 were divided en 4 groups: control diet (NFD); control diet supplemented with ZnCl2 (NFDZ); high fat diet (HFD); and high fat diet supplemented with ZnCl2 (HFDZ). Body weight, feed intake and water and the glucose levels were monitored weekly. Intraperitoneal glucose tolerance test (ipGTT) and insulin (ipITT) were performed at the 14th week of treatment. Completing the 15 weeks of the treatment glycemia, insulinemia and zincemia were analyzed, being applied HOMA-IR and HOMA-β tests. In isolated islets was assessed the static insulin secretion at different glucose concentrations. The uptake and glucose metabolism test was done in the soleus muscle and the content analysis of the AKT and GSK3-β protein was made in the soleus muscle and liver. The data (mean ± SEM) were analyzed by two-way ANOVA with Bonferoni post-test or Student\'s t test (P < 0,05). Zinc supplementation improves glucose dysfunction induced by high fat diet, without nonetheless affecting insulin resistance and insulin secretion by isolated islets.
2
Napolitano, Tiziana. "Confidentiel." Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4141.
3
GRANCINI, VALERIA. "RUOLO CENTRALE DELLA BETA-CELLULA NEL PROMUOVERE LA REGRESSIONE DEL DIABETE DOPO TRAPIANTO DI FEGATO IN PAZIENTI CON CIRROSI EPATICA." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/658515.
Анотація:
BACKGROUND & AIMS:
Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT.
METHODS:
Eighty cirrhotic patients with non-diabetic FPG and HbA1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity.
RESULTS:
At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups.
CONCLUSIONS:
Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity.
4
Pappalardo, Alessandro Orazio Giovanni. "Ruolo del recettore Gabaa nelle cellule alfa pancreatiche e suo coinvolgimento nelle fasi di desensibilizzazione indotta dalla lipotossicità nel diabete di tipo II." Doctoral thesis, Università di Catania, 2016. http://hdl.handle.net/10761/3991.
Анотація:
Il GABA o acido gamma-aminobutirrico è il principale neurotrasmettitore inibitorio del sistema nervoso centrale (SNC) dei mammiferi. Circa il 20 - 50% di tutte le sinapsi utilizzano questo neurotrasmettitore. Esso è presente in quantità elevate, anche nello spazio interstiziale delle isole pancreatiche e nelle beta cellule pancreatiche dalle quali viene secreto. Il GABA oltre ad avere funzione trofica sulle beta cellule, attraverso il suo recettore (GABAA) controlla la riduzione della secrezione di glucagone insieme con lâ insulina.
Nel nostro lavoro abbiamo studiato gli effetti dell'esposizione cronica al palmitato sul signaling del GABA e sulla pathway dellâ insulina in un modello di alfa cellule pancreatiche. Le cellule alfa-TC1-C6 sono state coltivate in presenza o in assenza di palmitato (0,5 mmol / l) per 48 h. Al termine del trattamento si osservava un aumento della secrezione basale di glucagone, induzione di uno stato di insulino-resistenza (diminuzione della fosforilazione di IRS-1 e Akt), e riduzione dellâ effetto inibitorio del GABA sulla secrezione di glucagone; inoltre anche la fosforilazione del canale GABAA indotta dal GABA era notevolmente ridotta dopo l'esposizione a palmitato.
Nella seconda parte di questo lavoro abbiamo studiato la possibilità di prevenire i danni causati dell'esposizione cronica al palmitato sul nostro sistema co-trattando le nostre cellule con GLP-1 (100 nmol /l ).
Nei gruppi trattati con GLP-1, la secrezione basale di glucagone non risultava aumentata e l'effetto inibitorio del GABA sulla secrezione di glucagone non era ridotto.
Questi risultati indicano che il clone alfa-TC1 6, una linea cellulare di cellule pancreatiche alfa, coltivate per 48 ore in presenza di elevate concentrazioni di palmitato (0,5 mmol / l) sviluppano insulino resistenza attraverso la riduzione della fosforilazione di IRS-1 e Akt; questo percorso controlla la secrezione di glucagone ed è critico per la traslocazione del recettore GABAA sulle membrane cellulari e quindi per la polarizzazione della membrana delle alfa cellule. Il GLP-1 sembra in grado di prevenire tali alterazioni. Questi risultati supportano l'ipotesi che l'esposizione cronica agli acidi grassi può contribuire alla alterazione della secrezione di glucagone; e il GLP-1 mostra un effetto positivo sulla prevenzione dell'insulino-resistenza e sull'attivazione del canale GABA.
5
Leança, Camila Canteiro. "O metabolismo de lipoproteínas e a sensibilidade à insulina são distintamente modulados em indivíduos saudáveis com concentração alta ou baixa de HDL-colesterol." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-27072012-143556/.
Анотація:
A síndrome metabólica (SM) e o diabete melito (DM) caracterizam-se por uma série de alterações no metabolismo de lipoproteínas, entre elas a hipertrigliceridemia e a redução nas concentrações de HDL-colesterol (HDL-C). Em estudo prévio demonstramos que indivíduos saudáveis, não obesos, com concentração de HDL-C abaixo de 40mg/dL, quando comparados àqueles com concentração de HDL-C acima de 60mg/dL, apresentam, no plasma, esteróis marcadores de absorção intestinal de colesterol alimentar diminuídos, e de síntese de colesterol aumentados. Achados semelhantes foram descritos por outros autores em portadores de SM e DM, sugerindo que a resistência à insulina participa na origem do distúrbio, embora não se saiba por quais mecanismos. Considerando nossos achados prévios, os objetivos deste estudo são investigar quais os mecanismos moleculares envolvidos nas alterações do metabolismo de colesterol presentes em indivíduos com concentrações alta (HIPERALFA, HDL-C > 60mg/dL, n = 36) ou baixa (HIPOALFA, HDL-C < 40mg/dL, n = 37) de HDL-C por meio de medida de: 1) conteúdo celular de colesterol e expressão gênica de enzimas e receptores críticos para a regulação intracelular de colesterol, tendo como modelo células linfomononucleares de sangue periférico; 2) parâmetros que regulam o metabolismo de lipoproteínas no plasma e que são influenciados pela insulina, tais como lecitina-colesterol aciltransferase (LCAT), lipoproteína lipase (LPL) e lipase hepática (LH) pós-heparina, proteína de transferência de colesterol esterificado (CETP), proteína de transferência de fosfolípides (PLTP) e pré- beta1 HDL. Os critérios de exclusão foram: diabete melito, IMC 30Kg/m2, tabagismo, consumo elevado de álcool e uso de fármacos capazes de interferir no metabolismo de lipoproteínas. Mostramos que, quando comparado ao grupo HIPERALFA, o grupo HIPOALFA apresentou maiores concentrações de insulina, triglicérides, ALT(TGP), índice HOMA, atividade de LCAT e LH, e menor atividade de LPL e concentração de pré-beta1 HDL. Não houve diferença entre os grupos com relação ao conteúdo celular de colesterol, à expressão dos genes estudados (ABCA1, ABCG1, SR-BI, LDLR, HMG CoA redutase, SREBP-1c e LXR alfa), às atividades de CETP e PLTP no plasma e à ultrassonografia de carótidas. Nossos resultados mostram que indivíduos com concentração alta ou baixa de HDL-C no plasma diferem com relação à sensibilidade à insulina, além de parâmetros envolvidos na regulação do metabolismo de lipoproteínas. Estes achados não se relacionaram com o metabolismo celular de colesterol no modelo estudado, mas sugerem que este quadro metabólico, cuja origem é desconhecida, precede o aparecimento, no decorrer da idade, de outras alterações típicas da síndrome metabólica no grupo com baixas concentrações de HDL-C no plasmaThe metabolic syndrome (MS) and the diabetes mellitus (DM) are characterized for a series of alterations in lipoprotein metabolism as hypertriglyceridemia and reduced HDL-cholesterol (HDL-C) concentration. In previous study we demonstrated that healthy non obese subjects with HDL-C concentration below 40mg/dL, when compared with those with HDL-C above 60mg/dL, present low plasma sterol markers of alimentary cholesterol intestinal absorption and high plasma sterol markers of cholesterol synthesis. Similar findings have been described by others in subjects with MS and DM, suggesting that insulin resistance participates in the origin of the disorder, although by unknown mechanisms. Considering our previous findings, the objectives of this study are to investigate the molecular mechanisms involved in alterations of cholesterol metabolism in subjects with high HDL-C (HYPERALPHA, HDL-C > 60mg/dL, n = 36) or low HDL-C (HYPOALPHA, HDL-C < 40mg/dL, n = 37) concentration by means of measuring: 1) cellular cholesterol content and gene expression of critical enzymes and receptors involved in the intracellular cholesterol regulation, having peripheral blood mononuclear cells as model; 2) parameters that regulate the plasma lipoproteins metabolism and that are influenced by insulin, such as lecithin: cholesterol acyltransferase (LCAT), post-heparin hepatic (HL) and lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP) and pre-beta1 HDL. The exclusion criteria were: diabetes mellitus, body mass index 30Kg/m2, smoking, heavy drinking and use of medications that interfere with lipoprotein metabolism. We demonstrated that, as compared with HYPERALPHA, the HYPOALPHA group presented higher insulin, triglycerides and alanine aminotransferase concentrations, HOMA index, LCAT and HL activities and lower LPL activity and pre-beta1 HDL concentration. There was no difference between the groups in the cellular cholesterol content, expression of genes (ABCA1, ABCG1, SR-BI, LDLR, HMG CoA reductase, SREBP-1c and LXR alpha), plasma CETP and PLTP activities and carotid ultrasonography. Our results show that subjects with high or low plasma HDL-C concentration differ in relation to insulin sensitivity and in parameters involved in lipoprotein metabolism regulation. These findings were not related to the cellular cholesterol metabolism in the studied model, but they suggest that this metabolic disturbance, whose origin is unknown, precedes the appearance, in the course of the human life of other typical alterations of metabolic syndrome in the low HDL-C concentration group
6
Kergoat, Micheline. "Secretion et mode d'action de l'insuline dans un modele de diabete non-insulinodependant chez le rat." Paris 7, 1988. http://www.theses.fr/1988PA077085.
7
Pickavance, Lucy Cecilia. "Thiazolidinedione treatment in models of insulin resistance." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367553.
8
GALLI, ANGELICA. "Ruolo dei PUFA OMEGA-3 nella regolazione della funzione endoteliale in parenti di primo grado di pazienti affetti da diabete mellito di tipo 2." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2007. http://hdl.handle.net/2108/377.
Анотація:
Obiettivi: La disfunzione endoteliale è il meccanismo iniziale nella patogenesi dell’aterosclerosi. Costituisce una delle alterazioni vascolari presenti in soggetti apparentemente sani parenti di primo grado di pazienti affetti da Diabete Mellito Tipo 2 (FDR). Gli acidi grassi polinsaturi n-3 (PUFA n-3), come l’acido eicosapentaenoico (EPA) e l’acido docosaesaenoico (DHA), hanno un’ampia serie di proprietà antinfiammatorie. Noi abbiamo voluto testare l’ipotesi che la somministrazione di PUFA n-3 potesse migliorare la funzione endoteliale in soggetti FDR, ad elevato rischio di sviluppare precocemente aterosclerosi.
DISEGNO DELLO STUDIO E METODI: Abbiamo condotto uno studio monocentrico, randomizzato, controllato con placebo, in doppio cieco, a gruppi paralleli. Sono stati inclusi 70 soggetti (età 30.5 ± 5.2 anni, 30 donne e 40 uomini) con un parente di primo grado affetto da Diabete di Tipo 2. I soggetti sono stati assegnati per randomizzazione ad assumere placebo (n = 34) o PUFA n-3 (n= 36) per 12 settimane. La funzione endoteliale è stata esaminata attraverso la tecnica del brachial artery reactivity test (BART) misurando la dilatazione flusso-mediata (FMD). Peso, BMI, pressione sisto-diastolica, e parametri di laboratorio (profilo lipidico, glicemia, insulinemia e C-peptide a digiuno, TNF-α, adiponectina, hs-PCR) sono stati misurati prima e dopo il trattamento. All’inizio dello studio, ciascun soggetto è stato sottoposto a una curva da carico orale di glucosio (OGTT).
RISULTATI: Dopo OGTT abbiamo identificato 53 soggetti normoglicmici (NGT) e 17 soggetti con alterata tolleranza ai carboidrati (IGT). Al baseline i soggetti IGT presentavano un’età maggiore, un livello significativamente più alto di BMI, trigliceridi ed insulinemia a digiuno, un aumento dell’insulino-resistenza, e una funzione endoteliale peggiore rispetto ai soggetti NGT. Dopo trattamento, il braccio placebo, non ha mostrato significative modificazioni dei parametri valutati rispetto alle misurazioni basali; viceversa, il gruppo PUFA n-3 ha mostrato livelli significativamente ridotti di trigliceridi e TNF-α, un aumento dell’adiponectina circolante e un significativo miglioramento della funzione endoteliale. Il cambiamento dei livelli di TNF-α emergeva come unico e significativo predittore indipendente dell’aumento della FMD.
CONCLUSIONI: La somministrazione di PUFA n-3 in soggetti NGT ed IGT parenti di primo grado di pazienti affetti da Diabete Mellito Tipo 2 determina un miglioramento della funzione endoteliale che si accompagna ad una diminuzione dei livelli circolanti TNF-α.Objective: Endothelial dysfunction is the early and fundamental step in the pathogenesis of atherosclerosis. It has been indicated as one of the precocious vascular abnormalities in apparently healthy first-degree relatives of type 2 diabetic patients.(FDR). N-3 polyunsaturated fatty acids (PUFA n-3), such as eicosapentaenoic acid (EPA) and docosahexaenoico acid (DHA), have a wide range of anti-inflammatory properties. The aim of this study is that a supplementation of n3-PUFA might be effective to improve the endothelial dysfunction in FDR subjects at higher risk of developing atherosclerosis. RESEARCH DESIGN AND METHODS: We carried out a randomized, controlled with placebo, double blind, parallel-groups clinical trial. The study included 70 subjects (age 30.5 ± 5.2 years, 30 women e 40 men), all first-degree relatives of type 2 diabetic patients. The subjects were randomly assigned to assume placebo (n = 34) or n-3 PUFA (n= 36) for 12 weeks. Endothelial function was assessed by brachial artery reactivity test (BART), measuring the flow-mediated dilatation (FMD). Weight, BMI, systolic and diastolic blood pressure, and laboratory parameters (lipid profile, fasting plasma glucose, insulin, and C-peptide, TNF-α, adiponectin, hs-PCR) were assessed at baseline and after treatment. At the beginning of the study, each subject underwent a standard oral glucose tolerance test (OGTT). RESULTS: Upon OGTT we identified 53 normoglycemic subjects (NGT) and 17 subjects with impaired glucose tolerance (IGT). At baseline, the subjects IGT were older and presented significant higher levels of BMI, triglycerides, and fasting insulin, as well an increased insulin resistance, and a worse endothelial function, compared with NGT individuals. After treatment, we found only little if any change in metabolic and biomarkers levels of the participants of the placebo group (NGT and IGT); on the contrary, the n-3 PUFA group showed some difference respect to the baseline characteristics: the triglycerides and the TNF-α levels were significantly decrease, the adiponectin was increase, and the endothelial function showed a significant improvement. The changing of TNF-α levels emerged as the unique independent and significant predictor of the improvement of the FMD after the period of assumption of n-3 PUFA. CONCLUSIONS: We concluded that the N-3 PUFA oral supplementation is associated with an improvement of endothelial function via decreasing TNF-alpha in NGT and IGT subjects offspring of patients with Type 2 Diabetes.
9
Guarilha, Alessandra Lia Gasparetti. "Transdução do sinal da insulina em animais expostos ao frio : o papel do cross-talk entre o receptor 'beta' 3 - adrenergico e o receptor de insulina em tecido adiposo marrom." [s.n.], 2004. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310365.
Анотація:
Orientador: Licio Augusto VellosoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A exposição de animais homeotérmicos ao mo é utilizada como um método reprodutível para se obter um modelo animal de hipoinsulinemiaacompanhada por elevada mobilização periférica de glicose. No presente estudo, avaliaram-se as etapas iniciais e intermediárias da via de sinalização da insulina em tecidos periféricos de ratos expostos ao mo. Avaliou-se ainda, a comunicação intracelular entre o receptor (33-adrenérgicoe as vias de sinalização da insulina em tecido adiposo marrom de ratos expostos ao mo e tratados, ou não, com compostos agonista ou antagonista (33-adrenérgicos.A exposição de ratos ao mo promoveu a redução da secreção de insulina, acompanhada de um elevado clearance de glicose e maior captação de glicose por tecido muscular esquelético, adiposo branco e adiposo marrom. Tais fenômenos foram acompanhados por inibição da ativação da maior parte dos componentes da via de sinalização da insulina em tecido muscular esquelético e adiposo branco; por estimulação da maior parte dos componentes da via de sinalização da insulina em tecido adiposo marrom; e por efeitos variados (estímulo, inibição e não-modulação) de componentes da via de sinalização da insulina em figado. Por fim, este estudo demonstrou que a exposição ao mo ativa a sinalização (33-adrenérgicaem tecido adiposo marrom. Tal ativação leva à modulação da atividade de vários componentes da via de sinalização da insulina neste tecido. Entretanto, fatores independentes da sinalização (33-adrenérgica parecem contribuir para a complexa regulação do sinal da insulina obseIVada em tecido adiposo marrom de ratos expostos ao mo. Em conclusão, o presente estudo revelou alguns dos intrincados mecanismos pelos quais a exposição ao mo controla a atividade da insulina em animais homeotérmicos, podendo favorecer a identificação de potenciais alvos para a ação terapêutica em doenças onde a resistência à insulina desempenha papel central
Abstract: Cold exposure provides a reproducible model of improved glucose turnover accompanied by reduced blood levels of insulin. In the present study, the initial and intermediate steps of the insulin-signaling pathway in peripheral tissues of rats exposed to cold environment were evaluated. Also, the intracellular connection between insulin and ~3-adrenergic signaling in brown adipose tissue of cold exposed rats treated, or not, with ~3-adrenergic agonist or antagonist compounds were evaluated. During cold exposure, insulin secretion was significantly impaired, while whole body glucose clearance rates were significantly improved. This was accompanied by an increased glucose uptake by skeletal muscle, white adipose tissue and brown adipose tissue. These phenomena were paralleled by an apparent molecular resistance to insulin in skeletal muscle and white adipose tissue; by improved molecular response to insulin in brown adipose tissue; and by ambiguous effects (stimulation, inhibition and not modulation) of regulation of the insulin-signaling pathway in liver. Finally, cold exposure activated the ~3-adrenergic signaling in brown adipose tissue. It leads to modulation of activity of several components of the insulin signal transduction pathway in this tissue. However, ~3-adrenergic receptor independent mechanisms seem to contribute to the complex regulation of the insulin signaling observed in brown adipose tissue of rats exposed to cold. In conclusion, the present study revealed some of the complex mechanisms that participate in the cold-exposure-induced control of the insulin action in homeothermic animals. These results may favour the identification of novel potential targets for therapeutics in diabetes and related disorders
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
10
Lalli, Cristina Alba. "Efeito da rosiglitazona e da lovastatina na resistencia insulinica da dieta hiperlipidica." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311224.
Анотація:
Orientador: Mario Jose Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A insulina é o principal hormônio anabólico, que atua através da ativação de transportadores, regulação de enzimas e expressão de genes que codificam enzimas envolvidas na captação e armazenamento de substratos. Para exercer suas ações, a insulina emprega duas vias principais de sinalização intracelular: a via da PI 3-quinase e a via da MAPK. A regulação da ação do hormônio se faz por meio de vários mecanismos. O modelo animal de dieta hiperlipídica apresenta alterações metabólicas e de sinalização semelhantes aos encontrados na resistência insulínica de humanos com obesidade induzida por dieta. O objetivo de nosso trabalho foi estudar em ratos alimentados com dieta hiperlipídica, etapas da sinalização insulínica e também algumas vias de regulação da sinalização, após o uso de duas drogas: a rosiglitazona, uma tiazolidinediona usada para o tratamento do diabetes melito tipo 2 como sensibilizadora de insulina e a lovastatina, droga inibidora da HMGCoA redutase, que diminui a síntese de colesterol, mas que também tem apresentado efeito de aumentar a sensibilidade à insulina, tanto em modelos animais como em humanos. Ratos alimentados com dieta hiperlipídica por quatro semanas e tratados na última semana com as drogas, isoladamente, foram submetidos à extração de tecidos hepático e muscular e os fragmentos obtidos foram submetidos à análise de concentração protéica ou de grau de fosforilação de proteínas através de técnicas de imunoprecipitação e immunoblotting. A sensibilidade à insulina foi avaliada pelo teste de tolerância à insulina e cálculo da constante de decaimento da glicose (Kitt). No estudo. da rosiglitazona, foi observada diminuição significativa da sensibilidade à insulina expressa por diminuição no Kitt, nos animais que receberam a dieta e recuperação da sensibilidade após o uso da droga. A fosforilação do IRS-l, associação do substrato com a enzima PI3K e a ativação da Akt no tecido hepático e muscular também se mostraram diminuídas pela dieta e recuperadas com o uso da rosiglitazona. O estudo da lovastatina demonstrou efeito positivo da droga sobre a sensibilidade insulínica, revertendo a resistência induzida pela dieta hiperlipídica, expressa por valor de Kitt semelhante ao dos animais controle. Na via de sinalização da PI3K: fosforilação do IR e do IRS-I, associação do IRS-l à PI3k e ativação da Akt, tanto no tecido hepático como muscular, a lovastatina reverteu as alterações da dieta, com recuperação a valores semelhantes aos do grupo controle. Também nas vias de regulação, a dieta induziu maior fosforilação do IR em serina, maior fosforila do IRS-I em serina307, maior atividade da JNK e da proteína fosfatase PTPIB e menor ativação do IKB, efeitos que podem explicar a resistência desse modelo. A lovastatina reverteu todas essas alterações. Concluindo, a rosiglitazona reverteu as alterações causadas pela dieta hiperlipídica sobre as etapas iniciais da sinalização insulínica na via da PI3K. A lovastatina recuperou as alterações induzidas pela dieta hiperlipídica na transmissão do sinal insulínico, agindo sobre as vias de regulação da sinalização: ação da PTPIB, fosforilação do IR e do IRS-l em serina induzidos pela JNK e PTPIB e ativação da via inflamatória
Abstract: Insulin is the major anabolic hormone and acts through transporter activation, enzymes regulation and gene expression. This hormone uses' two main signaling pathways: the PI3K pathway, involved in its metabolic effects and the MAPK pathway, responsible for cell growth and differentiation. There are many mechanisms of regulation of insulin signaling. The use of a high- fat diet is a known model of insulin resistance with metabolic and signaling changes similar to those of human insulin resistance syndrome observed in diet induced obesity. Rosiglitazone is an agent of the class of thiazolidinediones, insulin-sensitizing agents whose effects are mainly due to the activation of PP ARy and are used to treat type 2 diabetes. Lovastatin is one of a class of a class of cholesterol synthesis inhibitors; recent studies have shown that this agent might have relevant effects on insulin resistance in both animal models and humans. The aim of this study was to evaluate the effects of two different drugs independent1y, rosiglitazone and lovastatin, on insulin signaling in liver and muscle of rats fed on a hígh-fat diet. We used four week old male Wistar rats, fed on a high- fat diet during four weeks and treated with rosiglitazone or lovastatin during the last week, compared to rats fed on standard chow. Fragments of liver and muscle tis sues were extracted from anesthetized animaIs and protein concentrations and phosphorylation degree were studied through immunoprecipitation and immunoblotting techniques. Insulin sensitivity was evaluated by insulin tolerance test and calculation of the disappearance rate constant (KitD. We observed that high-fat fed diet rats presented a significant decrease in Kitt compared to control rats. The animaIs that were fed with the high-fat diet and were treated with either one ofthe drugs presented a reversal ofthis effect. In the study of rosiglitazone, the high-fat model demonstrated a decrease in the IRS-I phosphorylation, IRS-l/PI3K association and activation of Akt and rosiglitazone administration resulted in the reversion of all the effects in liver and muscle. In addition to the effect on insulin sensitivity, the use of lovastatin was also associated with an increase in insulin-induced IR tyrosine phosphorylation and, in parallel, a decrease in IR serine phosphorylation and association with PTPIB. Our data also show that lovastatin treatment was associated with an increase in the insulin-stimulated IR/IRS-l/PI3KJ Akt pathway in the liver and musc1e of high-fat fed rats, in parallel with a decrease in the inflammatory pathway (JNK and IKKI3/IKB/NFKB) related to insulin resistance. In conclusion, rosiglitazone and lovastatin improved the altera_s in insulin signaling pathways presented by the high-fat model of insulin resistance
Doutorado
Clinica Medica
Doutor em Clínica Médica
11
Hale, P. J. "Insulin resistance in diabetes mellitus and obesity." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371516.
12
Eason, Robert C. "Treating type 2 diabetes through insulin resistance." Thesis, Aston University, 2002. http://publications.aston.ac.uk/10953/.
Анотація:
Type 2 diabetes is an insidious disorder, with micro and/or macrovascular and nervous damage occurring in many patients before diagnosis. This damage is caused by hyperglycaemia and the diverse effects of insulin resistance. Obesity, in particular central obesity, is a strong pre-disposing factor for type 2 diabetes. Skeletal muscle is the main site of insulin-stimulated glucose disposal and appears to be the first organ that becomes insulin resistant in the diabetic state, with later involvement of adipose tissue and the liver. This study has investigated the use of novel agents to ameliorate insulin-resistance in skeletal muscle as a means of identifying intervention sites against insulin resistance and of improving glucose uptake and metabolism by skeletal muscle. Glucose uptake was measured in vitro by cultured L6 myocytes and isolated muscles from normal and obese diabetic ob/ob mice, using either the tritiated non-metabolised glucose analogue 2-deoxy-D-glucose or by glucose disposal. Agents studied included lipoic acid, isoferulic acid, bradykinin, lipid mobilising factor (provisionally synonymous with Zinca2 glycoprotein) and the trace elements lithium, selenium and chromium. The putative role of TNFa in insulin resistance was also investigated. Lipoic acid improved insulin-stimulated glucose uptake in normal and insulin resistance murine muscles, as well as cultured myocytes. Isoferulic acid, bradykinin and LMF also produced a transient increase in glucose uptake in cultured myocytes. Physiological concentrations of TNFa were found to cause insulin resistance in cultured, but no in excised murine muscles. The effect of the M2 metabolite of the satiety-inducing agent sibutramine on lipolysis in excised murine and human adipocytes was also investigated. M2 increased lipolysis from normal lean and obese ob/ob mouse adipocytes. Arguably the most important observation was that M2 also increased the lipolytic rate in adipocytes from catecholamine resistant obese subjects. The studies reported in this thesis indicate that a diversity of agents can improve glucose uptake and ameliorate insulin resistance. It is likely that these agents are acting via different pathways. This thesis has also shown that M2 can induce lipolysis in both rodent and human adipocytes. M2 hence has potential to directly reduce adiposity, in addition to well documented effects via the central nervous system.
13
Kershner, David. "Oral Glucose Insulin Secretion Test for Identifying Patients with Insulin Resistance." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5634.
Анотація:
Insulin resistance is an increasing public health issue with the current literature, suggesting reduced sensitivity of insulin leads to adult onset diabetes and associated downstream pathologies that reduce life expectancy. The main objectives of this study were to evaluate the ability of the Oral Glucose Insulin Secretion Test (OGIST) to identify insulin resistance and examine differences in the insulin sensitivity based on gender, age, and ethnicity. This study was supported by the insulin resistance theory which focuses on the reduced ability of insulin to bind to the cellular insulin receptor, reducing the sensitivity of insulin. The OGIST lab results of a total of 250 patients, aged 18-65, were included in this study from a major city in the midwestern United States. Binomial logistic regression was used to evaluate the relationship between the dependent variables and the validation independent variables and analyze the possible differences seen in insulin, proinsulin, C-peptide, and HbA1c with age. The OGIST demonstrated the ability to identify elevated levels of insulin, proinsulin, and C-peptide at the end of the first phase insulin secretion to glucose. The results of this study demonstrated patients with insulin resistance exhibited a greater reduction in insulin production with age compared to those without insulin resistance. There were no changes observed between gender or ethnicity. The OGIST was the only test that demonstrated the ability to identify the individual's insulin sensitivity, β-cell function, and progression to diabetes. The ability of the OGIST to identify both insulin resistance and β-cell function can contribute to positive social change by encouraging further research for the early diagnosis and treatment of insulin resistance and the reduction in adult onset diabetes.
14
Wiggam, Malcolm Ivan. "Aspects of insulin resistance in essential hypertension and insulin-dependent diabetes mellitus." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387971.
15
MAIORANA, ARIANNA. "A Method to isolate omental adipose stem cells in pediatric patients: perspectives in investigating the pathogenesis of metabolic syndrome." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/516.
Анотація:
Il tessuto adiposo è coinvolto nella regolazione di metabolismo glucidico e lipidico, omeostasi energetica, infiammazione e risposta immune. L’obesità addominale gioca un ruolo chiave nella regolazione dello sviluppo dell’ insulino-resistenza per l’elevata lipolisi del tessuto adiposo viscerale e la secrezione della adipochine. Gli individui nati con basso peso alla nascita tendono ad avere una redistribuzione centrale del tessuto adiposo e sono ad alto rischio di sviluppare sindrome metabolica, diabete di tipo 2 e patologie cardiovascolari. Diversi studi volti a caratterizzare le cellule staminali di derivazione adipocitaria e la loro capacità di differenziamento sono stati effettuati sul tessuto adiposo sottocutaneo e viscerale di individui obesi. Nessuno studio è stato finora eseguito sul tessuto adiposo viscerale di soggetti pediatrici. La ragione principale è che la quantità di tessuto adiposo prelevabile dai bambini non è tale da consentire l’estrazione delle cellule staminali. Scopo di questo studio è stato stabilire un metodo per isolare cellule staminali di derivazione adipocitaria da campioni molto piccoli di tessuto adiposo omentale, ottenuto da bambini sottoposti a interventi di chirurgia addominale. Abbiamo stabilito un metodo riproducibile per isolare tali cellule da campioni pediatrici di tessuto adiposo omentale. La natura mesenchimale delle cellule è stata confermata dal loro profilo antigenico di superficie. Le cellule sono state inoltre sottoposte a differenziamento adipogenico e osteogenico in vitro. La disponibilità di linee di cellule staminali ottenute da tessuto adiposo omentale di soggetti in età pediatrica apre il sipario per ricerche future con l’intento di chiarire se la programmazione fetale dell’adipogenesi possa giocare un ruolo chiave nella patogenesi dell’origine fetale della sindrome metabolica, del diabete di tipo 2 e delle patologie cardiovascolari. Pertanto, la caratterizzazione di tali cellule potrebbe fornire maggiore comprensione del rischio metabolico correlato al ritardo di crescita ad inizio intrauterino, con potenziali implicazioni nella prevenzione delle alterazioni metaboliche a lungo termine.Adipose tissue is involved in the regulation of glucose and lipid metabolism, energy balance, inflammation and immune response. Abdominal obesity plays a key role in the development of insulin-resistance due to the high lipolytic rate of visceral adipose tissue and its secretion of adipocytokines. Subjects with low birth weight are prone to central redistribution of adipose tissue and are at high risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Several investigations refer to the physiology and pathophysiology of subcutaneous and visceral adipose tissue of adult obese subjects, focusing on the characterization of adipose-derived stem cells and their differentiation capacity. No study has been carried out so far on the visceral adipose tissue of paediatric patients. The main limitation is the amount of fat tissue available from children, adipose stem cells can be extracted from. Aim of this investigation was to establish a method to successfully isolate adipose stem cells from very small specimens of omental fat obtained from children undergoing abdominal surgery. procedure employed to extract adipose stem cells from large amounts of lipoaspirate. We established a feasible method to isolate adipose stem cells from paediatric specimens of omental fat. The mesenchymal nature was confirmed by the surface antigenic profile of these cells. Cells also underwent adipogenic and osteogenic differentiation in vitro. The availability of stem cell lines from omental adipose tissue of paediatric subjects sets up the stage for future investigations aimed to unravel whether a fetal programming of adipogenesis may play a key role in the pathogenesis of fetal origin of metabolic syndrome, type 2 diabetes and cardiovascular disease. Therefore, the knowledge of the behavior of visceral adipose tissue derived stem cells could provide more understanding of the metabolic risk related to intrauterine growth retardation, with potential clinical implications in the prevention of long-term metabolic alterations.
16
Hunter, Steven J. "Insulin resistance : underlying mechanisms and influence of treatment." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337044.
17
Frangioudakis, Georgia St Vincent's Clinical School UNSW. "Insulin signal transduction in vivo in states of lipid-induced insulin resistance." Awarded by:University of New South Wales. St Vincent's Clinical School, 2004. http://handle.unsw.edu.au/1959.4/27419.
Анотація:
Insulin resistance is the major metabolic defect in obesity and Type 2 diabetes. Increased lipid accumulation is strongly associated with insulin resistance. A significant component of insulin resistance is thought to be a reduced ability of insulin to activate the cascade of phosphorylation events that lead to the metabolic effects of this hormone. The broad aims of this thesis were to examine the effect of high-fat diets containing different fat subtypes on in vivo insulin signalling, under conditions normally used to detect whole body insulin resistance, and to compare the effects of acute and chronic lipid oversupply on insulin signalling in vivo. Time-course and dose-response effects of insulin stimulation on site-specific phosphorylation of key signalling proteins were studied in rat tissues in vivo, to establish an appropriate experimental system to examine the onset of activation of the insulin signalling pathway. It was determined that short insulin infusions with concurrent glucose infusion, similar to the beginning of a euglycaemic-hyperinsulinaemic clamp, significantly increased the phosphorylation of major intermediates of the insulin signalling pathway in important tissues of insulin action (skeletal muscle [RQ], liver [LIV] and white adipose tissue [EPI]). These experiments provided a platform to study insulin signalling under the same conditions used to study lipid-induced insulin resistance. The provision of diets enriched in polyunsaturated or saturated fatty acids (FA) resulted in the corresponding enrichment of these fat subtypes in rat plasma and tissues. However, the effects on insulin signalling were essentially the same. Both fat diets induced defects in sitespecific phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (PKB) in RQ and LIV, but not EPI. This suggests that the amount of fat in the diet, rather than enrichment in a particular fat subtype, had a greater impact on the development of signalling defects and that the response to high-fat feeding was tissue-specific. A 3hr elevation of circulating FA (using a lipid/heparin infusion), to a level that is relevant in clinical Type 2 diabetes, impaired insulin-stimulated PKB phosphorylation with no significant effect on IRS-1 phosphorylation. This suggests that there may be differences in the way acute and chronic exposure to increased FA impair insulin signalling. The phosphorylation defects observed in both chronic and acute studies did not seem to be associated with activation of major stress signalling pathways (JNK and NFkB), which have been suggested to have a role in lipidinduced insulin resistance. In conclusion, these studies demonstrate that impaired IRS-1 and PKB phosphorylation do have a role in the reduced insulin action observed with lipid oversupply in vivo, because the changes were detected under similar conditions as those used to determine whole body insulin resistance.
18
Vella, Sandro. "Pharmacological modulation of insulin resistance : benefits and harms." Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/4428eca5-5018-4816-95d0-30c0a3043409.
Анотація:
Aims: Thiazolidinediones have been advocated as second or third line insulin sensitizing agents in the management of type 2 diabetes (T2DM). Their widespread use has been hampered by concerns about their cardiovascular safety, including fluid retention. Metformin is established as first-line glucose-lowering pharmacotherapy in T2DM. It has also been suggested that it may have benefits in alleviating insulin resistance in type 1 diabetes (T1DM). This thesis examined: (i) cardiovascular, renal and metabolic differences between individuals with T2DM ‘tolerant’ or ‘intolerant’ of TZDs; (ii) risk factors for TZD-associated oedema in T2DM; and (iii) the potential for metformin as adjunct therapy in T1DM. Methods: (i) A small clinical study characterising TZD tolerant and intolerant individuals with T2DM; (ii) A population-based epidemiological study of TZD induced oedema in individuals with T2DM in Tayside, Scotland (using incident loop diuretic prescription as a surrogate); (iii) A systematic review and meta-analysis of published studies of adjunct metformin in T1DM. Results (i) During a five-day high sodium diet, two known TZD-intolerant individuals with T2DM had reductions in haematocrit, aldosterone, and diastolic BP and increases in ANP and central and peripheral augmentation indices which were outwith reference ranges derived from nine TZD-tolerant individuals; (ii) Predictors of time to loop diuretic prescription included age, body mass index, systolic BP, haematocrit, ALT and macrovascular disease but rates of this outcome did not differ by therapy: 4.3% (TZDs) vs 4.7% (other agents) [unadjusted OR 0.909 (95% CI 0.690, 1.196); p = 0.493]; (iii) In meta-analysis of nine small studies in T1DM (192.8 patient-years of follow-up), metformin was associated with a reduction in total daily insulin dose (6.6 units/day; p < 0.001) but no studies examined cardiovascular surrogates or outcomes. Conclusions: Hypotheses were generated for several potential biomarkers predictive of TZD-induced oedema but the clinical importance of TZDs as a risk factor for oedema in individuals with T2DM was questioned. As there is some evidence for the safety of metformin as an adjunct therapy in T1DM but little evidence of efficacy, larger studies are warranted.
19
Song, Xiao Mei. "Insulin signal transduction in skeletal muscle : special consideration for insulin resistance and diabetes /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4502-0/.
20
Danielsson, Anna. "Insulin signalling in human adipocytes : mechanisms of insulin resistance in type 2 diabetes." Doctoral thesis, Linköping : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-10327.
21
Lindmark, Stina. "Neurohormonal mechanisms in insulin resistance and type 2 diabetes." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-225.
22
Reali, Federico. "Dynamical models for diabetes: insights into insulin resistance and type 1 diabetes." Doctoral thesis, Università degli studi di Trento, 2017. https://hdl.handle.net/11572/369184.
Анотація:
This thesis summarizes my work in systems biology as a PhD student at The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI) and at the University of Trento, department of Mathematics.
Systems biology is an interdisciplinary field that aims at integrating biology with computational and mathematical methods to gain a better understanding of biological phenomena [5, 6]. Among these methods, mathematical and dy- namical modeling have driven the discovery of mechanistic insights from the static representations of phenomena, that is, data. As a result, mathematical and dynamical models have now become standard tools to support new discoveries in biology and in public health issues. For example, models assist governments in determining the policies to contain the spreading of the diseases and in decisions such as vaccine purchases [7]. Similarly, complex and accurate models of the cardio-vascular systems guide surgeons during many procedures on pa- tients [8]. Furthermore, dynamical models of signaling cascades help researchers in identifying new potential drug targets and therapies for many diseases [9]. We used these modeling techniques to address biological questions related to diabetes and insulin resistance. Within this framework, this thesis contains two articles I contributed to, that focus on diabetes. These works are published in the journal of Nature Scientific Reports and are included in Chapters 3 and 4.
A significant contribution to the development of these models, and models in general, is given by optimization. Optimization is often used in modeling to determine certain unknown values or factors in a way that allow the model to optimally reproduce the experimental data. Moreover, the parameters of a model that correctly describe the undergoing dynamics may be used as diagnostic tools [10–13]. To this end, this thesis contains a methodological appendix that includes a review of optimization algorithms that has been submitted to the journal of Frontiers in Applied Mathematics and Statistics, special topic Optimization. The content of this article is reported in Appendix A.
23
Reali, Federico. "Dynamical models for diabetes: insights into insulin resistance and type 1 diabetes." Doctoral thesis, University of Trento, 2017. http://eprints-phd.biblio.unitn.it/1962/1/Reali_PhDThesis.pdf.
Анотація:
This thesis summarizes my work in systems biology as a PhD student at The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI) and at the University of Trento, department of Mathematics.
Systems biology is an interdisciplinary field that aims at integrating biology with computational and mathematical methods to gain a better understanding of biological phenomena [5, 6]. Among these methods, mathematical and dy- namical modeling have driven the discovery of mechanistic insights from the static representations of phenomena, that is, data. As a result, mathematical and dynamical models have now become standard tools to support new discoveries in biology and in public health issues. For example, models assist governments in determining the policies to contain the spreading of the diseases and in decisions such as vaccine purchases [7]. Similarly, complex and accurate models of the cardio-vascular systems guide surgeons during many procedures on pa- tients [8]. Furthermore, dynamical models of signaling cascades help researchers in identifying new potential drug targets and therapies for many diseases [9]. We used these modeling techniques to address biological questions related to diabetes and insulin resistance. Within this framework, this thesis contains two articles I contributed to, that focus on diabetes. These works are published in the journal of Nature Scientific Reports and are included in Chapters 3 and 4.
A significant contribution to the development of these models, and models in general, is given by optimization. Optimization is often used in modeling to determine certain unknown values or factors in a way that allow the model to optimally reproduce the experimental data. Moreover, the parameters of a model that correctly describe the undergoing dynamics may be used as diagnostic tools [10–13]. To this end, this thesis contains a methodological appendix that includes a review of optimization algorithms that has been submitted to the journal of Frontiers in Applied Mathematics and Statistics, special topic Optimization. The content of this article is reported in Appendix A.
24
Beatty, Olivia Louise. "Aspects of insulin resistance, insulin secretion and microalbuminuria in diabetic, hypertensive and non-diabetic subjects." Thesis, Queen's University Belfast, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484068.
25
Ng, Foong Loo Yvonne Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Insulin action: unravelling AKT signalling in Adipocytes." Awarded by:University of New South Wales. Biotechnology & Biomolecular Sciences, 2009. http://handle.unsw.edu.au/1959.4/44628.
Анотація:
The Ser/Thr kinase Akt plays an important role in many of insulin's actions including GLUT4 translocation to the plasma membrane (PM). However, there are several features of Akt's regulation of GLUT4 translocation that remain unclear. The goal of my thesis was to resolve some of the following questions: Is activation of Akt sufficient to stimulate GLUT4 translocation? What is the quantitative relationship in signal transmission between individual components within the Akt cascade? What is the role of Akt in insulin resistance? To determine if activation of Akt is sufficient to mediate GLUT4 translocation, I developed a drug-inducible heterodimerisation strategy to activate Akt2 independently of other potential insulin signalling pathways. These studies revealed that activation of Akt2 resulted in rapid stimulation of GLUT4 translocation to a similar extent with maximum insulin, indicating that Akt2 is sufficient for this event. It was previously observed that maximum effect of insulin on GLUT4 translocation was obtained with minimum activation of Akt. To resolve this discrepancy, the relationship between Akt signalling components was examined using a quantitative kinetic and dose response approach combined with hierarchical cluster analysis. Most notably I observed a strong relationship between Akt at the PM, but not Akt in the whole cell lysate, with its substrate phosphorylation. Active pools of phospho-Akt and -AS160, a major substrate involved in GLUT4 translocation, were found in the lipid raft, highlighting the importance of subcellular partitioning of key signalling components for achieving biological specificity. The involvement of Akt in insulin resistance was investigated using the heterodimerisation strategy. These studies revealed that insulin itself initiates a pathway that causes insulin resistance by converging on target(s) downstream of Akt. This inhibitory pathway emanates from PI3-kinase and is likely induced by a range of insults including chronic insulin and dexamethasone. In conclusion, Akt is a crucial element in the insulin action pathway that exhibits precise spatial regulation. While the role of this nanoregulation of Akt in disease remains to be evaluated, my studies suggest that the major defect contributing to insulin resistance occurs downstream of Akt. The elucidation of this target will have major implications for metabolic diseases.
26
Botteri, Gaia. "Novel potential determinants in endoplasmic reticulum stress, inflammation and insulin resistance: Apo CIII and sAPPβ". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/553241.
Анотація:
Diabetes represents one of the biggest health challenges of the 21st century. Insulin resistance is the primary defect in the most common form of diabetes, type 2 diabetes mellitus (T2D), and is defined as a failure in the capacity of insulin to drive glucose into its target tissues. This condition both predicts and precedes the development of T2D.
Loss of insulin sensitivity in skeletal muscle is the major defect in T2D and is believed to be critical in the pathogenesis of this disease. Elucidating new molecular mechanisms involved in insulin resistance in skeletal muscle may lead to the development of new strategies for the prevention and treatment of T2D.
Insulin resistance develops as the result of the expansion of adipose tissue in obese individuals, which releases increased amounts of fatty acids, hormones, pro-inflammatory cytokines and other factors. Most of these molecules induce the activation of a chronic low-level inflammatory process that contributes to insulin resistance and T2D. The molecular mechanisms by which these molecules induce a low-grade and chronic inflammatory process in obese patients are not completely understood. However, some studies have shown that alterations in the endoplasmic reticulum (ER) might contribute to the development of an inflammatory status and consequently to insulin resistance.
Obesity and insulin resistance are also characterized by the presence of atherogenic dyslipidemia, which refers to elevated levels of triglycerides (TG) and the particles responsible for carrying these lipids in the plasma, the very low-density lipoproteins (VLDL), low levels of high-density lipoproteins (HDL), and increased levels of small, dense low-density lipoproteins (sdLDL). In addition to TG, VLDL also contain apolipoproteins, of which apolipoprotein CIII (Apo CIII) is one of the most abundant. Although plasma levels of VLDL and Apo CIII are increased in diabetic patients, little was known about whether the increase in the levels of these lipoproteins and apolipoproteins contributes to exacerbate insulin resistance and the mechanisms involved.
Recent evidence indicates that subjects suffering T2D are at higher risk of developing Alzheimer’s Disease (AD). In addition, several evidences point out that the converse is also true, since cognitive impairment and Alzheimer’s dementia can induce central and peripheral insulin resistance, thus increasing the risk of T2D.
The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) or β-secretase is a key enzyme involved in AD and is responsible for the cleavage of Amyloid Precursor Protein in the amyloidogenic pathway. It has been recently reported that BACE1 is also implicated in glucose metabolism. Thus, BACE1-deficient mice are protected against high fat diet (HFD)-induced glucose intolerance and inhibition of BACE1 activity increases insulin-independent glucose uptake. BACE1 is proteolytically active not only in the brain but also in skeletal muscle, suggesting that this enzyme might be involved in development of systemic insulin resistance. However, little was known about whether BACE1 contributes to ER stress, inflammation and insulin resistance.
In this thesis, we report that the increase in the levels of VLDL can promote ER stress, inflammation, and insulin resistance in skeletal muscle through Apo CIII-mediated activation of the toll-like receptor 2.
Moreover, BACE1 inhibition in myotubes results in an improvement in lipid-induced ER stress, inflammation, and insulin resistance. Further, the product of BACE1 enzymatic activity, soluble amyloid precursor protein β (sAPPβ), mimics the effects of palmitate and induces ER stress, inflammation and insulin resistance.
Overall, these findings suggest that both VLDL-Apo CIII and sAPPβ are new determinants involved in ER stress, inflammation and insulin resistance in skeletal muscle.
27
Relton, Caroline L. "The identification and characterisation of genes associated with insulin resistance." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264425.
28
Al-Rifai, Sarah. "Rôle de la résistine hypothalamique dans l'installation de l’inflammation hypothalamique et l’insulino-résistance : impact de la consommation aigüe ou chronique d'un régime hyper lipidique." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS095/document.
Анотація:
La prévalence de l’obésité est en net progrès et constitue un problème majeur de santé publique. Cette pathologie est d’autant plus dangereuse qu’elle s’accompagne d’un cluster de désordres métaboliques dont l’inflammation chronique de bas grade et la résistance à l’insuline, principal facteur de risque du diabète de type 2. Les études montrent que la consommation d’un régime hyper lipidique (HFD) représente la cause majeure qui expose à l’obésité et aux pathologies qui lui sont associées. L’obésité induite par un régime HFD s’associe en effet à une inflammation hypothalamique ainsi qu’une altération des circuits neuronaux régissant le contrôle de la balance énergétique, ces altérations sont propices aux développements de résistances à l’insuline et à la leptine. De récentes études montrent que la consommation d’un régime HFD de quelques jours seulement s’accompagne d’une inflammation hypothalamique transitoire, antérieure à l’installation de l’obésité et à l’inflammation périphérique. Ces résultats suggèrent que l’inflammation hypothalamique précoce représente une étape critique dans le développement de l’obésité et de ses altérations. Les médiateurs et les voies de signalisations impliqués dans l’installation de l’inflammation hypothalamique ne sont pas totalement élucidées. Chez les rongeurs, la résistine est associée à l’inflammation et l’insulino-résistance au cours de l’obésité. Bien que majoritairement produite par le tissu adipeux, les études montrent que la résistine est également exprimée par l’hypothalamus ; toutefois, peu d’études renseignent sur son action au niveau central. Notre équipe a démontré chez le rat, qu’une perfusion centrale de résistine altère fortement la sensibilité à l’insuline via l’activation du récepteur TLR4 et l’induction des principales voies de l’inflammation. Dans ce contexte, l’objectif de cette étude a été d’investiguer le rôle de la voie résistine/TLR4 dans l’installation de l’inflammation hypothalamique associée au régime HFD. Nous montrons pour la première fois que, chez la souris, la consommation d’un régime HFD provoque une augmentation de l’expression génique de la résistine dans l’hypothalamus dès 3 jours de régime HFD. L’expression de la résistine est diminuée jusqu’au niveau basal après 8 jours et est de nouveau fortement augmentée après 8 semaines de régime HFD. Nous montrons que l’augmentation de l’expression de la résistine est concomitante avec la gliose réactionnelle associée au régime HFD de court terme, connue pour précocement altérer l’équilibre de la balance énergétique. De façon intéressante, nous montrons quel’augmentation de l’expression de la résistine est observée dans les neurones anorexigènes POMC, critiques pour le maintien de l’homéostasie énergétique ainsi que dans les tanycytes dont les prolongements contactent les capillaires fenêtrés du sang porte hypothalamohypophysaire et dont l’importance pour l’équilibre de la balance énergétique a été démontrée. De façon intéressante, nous montrons que la résistine active l’inflammation dans les tanycytes via TLR4 suggérant que la résistine pourrait promouvoir l’inflammation au sein des tanycytes en réponse au régime HFD, et ce même à court terme. De plus, nous montrons qu’une ICV de 3 jours de résistine chez la souris provoque une inflammation hypothalamique ainsi qu’une gliose réactionnelle au sein de l’ARC qui rappellent les effets du régime HFD. De façon intéressante, nos résultats montrent que l’invalidation du récepteur TLR4 aboli l’inflammation et la gliose réactionnelle hypothalamiques induites par l’ICV de résistine. L’ensemble nos données démontrent que la voie résistine/TLR4 pourrait jouer un rôle critique dansl’inflammation hypothalamique associée au régime HFD de court et long terme, quiprédispose à l’obésitéObesity is closely linked to a cluster of metabolic disorders including chronic low-grade inflammation and insulin resistance, which constitutes a principal risk factor for type 2 diabetes. In rodents, cumulative evidence support that the consumption of high fat diet (HFD) is among the most important nutritional factors predisposing to obesity associated insulin resistance and low-grade inflammation. Indeed, HFD induces hypothalamic inflammation and deregulates energy homeostasis control through the alteration of hypothalamic insulin and leptin responsiveness, considered as the main anorexigenic hormones. In addition, it has been shown that unlike peripheral inflammation, which occurs as a consequence of obesity, hypothalamic inflammation develops selectively in the hypothalamic arcuate nucleus (ARC) within the first days of HFD exposure. These data suggest that hypothalamic inflammation is a critical step in the early onset of the deregulation of energy homeostasis by HFD. The cellular and molecular mechanisms underlying obesity-induced hypothalamic inflammation are still not fully characterized. In rodents, resistin is described as a causal factor in obesitymediated insulin resistance and type 2 diabetes. Resistin is mainly secreted by adipose tissue in rodents but an endogenous expression of resistin was also reported in the hypothalamus. However, its action at the central level is not fully understood. Our group recently demonstrated that central resistin, via hypothalamic TLR4, promotes overall insulin resistance through the promotion of inflammatory pathway. In this context, we aimed to investigate the role of resistin/TLR4 pathway in HFD-induced hypothalamic inflammation and insulin resistance. In the present study we report for the first time that both short and long term HFD are associated with a significant increase of resistin expression throughout the MBH. Our results revealed a transient increase in resistin mRNA expression in the ARC after 3 days of HFD, followed by a decline to baseline at day 8 and an expression that increases again after 8 weeks of HFD. We showed that the increase of resistin expression is concomitant with short term HFD-induced ARC reactive gliosis, known to early disrupt energy balance and to predispose to obesity. Interestingly, our results revealed that resistin is expressed by POMC neurons which are critical for energy balance and tanycytes that have the specificity to contact both cerebro-spinal fluid and fenestrated capillary in the mediane eminence. Interestingly, we show that resistin induces tanycytes inflammation through TLR4 suggesting that resistin could promote inflammation in tanycytes in response to short term HFD. Additionally, we show that ICV resistin markedly increases inflammatory markers in the hypothalamic arcuate nucleus in association with reactive gliosis involving recruitment of both microglia and astrocytes. Interestingly, we report that the knockdown of TLR4 almost completely abolished resistin-dependent both hypothalamic inflammation and reactive gliosis. Our data demonstrate that restitin/TLR4 pathway could play a critical role in HFD-diet induced hypothalamic inflammation in response to short and long term HFD which predispose to obesity, a hallmark of metabolic syndrome
29
Agbaje, Olorunsola Fatai. "Modelling methodologies to assess insulin resistance and insulin secretion in type 2 diabetes subjects." Thesis, City University London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397933.
30
Clarke, Stephen. "Liver steatosis and insulin-resistance : reversal by Sutherlandia frutescens." Thesis, Nelson Mandela Metropolitan University, 2014. http://hdl.handle.net/10948/d1020788.
Анотація:
Type 2 diabetes mellitus (T2DM) is rapidly emerging as one of the greatest global health issues of the 21st century. Insulin-resistance is a condition associated with T2DM and in the cell it is defined as the inadequate strength of insulin signalling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic, gene expression, and mitogenic aspects of cellular function. To investigate the potential mechanisms involved in the development of insulin-resistance, two in vitro liver cell models were established using palmitate or a combination of insulin and fructose as inducers. The development of insulin-resistance was determined via the capacity of the hepatocytes to maintain normal glucose metabolism functionality by measuring hepatic gluconeogenesis and glycogenolysis. It was established that the treatments induced the development of insulinresistance after 24 hours chronic exposure. Previous studies have investigated the potential of Sutherlandia frutescens extracts as therapeutic agents for insulin-resistance. The aim of this study was thus to investigate the ability of a hot aqueous extract of S. frutescens to reverse the insulin-resistant state, via measuring gluconeogenesis and glycogenolysis, the associated changes in cellular physiology (lipid accumulation, oxidative stress, and acetyl- CoA levels), and changes in mRNA expression. The results showed that S. frutescens had a significant effect on reversing the insulin-resistant state in both models of insulin-resistance. Furthermore, S. frutescens was capable of reducing lipid accumulation in the form of triacylglycerol in the high insulin/fructose model, while this was unaffected in the palmitate model. However, S. frutescens did reduce the accumulation of diacylglycerol in the palmitate model. Oxidative stress, seen to be associated with the insulin-resistant state, was successfully treated using the extract, as indicated by a reduction in reactive oxygen species. However no change was seen in the nitric oxide levels, in either model. Interestingly, although S. frutescens had no effect on the level of acetyl-CoA in the insulin/fructose model, it was found to increase this in the palmitate model. It is suggested that this may be due to increased β-oxidation and metabolic activity induced by the extract. The analysis of mRNA expression gave some insight into possible mechanisms by which insulin-resistance develops, although the results were inconclusive due to high variability in samples and the possibility of the RNA being compromised. Future studies will address this issue. The results of this study reflect different proposed clinical causes of insulin-resistance through the responses seen in the two cell models. These indicate that liver steatosis and insulin-resistance are induced by high palmitate as well as high insulin and fructose levels, and reversed by S. frutescens. Therefore the potential of S. frutescens to be used as a therapeutic agent in the treatment of insulin-resistance is indicated by this study.
31
Nowak, Christoph. "Insulin Resistance : Causes, biomarkers and consequences." Doctoral thesis, Uppsala universitet, Molekylär epidemiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316891.
Анотація:
The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors. The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality. In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk. In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.
32
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/.
33
Tobar, Natália. "Efeitos da diacereína sobre a resistência à insulina em modelo animal de obesidade e diabetes mellitus tipo 2." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311205.
Анотація:
Orientador: Mario Jose Abdalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: As alarmantes estatísticas mundiais sobre a incidência de obesidade e diabetes mellitus tipo 2 (DM2) associadas aos seus índices de avanço já considerados epidêmicos permitem classificá-los como alguns dos mais desafiadores problemas de saúde pública da atualidade. A obesidade representa um dos principais fatores de risco para o desenvolvimento da resistência à insulina e DM2 e o solo comum entre estes eventos encontra-se em um processo inflamatório sistêmico exacerbado, caracterizado por uma produção anormal de citocinas pró-inflamatórias e proteínas de fase aguda. Além de contribuem para o desenvolvimento de dislipidemia, hipertensão arterial, obesidade e aterosclerose, mediadores inflamatórios atuam como moduladores negativos da ação da insulina principalmente através da ativação de proteínas intracelulares serina quinases, como JNK e IKK?, que prejudicam a transdução do sinal desencadeado pela ligação da insulina ao seu receptor celular. A Diacereína é um composto de origem vegetal que apresenta propriedades anti-inflamatórias pouco exploradas em doenças não articulares. A Reína, seu metabólito ativo, tem demonstrado inibir a síntese e atividade de citocinas pró-inflamatórias como TNF-?, IL-6 e principalmente IL-1? através do constante bloqueio de NF B. Sendo a resistência à insulina e DM2 distúrbios metabólicos associados à obesidade e a um processo inflamatório crônico, e sabendo-se ainda que atualmente os recursos disponíveis para o tratamento de tais desordens apresentam limitada eficácia, acreditamos que os efeitos anti-inflamatórios da Diacereína reflitam positivamente sobre a sinalização insulínica, permitindo classificá-la como uma alternativa terapêutica em potencial para a redução ou atenuação da manifestação clínica da resistência à insulina e DM2
Abstract: Obesity represents one of the main risk factors to the development of insulin resistance and type 2 diabetes. The common basis among these events is a chronic and systemic inflammatory process characterized by the activation of JNK and IKK?/NF B pathways and upregulated cytokine synthesis. The objective of this work was to evaluate the effects of diacerhein administration, an anti-inflammatory anthraquinone which is probably a JNK and IKK?/ NF?B pathways inhibitor, on the insulin sensitivity in diet-induced obese mice. Swiss mice were fed with conventional chow (C group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided in DAR10 and DAR20 groups according to the doses of 10 or 20 mg/kg of diacerhein administered. Through the Western Blot analysis, we quantified the expression and phosphorylation of IR, IRS-1 and Akt and of inflammatory mediators which modulate the insulin signaling in a negative way (IKK?, JNK and iNOS). DAR 10 and DAR20 animals presented an expressive improvement in their ITT and GTT, fasting serum glucose and insulin levels and a significant increase in the phosphorylation levels of insulin induced IR, IRS-1 and Akt in liver, muscle and adipose tissue. There was also a relevant inhibition of IKK?, I?B? and JNK phosphorylation and iNOS expression in treated mice. Our results show that trough the reversion of the low-grade subclinical inflammation, diacerhein improved glucose tolerance and insulin sensitivity in DIO animals. It suggests potential beneficial effects of this drug in the treatment of insulin resistance and type 2 diabetes
Mestrado
Ciencias Basicas
Mestre em Clinica Medica
34
Calixto, Antonio Ramos 1976. "Obesidade central e hiperglicemia influênciam o aumento da concentração plasmática da enzima dipeptidil peptidase 4 (DPP-4)." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308482.
Анотація:
Orientador: Bruno Geloneze NetoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Objetivo: O principal objetivo deste estudo foi avaliar as relações das concentrações enzimáticas da DPP-4 com adiposidade e o grau de tolerância à glicose. Métodos: Foram avaliados 227 indivíduos (Mulheres: 64,8% Homens: 35,2%) de ambos os sexos, 73 indivíduos com DM2, com idade entre 18-80 anos e com IMC entre 18,5 a 47 kg/m². Os indivíduos foram divididos em 4 grupos: Não Obesos Normoglicêmicos (nOb-NG), Não Obesos Hiperglicêmico (nOb-HG), Obesos Normoglicêmicos (Ob-NG) e Obesos Hiperglicêmicos ( Ob-HG). Foram considerados obesos indivíduos com IMC>30 e hiperglicêmicos HbA1c >6,0. Resultados: Observamos um aumento na concentração da DPP-4 no grupo de Ob-HG (p>0,05), comparado à outros três grupos (nOb-NG, nOb-HG e Ob-NG); houve correlação positiva entre a concentração da DPP-4 e HbA1c (p>0,05), nos grupos separados em: Não Obesos, Obesos, Normoglicêmicos e hiperglicêmicos; entre as mulheres, a concentração de DPP-4 teve correlação negativa (p<0,05) com a circunferência do quadril e a circunferência da coxa em mulheres; correlação positiva (p<0,05) com as razões pescoço/coxa e cintura/coxa; entre os homens a concentração da DPP-4 teve correlação negativa com a massa magra. Conclusões: Pacientes obesos e com hiperglicemia apresentam a concentração da DPP-4 elevada, quando comparados com indivíduos normoglicêmicos magros ou obesos. Existe uma associação entre a distribuição centrípeta do tecido adiposo e o aumento da concentração da DPP-4, cuja causalidade não está caracterizada até o presente momento. Nosso trabalho fornece bases fisiopatológicas para o tratamento do DM2 baseado na inibição da DPP-4 corroborando com os achados clínicos em ensaios randomizados e na prática clínica. De fato, as terapias baseadas em incretinas, em destaque para a inibição da DPP-4, tem se mostrado efetivas no tratamento do DM2
Abstract: Objective: the aim of this study was to evaluate the relationship between enzymatic concentrations of DPP-4 and the level of adiposity and glucose tolerance. Methods: we assessed 227 participants (women: 64,8% male: 35,2%) of both sexes, 73 subjects with T2DM, aged between 18 and 80 years, with BMI between 18,5 and 47 kg / m². The subjects were divided into 4 groups: normoglycemic nonobese (NG-NOB), hyperglycemic nonobese (HG-NOB), normoglycemic obese (Ob-NG) and hyperglycemic obese (Ob-HG). Were considered obese subjects with BMI> 30 and hyperglycemic A1c> 6,0. Results: We reported an increased enzymatic concentration of DPP-4 in Ob-HG group (p> 0.05) compared to the other three groups (NG-NOB, NOB and Ob-HG-NG); a positive correlation was found between concentration of DPP -4 and HbA1c (p> 0.05) in groups: not obese, obese, normoglycemic and hyperglycemic; among women, the concentration of DPP-4 had a negative correlation (p <0.05) and hip and thigh circumferences; positive correlation (p <0.05) with neck-to-thigh and waist-to-thigh ratio; among men, the concentration of DPP-4 had a negative correlation with lean mass. Conclusions: obese patients with hyperglycemia have higher concentrations of DPP-4 compared with normoglycemic lean or obese individuals. There is an association between the centripetal distribution of body fat and increasing concentrations of DPP-4, whose mechanisms remain unclear. Our work provides pathophysiological bases for treatment of T2DM based on inhibition of DPP-4 confirming findings of randomized clinical trials and clinical practice. In fact, incretin-based therapies, in particular the inhibition of DPP-4, has proven effective in the treatment of T2DM
Mestrado
Clinica Medica
Mestre em Clinica Medica
35
Malvezzi, Maria Aparecida Pereira Nunes. "Efeito dose-resposta do fluoreto em parâmetros relacionados à resistência à insulina e na expressão de proteínas hepáticas e musculares em camundongos NOD." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-24012019-090227/.
Анотація:
Enquanto alguns trabalhos relatam que a administração crônica de F causa resistência à insulina, estudo recente do nosso grupo revelou que em animais com diabetes previamente induzido por estreptozotocina, a administração crônica de baixas doses de F aumenta a sensibilidade à insulina, por interferir em vias metabólicas musculares e hepáticas. Entretanto, o diabetes induzido por estreptozotocina causa alterações metabólicas diferentes do diabetes tipo 1. Desta forma, seria interessante verificar se o aumento da sensibilidade à insulina induzido por baixas doses de F também ocorreria utilizando um modelo de diabetes que mimetiza melhor o diabetes tipo 1 (camundongos NOD non-obese diabetic). Com base no exposto, o presente estudo investigou, em camundongos NOD recémdesmamados e expostos cronicamente a doses de F na água de beber que simulam a ingestão de F pela água artificial ou naturalmente fluoretada, se ocorrem alterações relacionadas à resistência à insulina, bem como na expressão de proteínas hepáticas e musculares. Para tanto, 24 camundongos NOD (não obesos diabéticos), obtidos imediatamente após o desmame, foram divididos em 3 grupos, de acordo com a concentração de F presente na água de beber (0, 10 ou 50 ppm), que foi administrada por um período de 21 dias. Decorrido o período experimental, os animais foram eutanasiados, sendo coletado o sangue para análise de F (eletrodo íon específico), glicose (método da glicose-oxidase) e insulina (ELISA), bem como o fígado e músculo gastrocnêmio, para análise proteômica quantitativa livre de marcadores (software Protein Linx Global Service). Os dados foram analisados por ANOVA e teste de Tukey, ou teste de Kruskal-Wallis e teste de Dunn (p<0,05). Apenas o grupo tratado com 50 ppm F apresentou concentração plasmática de F significativamente maior que o controle. Os animais tratados com 10 ppm F tiveram glicemia significativamente menor que o grupo controle, mas não houve diferença significativa entre os grupos em relação à insulinemia. A % de função das células pancreáticas foi significativamente maior no grupo tratado com 10 ppm F, quando comparado aos demais. A análise proteômica revelou alterações no perfil proteômico tanto do tecido muscular quanto do hepático. No tecido muscular, o grupo de 10 ppmF apresentou, em relação ao controle, expressão aumentada de proteínas envolvidas no metabolismo energético. Já o grupo de 50 ppm F, em relação ao controle, apresentou expressão aumentada de proteínas relacionadas à contração muscular, diferenciação do tecido adiposo marrom e apoptose. Para o tecido hepático, também foi observada expressão aumentada no grupo submetido a 10 ppm F em relação ao controle de proteínas envolvidas no metabolismo energético e síntese proteica, com destaque ainda para o aumento de isoformas de Glutathione S transferase, bem como de Heat shock-related 70 kDa protein 2. No grupo submetido a 50 ppmF foi observada alteração de proteínas envolvidas no metabolismo de espécies reativas de oxigênio e metabolismo energético. O aumento na expressão de proteínas antioxidantes, mediante tratamento com a baixa concentração de F, pode ajudar a explicar a proteção contra o desenvolvimento do diabetes, o que deve ser comprovado em estudos mecanísticos futuros.While some studies report that chronic administration of fluoride (F) causes insulin resistance, a recent study in our group found that in animals with diabetes previously induced by streptozotocin diabetes, chronic low-dose F administration increases insulin sensitivity by interfering with metabolic pathways in muscle and liver. However, streptozotocin-induced diabetes causes different metabolic changes from type 1 diabetes. Thus, it would be interesting to see whether increased insulin sensitivity induced by low doses of F would also occur using a diabetes model that better mimics type1 diabetes (NOD mice - non-obese diabetic). Based on the foregoing, the present study investigated in NOD mice chronically exposed to doses of F in drinking water that simulate the ingestion of F by artificial or naturally fluoridated water, if there are changes related to insulin resistance as well as in the expression of liver and muscle proteins. Twenty-four NOD mice, obtained immediately after weaning, were divided into three groups, according to the concentration of F present in the drinking water (0, 10 or 50 ppm), which was administered by a period of 21 days. After the experimental period, the animals were euthanized and the blood was collected for analysis of F (ionspecific electrode), glucose (glucose oxidase method) and insulin (ELISA), as well as the liver and gastrocnemius muscle, for quantitative proteomic analysis (Protein Linx Global Service software). Data were analyzed by ANOVA and Tukey\'s test, or Kruskal- Wallis and Dunn\'s test (p <0.05). Only the group treated with 50 ppm F had plasma F concentration significantly higher than the control group. Animals treated with 10 ppm F had significantly lower glycemia than the control group, but there was no significant difference between the groups in relation to insulinemia. The % of pancreatic -cell function was significantly higher in the group treated with 10 ppm F compared to the others. Proteomic analysis revealed changes in the proteomic profile of both muscle and hepatic tissue. In the muscle tissue, the group of 10 ppm presented, in relation to the control, increased expression of proteins involved in energy metabolism. The group of 50 ppm F, in relation to 7control, presented increased expression of proteins related to muscle contraction, differentiation of brown adipose tissue and apoptosis. For hepatic tissue, increased expression was also observed in the group of 10 ppm F in relation to the control of proteins involved in energetic metabolism and protein synthesis, with emphasis also on the increase of Glutahione S transferase isoforms as well as Heat shock-related 70 kDa protein 2. In the group treated with 50 ppm F proteins related to ROS metabolism and energetic metabolism were altered. Increased expression of antioxidant proteins by treatment with low F concentration may help explain protection against the development of diabetes, which should be demonstrated in future mechanistic studies.
36
Marakis, Georgios. "Natural therapy for insulin-resistance syndrome and type II diabetes." Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340013.
37
Bagstaff, Stephanie M. "Hyperinsulinemia and insulin resistance in cultured human muscle cells." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270177.
38
Erickson, Andrea Rose. "The Association Between Dairy Consumption and Insulin Resistance." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4262.
Анотація:
Background: A cross-sectional design was employed to ascertain the relationship between dairy consumption and insulin resistance (IR) in 272 middle-aged, nondiabetic women. Methods: Participants kept a seven-day weighed food record to report their diets, including consumption of dairy foods. IR was assessed using the homeostatic model assessment (HOMA), using the following formula: fasting plasma insulin (µU/ml) x fasting plasma glucose (mg/dL)/405. The Bod Pod was used to examine body fat percentage, and accelerometry over a seven-day period was used to assess physical activity. HOMA values were log-transformed and regression analysis and the General Linear Model procedure were used to determine how mean HOMA differed across low, moderate, and high dairy intake groups. Results: (Mean ± SD) age: 40.1 ± 3.0 years, physical activity (average activity counts for one week, divided by 1,000): 2700.1 ± 781.9, body fat percentage: 31.7 ± 6.9, weight (kg): 66.1 ± 10.0, fasting glucose (mg/dL): 86.7 ± 5.9, fasting insulin (µU/mL): 7.0 ± 4.2, energy intake (kcal/day): 2051.9 ± 319.1, kcal from carbohydrate (%): 55.7 ± 6.2, kcal from protein (%): 13.8 ± 2.5, kcal from fat (%): 30.5 ± 5.8, soluble fiber (g per 1,000 kcal): 1.7 ± 0.9, insoluble fiber (g per 1,000 kcal): 3.8 ± 1.9, dairy intake (servings/day): 1.1 ± 1.0, HOMA: 1.5 ± 1.0, log-transformed HOMA: 0.3 ± 0.6. Those in the highest quartile for dairy consumption had significantly higher log-transformed HOMA (0.41 ± 0.53) than those in the moderate (0.22 ± 0.55) or low (0.19 ± 0.58) consumption categories (F = 6.90, p = 0.0091). This relationship remained significant after controlling for all covariates (F = 4.71, p = 0.030). Controlling for physical activity strengthened the relationship between dairy consumption and IR by 7%. Adjusting for body weight, percent of kcal from fat, and insoluble and soluble fiber intake also strengthened the relationship. Controlling for energy intake and body fat percentage weakened the relationship by 32% and 13%, respectively, though it remained significant. Conclusion: High dairy consumption is significantly associated with IR in middle-aged, nondiabetic women.
39
Tubbs, Emily. "Importance of intracellular Mitochondria-Associated endoplasmic reticulum Membranes (MAM) in insulin-resistance." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10210.
Анотація:
Les mitochondries et le réticulum endoplasmique (RE) interagissent au niveau de points de contacts appelés « Mitochondria-Associated ER Membranes » (MAM), afin d'échanger du Ca2+ via le complexe TP3Rl/Grp75/VDACl et maintenir l'homéostasie énergétique. Bien que des dysfonctions mitochondriales, un stress du RE et des altérations de l'homéostasie du Ca2+ participent au développement de l'insulino-résistance, on ne sait pas si ce sont des facteurs indépendants ou s'ils sont inter-reliés par une altération des MAM. Mes travaux de thèse ont permis de mettre en évidence un nouveau rôle des MAM dans l'insulino-résistance hépatique. J'ai mis au point et validé la technique d'in situ PLA pour visualiser et quantifier les interactions mitochondrie-RE dans les cellules. J'ai montré que l'intégrité des MAM était nécessaire pour la signalisation de l'insuline dans le foie, et qu'un défaut d'intégrité des MAM était impliqué dans l'insulino-résistance hépatique. Des données préliminaires suggèrent qu'une altération des MAM est également associée à l'insulino-résistance musculaire. J'ai ensuite mis en évidence la présence de la protéine kinase B, une protéine clé de la signalisation de l'insuline, dans les MAM, et démontré que sa phosphorylation par l'insuline est altérée dans cette fraction dans le foie de souris diabétique. Enfin, j'ai participé à la mise en évidence l) de la présence de la cyclophilin D à l'interface des MAM régulant les échanges calciques entre les deux organites dans les cardiomyocytes et les hépatocytes, et 2) d'une régulation des MAM par le glucose dans le foie qui permet un contrôle de la dynamique et de la fonction mitochondriale au cours des transitions nutritionnelles. Par conséquent, mes travaux ont permis d'améliorer les connaissances actuelles sur les partenaires, la fonction et la régulation des MAM et de dévoiler les MAM comme une nouvelle cible pour moduler la signalisation de l'insuline et le métabolisme hépatiqueMitochondria-associated endoplasmic reticulum membranes (MAM) are functional domains between both organelles involved in Ca2+ exchange, through the voltage-dependent anion channel (VDAC)-1/glucose regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (TP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca2+ homeostasis are associated with altered insulin signalling, the implication of MAM dysfunctions in insulin resistance is unknown. During my PhD, my work has underlined a new role of MAM in hepatic insulin- resistance. T have developed a quantitative method called in situ Proximity Ligation Assay to visualise and quantify the interactions between ER and mitochondria. T have shown that MAM integrity is required for insulin signalling and that disruption of MAM is implicated in hepatic insulin resistance. Preliminary data also suggest that MAM alterations are also associated with muscle insulin resistance. T have also identified the presence of the protein kinase B (PKB), a key protein involved in metabolic effects of insulin, at the MAM interface, and demonstrated that its phosphorylation by insulin is altered in this fraction in liver of diabetic mice. Lastly, T have also participated to the identification of: 1) the presence of cyclophilin D (CypD) at MAM interface which regulates calcium transfer from ER to mitochondria in both cardiomyocytes and hepatocytes, and 2) a regulation of MAM by glucose in liver, which is involved in the regulation of mitochondria dynamics and function during nutritional transitions. Consequently, my work improved the knowledge on the composition, function and regulation of MAM, and highlighted MAM as a potential new target for the modulation of hepatic insulin action and metabolism
40
Talbot, Nicola A. "Obesity, inflammation and insulin resistance in skeletal muscle." Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618327.
41
Crawford, Lynne Mary. "The regulation of triglyceride metabolism in the liver and adipose tissue." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263457.
42
Higa, Karen Cristiane. "A influencia da periodontite na via de sinalização da insulina em musculo e figado de ratos machos wistar." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311207.
Анотація:
Orientador: Mario Jose Abdalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Existem indicações de que há uma relação bidirecional entre diabetes mellitus e doença periodontal. Tanto o diabetes quanto a doença periodontal podem estimular a liberação crônica de citocinas pró-inflamatórias que têm um efeito deletério nos tecidos periodontals e na sensibilidade à insulina. Entretanto, não se investigou ainda o efeito da doença periodontal na via de sinalização insulínica. Portanto, os objetivos do presente estudo são: avaliar o efeito da doença periodontal na via de transmissão do sinal insulínico em ratos Wistar machos. Utilizou-se a extração de tecidos hepáticos e muscular após estimulação com insulina e imunoprecipitação seguida de "immunoblotting" com anticorpos anti receptor de insulina, anti-ERS-1, anti-IRS-2, antifosfotirosina, anti-p-Akt, anti-p-ERK Vi, anti-p-JNKl/2, anti-lKfi-o: e anti- fosfoserina 307 IRS-1 nos grupos controle e com periodontite. Os resultados mostraram que a concentração do receptor de insulina, do IRS-1, do IR.S-2, da Akt, da JNK1/2, da ERK 112 estimulada e não estimulada pela insulina no fígado e músculo permaneceram inalteradas nos dois grupos. No músculo, os animais com periodontite estimulados com insulina sofreram uma redução de 15±33% na fosforilação em tirosina do receptor de insulina, de 55±3% na fosforilação em tirosina do IRS-1, de 48±1,5% na fosforilação em tirosina do IRS-2, de 34 ±2,8% na fosforilação em serina da Akt e de 20±1% na fosforilação em tirosina da ERK1/2 (p< 0,05). Além disso, nos ratos com periodontite houve um aumento de 40±0,4% na fosforilação em tirosina da JNK 1/2, de 60±5,4% na fosforilação em serina 307 do IRS-1 e a expressão do iKp-a foi reduzida em 70±4,2% (p< 0,05). No fígado, os animais com periodontite estimulados com insulina sofreram uma redução de 62±2% na fosforilação em tirosina do receptor de insulina, de 45±3,8% na fosforilação em tirosina do IRS-1, de 55±0,5% na fosforilação em tirosina do IRS-2, de 31 ±3% na fosforilação em serina da Akt e de 22±4% na fosforilação em tirosina da ERK1/2 (p< 0,05). Além disso, nos ratos com periodontite houve um aumento de 50±0,5% na fosforilação em tirosina da JNK 1/2, de 40±4% na fosforilação em serina 307 do IRS-1 e a expressão do iKp-ct foi reduzida em 55±4,2% (p< 0,05). Além disso, ao realizar o teste de tolerância a glicose (ITT), o Kitt dos ratos com periodontite apresentaram valores menores como de 2,17± 0.38 em relação aos controles 4,88+ 0.56. No teste oral de tolerância a glicose (oGTT) a área sobre a curva da glicemia dos ratos com periodontite foi 18,7% maior em relação aos controles e a área sobre a curva da insulinemia dos ratos com periodontite foi 43,4% maior em relação aos controles. Tais resultados sugerem que alterações na via de sinalização da insulina no fígado e no músculo, podem estar envolvidas na resistência a insulina apresentada nesse modelo animal
Abstract: Traditional thinking/paradigms have maintained that periodontits is na oral disease and that the tissue destructive response remains localized within the periodontium, limiting effects of the disease to oral tissues supporting the teeth. Recent studies have indicated that periodontits may produce any number of alterations in systemic health and in the present study we investigated the pathophysiological relationships between periodontitis and insulin resistance. However, the exact molecular mechanism in unknown. We have examined the levels and the tirosine phosphorylation status of insulin receptor (IR), IRS-1, IRS-2, ERK1/2, JNK1/2, the serine phosphorylation status of Akt , IRS-1 and the expression of IicjJ-a, in liver and muscle of rats with periodontitis by immunoblotting with specific antibodies. The results show that the levels of the insulin receptor, IRS-1, IRS-2, Akt, JNK1/2, ERK 1/2 with and without insulin stimulated remains unchanged in both tissues. In the muscle, animals with periodontits, the insulin stimulated IR tirosine phosphorylation was decrease to 15±33%, the IRS-1 tirosine phosphorylation was decrease to 55±3%, the IRS-2 tirosine phosphorylation was decrease to 48±1,5%, the Akt serine phosphorylation was decrease to 34 ±2,8%, the ERK1/2 tirosine phosphorylation was decrease to 20±1% (p< 0,05). In addition, rats with periodontitis had a increase of 40±0,4% in tyrosine phosphorylation of JNK. 1/2, 60±5,4% in serine phosphorylation of IRS-1 and the expression of Ik(3-o. was reduced in 70±4,2% (p< 0,05). In the liver, animals with periodontite insulin stimulated had a decrease of 62±2% in tirosine phosphorylation of insulin receptor, the IRS-1 tirosine phosphorylation was decrease to 45±3,8%, the IRS-2 tirosine phosphorylation was decrease to 55±0,5%, the Akt serine phosphorylation was decrease to 31 ±3%, the ERK1/2 tirosine phosphorylation was decrease to 22±4% (p< 0,05). In addition, rats with periodontitis had a increase of 50±0,5% in tirosine phosphorylation of INK 1/2, 40±4% in serine phosphorylation of IRS-1 and the expression of Ik(3-o; was reduced in 55±4,2% (p< 0,05). In addition, the thirty minute insulin tolerance test (ITT), the rats with periodontitis had a decrease of 50% in the value of Kitt. In the oral glucose tolerance test (oGTT) the area under the glucose curve was 18,7% higher in rats with periodontitis and the area under the insulin curve was 43,4% higher in rats with periodontitis. These data suggest that periodontitis impair insulin signaling in muscle and liver of rats Wistar
Mestrado
Medicina Experimental
Mestre em Fisiopatologia Médica
43
Ribeiro, Daniele Lisboa. "Efeitos da resistencia periferica a insulina e do diabetes na prostata ventral de ratos." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317901.
Анотація:
Orientadores: Rejane Maira Goes, Sebastião Roberto TabogaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O diabetes mellitus leva a complicações em diversos órgãos, incluindo as glândulas acessórias do sistema genital masculino. Na próstata, é bem estabelecido que essa doença acarreta atrofia epitelial, mas ainda não é claro o seu efeito sobre os componentes estromais e sua associação com alterações patológicas. Esse estudo visa esclarecer três aspectos controversos referentes ao impacto do diabetes sobre a próstata: 1) como as condições metabólicas do diabetes crônico não tratado afeta o compartimento estromal, em especial os componentes da matriz extracelular; 2) as possíveis associações entre essa doença e a incidência de alterações neoplásicas e 3) examinar as alterações prostáticas causadas pela resistência à insulina em comparação com o diabetes. A resistência à insulina, induzida pela administração do glicocorticóide dexametasona (1mg mg/Kg pc, durante 5 dias) causa, em curto prazo, efeitos semelhantes aos do diabetes, tais como a atrofia epitelial e alteração fenotípica das células musculares lisas (cml). Contudo, esta situação difere do diabetes pela atrofia das cml e ativação dos fibroblastos. Os efeitos do diabetes (90 dias), induzido experimentalmente pela administração de aloxana (45 mg/Kg pc), foram examinados com microscopia de luz, imunocitoquímica e microscopia eletrônica de transmissão. Nesta situação experimental observou-se uma incidência de 64% de neoplasia intraepitelial (NIP) e 35% de adenocarcinoma. Também se verificou uma ampla variação da resposta histológica da próstata entre os indivíduos diabéticos. Assim, três grupos foram diferenciados segundo a gravidade das alterações teciduais: 1) modificações leves; 2) intensa atrofia e 3) ocorrência de lesões pré-malignas (NIP e atrofia inflamatória proliferativa- PIA) e malignas (adenocarcinomas). Nos dois primeiros grupos, a remodelação estromal caracteriza-se por um aumento da espessura da membrana basal acinar, maior ocorrência de colágeno e de grandes proteoglicanos de condroitim sulfato. Esses dados em conjunto indicam que o diabetes induzido experimentalmente modifica o ambiente estromal de maneira a favorecer o desenvolvimento de lesões patológicas na próstata. Devido a complexidade das interações metabólicas relacionadas ao diabetes, torna-se difícil definir os principais fatores responsáveis pelas alterações acima mencionadas. Entretanto, é possível afirmar os efeitos prejudiciais da resistência à insulina e do diabetes para a morfofisiológica prostática
Abstract: Diabetes mellitus leads to complications in several organs including acessory glands of the male genital system. In the prostate, it is well established that diabetes causes epithelial atrophy, but its effects on the stromal components is not defined, as well as its relation with pathological alterations in the prostate. This study aims to elucidate three controversial aspects decurrent from the impact of diabetes in the prostate:1) How the metabolic conditions of chronic diabetes affects the stromal compartiment, specially extracellular matriz components; 2) the possible association between diabetes and prostatic neoplasic alterations and 3) Evaluate prostatic changes caused by insulin resistence in comparison to diabetes. Insulin resistence, induced by administration of the glucocorticoid dexamethasone (1mg mg/Kg bw, 5 days) causes, in short term, similar effects to diabetes, such as epithelial atrophy and phenotypical alteration in the smooth muscle cells (smc). However, this situation is different from diabetes regarding the smc atrophy and fibroblast activation. The effects of chronic diabetes (90 days), induced experimentally by alloxan (45 mg/Kg bw), were examined by light microscopy, imunohistochemistry and transmission electron microscopy. In this experimental situation, it was observed the incidence of 64% of prostatic intraepithelial neoplasia (PIN) and 35% of adenocarcinoma. It was also analysed a wide variation in the histological answer between diabetic individuals. Thus, three groups was determined according to the severity of their tissue alterations: 1) light modifications; 2) intense atrophy and 3) occurency of pre-malignant (PIN and proliferative inflammaotry atrophy- PIA) and malignant lesions (adenocarcinoma). In the first two groups, the stromal remodelation characterize for thickning of acini basement membrane, higher distribution of collagen and large proteoglycans of chondroitin sulphate. Together these data indicates that induced diabetes changes the stromal environment and consequently promotes the development of pathological lesions in the prostate. Due to the complexity of metabolic interactions related to diabetes, it is not possible to define the main factors responsible for those changes above mentioned. However, it is possible to confirm the injurious effects of insulin resistence and diabetes for the prostatic morfophisiology
Doutorado
Biologia Celular
Doutor em Biologia Celular e Estrutural
44
Santos, Kelly Ferreira dos 1988. "Impacto da ingestão de proteínas do soro do leite pré-hidrolisadas na diabetes melitus induzida em ratos = Impact of pre-hydrolyzed milk whey protein intake on induced diabetes mellitus in rats." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/254460.
Анотація:
Orientador: Jaime Amaya FarfánDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos
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Resumo: O presente trabalho teve por objetivo avaliar a capacidade da proteína do soro do leite, sob suas duas formas (concentrada e hidrolisada) em auxiliar na prevenção do desenvolvimento de obesidade e diabetes em ratos Wistar diabéticos. Foram utilizados 40 ratos machos Wistar de 8 semanas, alimentados com dieta hiperlipídica por 31 dias. No 20º dia de dieta, os animais receberam uma dosagem de 40mg/kg de estreptozotocina (STZ). Os grupos experimentais eram: CASControl ¿ animais alimentados com dieta normolipídica AIN-93G, contendo caseína como fonte proteica; HFCAS ¿ dieta hiperlipídica, com 62% do valor calórico total (VCT) em lipídios, e caseína como fonte proteica; HFPSL - dieta hiperlipídica, com 62% do VCT em lipídios e concentrado de proteína do soro do leite como fonte proteica; HFPSLH ¿ dieta hiperlipídica, com 62% do VCT em lipídios e proteína do soro de leite hidrolisada como fonte proteica. Foi realizado teste de tolerância à glicose (GTT) e, ao término do experimento, as dosagens séricas de glicose, aspartato aminotransferase (AST), alanina aminotransferase ALT, albumina, proteínas totais, colesterol total, HDL-c, triacilgliceróis e insulina, além de análise da composição centesimal das carcaças liofilizadas e fígados dos animais. O grupo HFPSLH apresentou menor ganho ponderal em relação aos demais grupos tratados com dieta hiperlipídica, além de tendência a uma melhor reação glicêmica no GTT. Após administração de STZ, todos os grupos com dieta hiperlipídica desenvolveram hiperglicemia e alguns danos hepáticos. Os dados sugerem que substituição da caseína pela proteína do soro do leite hidrolisada foi significativamente positiva no sentido de amenizar o excessivo ganho de peso e o nível hiperglicêmico produzidos pelo tratamento. Por outro lado, o parâmetro clássico da função hepática, ALT, e os níveis de triacilgliceróis séricos sugeriram a existência de um possível antagonismo entre o uso da hepatotóxica estreptozotocina e as proteínas do soro lácteo
Abstract: The purpose of this study was to explore the possible ability of the milk whey protein, under its two forms (concentrated and hydrolyzed) to assist in preventing the development of obesity and diabetes in rats submitted to a diabetes-induction procedure. Forty 8-week old male Wistar rats were fed a high fat (HF) diet for 31 days and, on day 20, received an injection of 40mg/kg streptozotocine (STZ). The experimental groups were: CAS Control (animals fed the AIN 93-G normolipidic diet, containing casein as protein source); HFCAS (HF diet, with 62% TCV in lipids plus casein as protein source); HFWPC (HF diet, with 62% TCV in lipids plus whey-protein concentrate (WPC) as protein source); HFWPH (HF diet, with 62% TCV in lipid plus whey-protein hydrolyzate (WPH) as a protein source). At the end of the feeding experiment, the following tests were performed: glucose tolerance test (GTT), serum glucose, AST, ALT, albumin, total protein, total cholesterol, HDL-c, triacylglycerols and insulin, as well as analysis of the chemical composition of lyophilized carcasses and livers of the animals. The HFWPH group exhibited lower weight gain than the other groups treated with HF diet, and a tendency to a better glycemic response in the GTT. After administration of the STZ, all groups developed the expected hyperglycemia, body-fat accumulation and some liver damage. The data suggest that replacement of casein by the whey-protein hydrolyzate was significantly positive in order to mitigate excessive weight gain and the hyperglycemia produced by the treatment. On the other hand, the classic parameter of liver function, ALT and serum triacylglycerols suggested the existence of a possible antagonism between the use of hepatotoxic streptozotocin and whey proteins
Mestrado
Nutrição Experimental e de Alimentos
Mestra em Alimentos e Nutrição
45
Izard-Sudres, Hélène. "Evaluation de la sensibilité à l'insuline et de l'insulinosécrétion selon la méthode du Minimal Model de Bergman dans une population de sujets obèses." Montpellier 1, 1996. http://www.theses.fr/1996MON11031.
46
Fryer, Lee George Daniel. "Studies into the role of glucose transporter function in insulin resistance." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265007.
47
Järvi, Anette. "Carbohydrate-rich foods in the treatment of the insulin resistance syndrome : studies of the importance of the glycaemic index and dietary fibre /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5166-7/.
48
Fornari, Adriana. "Avaliação de medidas de resistência e secreção de insulina em pacientes HCV positivos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/15917.
49
Campisi, Raffaele. "Insuline resistance and insuline sensibility in patients with obstructive sleep apnea." Doctoral thesis, Università di Catania, 2014. http://hdl.handle.net/10761/1596.
Анотація:
Obstructive sleep apnea (OSA), also referred to as obstructive sleep apnea-hypopnea (OSAH), is a sleep disorder that involves cessation or significant decrease in airflow in the presence of breathing effort. It is the most common type of sleep disordered breathing (SDB) and is characterized by recurrent episodes of upper airway collapse during sleep. These episodes are associated with recurrent oxyhemoglobin desaturations and arousals from sleep. Despite being a common disease, OSAS is underrecognized by most primary care physicians; an estimated 80% of Americans with OSAS are not diagnosed. Apnea may occur hundreds of times nightly, 1-2 times per minute, in patients with severe OSA, and it is often accompanied by wide swings in heart rate, a precipitous decrease in oxygen saturation, and brief electroencephalographic (EEG) arousals concomitant with loud breathing sounds as a bolus of air is exhaled when the airway reopens. The cardinal symptoms of sleep apnea include the "3 S s": S noring, S leepiness, and S ignificant-other report of sleep apnea episodes.
Recent studies suggest that OSA increases the risk of developing insulin resistance and type 2 diabetes. The aim of the present study was to assess whether obstructive sleep apnea is a risk factor for insulin resistance, using surrogate estimates of insulin-mediated glucose uptake. We studied a population of 174 (122 males) subjects evaluated in our Sleep Lab for the suspect of OSA. All subjects underwent a standard nocturnal polysomnography (Compumedics S-Series). The HOMA index, an index of insulin resistance and the QUICKI index, an index of insulin sensitivity, were calculated from the values of fasting glucose and insulin obtained in the morning. The percentage of patients with iper-trigliceridemia was significantly higher in patients with OSAS than in controls (P <00.5) . Insulin resistance (HOMA > 2.4) was higher in OSAS patients than in controls (P < 00.5), as well as BMI values were higher in patients with OSAS than in controls (P < 00.5) .
The results showed that the risk factors for insulin resistance (HOMA > 2:45 ) were predominantly the BMI (OR 2.4, 95 % CI 1.3-4.6 , P <0.001) , OSA (OR 4.0, 95 % CI 1.6 -9.7 , P <0.001) and hypertension (OR 2.3 , 95% CI 1.2-4.3 , P<0.001). Revealed no correlation with sex , age, hypercholesterolemia and ipertrigligeridemia .
We did a multiple regression in which the OSAS (OR 2.7, 95 % CI 1.2-3.70 , P <0.05) and BMI (OR 2.3, 95% CI 0.29-2.70 , P <0.05), but not hypertension (OR 1.8, 95% CI 0.8-6.0, P <0.8) were independent risk factors for insulin resistance. From the correlation between insulin levels and OSAS we got a positive relationship between insulin and AHI (r = 0:32, P <0.001) and insulin levels and BMI (r = 0:43, P <0.001).
50
Andersen, Ditte K. "The role of microRNAs in skeletal muscle insulin resistance." Thesis, Royal Veterinary College (University of London), 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701676.