Orientador: Mario Jose Abdalla Saad / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T21:44:54Z (GMT). No. of bitstreams: 1 Zambon_RenataAlvaresBagarolli_D.pdf: 7972972 bytes, checksum: 0c4feccde8df219c21aef1c3e8740fc0 (MD5) Previous issue date: 2013 / Resumo: A obesidade é caracterizada por processo inflamatório crônico e resistência à insulina (RI), os quais são responsáveis por grande parte de suas doenças associadas. Sabe-se que diversas moléculas do sistema imune inato estão associadas à RI e obesidade, destacando-se o receptor toll-like-receptor 4 (TLR4). Sua via de sinalização está ativada na obesidade, devido à presença aumentada na circulação de seu principal ligante, lipopolissacarídeo (LPS). Acredita-se que esta endotoxemia metabólica seja causada por alterações na microbiota e na permeabilidade intestinais, o que torna o intestino e as bactérias que o habitam, grandes alvos para o tratamento da obesidade. O objetivo deste presente trabalho foi avaliar os efeitos dos probióticos (PB) na sensibilidade à insulina e na sinalização de TLR4 em tecidos insulino-sensíveis, além de verificar suas possíveis ações na microbiota intestinal. Dessa forma, camundongos Swiss foram divididos em 4 grupos: controles (C), controles tratados com PB (C+PB), obesos (DIO) e obesos tratados com PB (DIO+PB). O tratamento teve a duração de 5 semanas. O uso de PB em animais obesos proporcionou grandes melhoras nos parâmetros fisiológicos e moleculares de RI, além de atenuar a ativação da via de sinalização do TLR4, provavelmente pela redução dos níveis circulantes de LPS. O grupo DIO+PB ainda mostrou mudanças positivas na distribuição dos filos de bactérias intestinais e menor permeabilidade intestinal, quando comparado com o grupo DIO. Analisando o hipotálamo, observou-se que o uso de PB nesse modelo de obesidade regulou de forma favorável os mecanismos centrais de controle da fome, bem como alguns parâmetros de inflamação. Assim, conclui-se que a regulação da microbiota intestinal promovida pela administração de probióticos pode trazer benefícios no controle da obesidade, por reduzir ou atenuar mecanismos moleculares de resistência à insulina / Abstract: Obesity is the main risk factor to the development of insulin resistance and type 2 diabetes. The common basis among these events is an inflammatory process characterized by the activation of toll-like receptor 4 (TLR4) by its main ligand lipopolysaccharide, LPS. Its concentration is higher in obese people and it is believed that changes in composition of the gut microbiota and epithelial functions may play a role in the inflammation associated with obesity. The aim of the study was to evaluate the effects of probiotic on the insulin sensitivity, TLR4 signaling, intestinal permeability and microbiota composition in diet-induced obese mice. Male adult Swiss mice composed randomly 2 groups: chow diet (CTL) and high-fat diet by 5 consecutive weeks (DIO). During these 5 weeks, some mice of the DIO and CTL groups received daily a pool of probiotics. The DIO animals that received probiotic presented an expressive improvement in their glucose tolerance test, fasting glucose and in parallel a significant increase in the phosphorylation levels of insulin induced IR, IRS1 and Akt in muscle, liver and adipose tissue. There was a relevant reduction in the TLR4-Myd88 interaction, IKK? and JNK phosphorylation and iNOS expression in DIO mice treated with probiotic. This treatment also improved the expression of ileal tight-junctions proteins (ZO-1, Occludin), decreased LPS portal levels and the concentrations of bacteria of the phylum Firmicutes (associated with obesity) in feces. Analyzing the hypothalamus, it was observed that the use of probiotics in this model of obesity favorably regulated central mechanisms of food intake, as well as some inflammation parameters. In conclusion, our results show that probiotics, through their effects on intestinal permeability and microbiota composition, can improve insulin sensitivity and signaling of DIO mice, reducing their inflammation and suggesting potential beneficial effects in the treatment of insulin resistance and type 2 diabetes / Doutorado / Medicina Experimental / Doutora em Ciências

Orientador: Mario José Abdalla Saad / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T23:48:44Z (GMT). No. of bitstreams: 1 Oliveira_AlexandreGabarrade_D.pdf: 6128978 bytes, checksum: af963016d634f567a33807335a6f0148 (MD5) Previous issue date: 2012 / Reumo: Evidências recentes têm apontado para estreita correlação entre resistência à insulina, inflamação e obesidade. Nesse contexto, o toll-like receptor 4 (TLR4) parece exercer papel importante, pois sua ativação leva a aumentos na fosforilação de I?B kinase (IKK'beta') e c-Jun NH2-terminal kinase (JNK) e na expressão de citocinas inflamatórias como o fator de necrose tumoral alfa (TNF- ?), substâncias capazes de atenuar a sensibilidade à insulina.. Recentemente, nosso laboratório demonstrou que animais com TLR4 não funcional ficam protegidos da resistência à insulina e do ganho de peso, induzidos por dieta hiperlipídica, sugerindo papel de destaque do TLR4 na interface entre sistema imune inato e metabolismo energético. Por outro lado, o exercício físico pode melhorar a sensibilidade à insulina e a inflamação na obesidade, entretanto os mecanismos são pouco compreendidos. A relação entre TLR4 e exercício físico é um tópico ainda pouco investigado, no entanto há indícios de que o exercício físico possa levar à redução na sua expressão gênica. Assim buscamos analisar o efeito do exercício físico sobre a expressão e ativação do TLR4 e de suas consequências sobre a sinalização e sensibilidade à insulina em ratos obesos. O presente estudo demonstrou que apenas o exercício crônico foi capaz de reduzir a expressão de RNA mensageiro e de proteína do TLR4 em músculo, fígado e tecido adiposo. Contudo, tanto o exercício crônico quanto o agudo atenuaram a sinalização do TLR4 nesses tecidos, como evidenciado pela redução da fosforilação de JNK e IKK'beta'. Observamos também importante redução nos níveis circulantes de lipopolissacarídeo (LPS) nos dois protocolos de exercício, e menores níveis de ácidos graxos livres (AGL) apenas no exercício crônico. Em paralelo, demonstramos melhora na fosforilação em tirosina do IR'beta' e do IRS-1 e da Akt em serina após ambos os protocolos. Dessa forma, podemos concluir que o exercício físico promoveu importante atenuação sobre a sinalização do TLR4 em músculo, fígado e tecido adiposo; possivelmente mediada pela redução dos níveis de LPS circulante, que resultou em melhora na sinalização e sensibilidade à insulina em animais com obesidade induzida por dieta hiperlipídica. Esses dados promoveram considerável progresso no entendimento dos eventos moleculares que ligam o exercício físico com a melhora na inflamação e na resistência à insulina / Abstract: Recent evidences have suggested a strong correlation among insulin resistance, inflammation and obesity. In this context, the toll-like receptor 4 (TLR4) seems to play an important role in the development of insulin resistance, since the activation of this receptor increases I?B kinase (IKK'beta') and c-Jun NH2-terminal kinase (JNK)activity and pro-inflammatory cytokines expression such as tumor necrosis factor-alpha (TNF-?), substance known by its negative effects over insulin sensitivity. Previous results from our laboratory demonstrated that mice with loss-of-function mutation in TLR4 are protected from both weight gain and insulin resistance induced by high-fat diet, suggesting an important role of TLR4 in the link between the innate immune system and energy metabolism. In parallel, life style interventions involving exercise clearly improve insulin sensitivity, and possibly inflammation, in obese individuals, yet the mechanisms for these effects are not well understood. There is evidence that exercise leads to decreased gene expression of TLR4, however the relationship between TLR4 and exercise is still poorly investigated. Thus we aimed to analyze the effect of physical exercise on TLR4 expression and activation in obese rats and its consequences in insulin signaling and sensitivity. The present study demonstrated that chronic exercise was able to reduce the TLR4 expression of both mRNA and protein in muscle, liver and adipose tissue. However, the acute and chronic exercise blunted the TLR4 signaling in these tissues, as evidenced by reducing phosphorylation levels of JNK and IKK'beta'. We also observed a significant reduction in lipopolysaccharide (LPS) circulating levels in both exercise protocols and lower levels of free-fat acids (FFA) only in the chronic exercise. In parallel, we demonstrated improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation after both exercise protocols. Thus, we concluded that physical exercise promotes a significant attenuation of the TLR4 signaling pathway in muscle, liver and adipose tissue; possibly by reducing LPS circulating levels, that resulted in an improved insulin signaling and sensitivity diet-induced obese animals. These data provided considerable progress in our understanding of molecular events that link exercise with to an improvement in inflammation and insulin resistance / Doutorado / Clinica Medica / Doutor em Clínica Médica

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T14:09:45Z (GMT). No. of bitstreams: 1 Calixto_MarinaCiarallo_D.pdf: 2454146 bytes, checksum: 3f9d2c9797c668d719c59ae5fd3f277f (MD5) Previous issue date: 2012 / Resumo: A obesidade e a asma são doenças prevalentes e crescentes, e ambas têm impacto significativo na saúde pública mundial. O aumento simultâneo da prevalência da asma e da obesidade tem levado investigadores a sugerir que a obesidade possa ser um fator importante no desenvolvimento da asma, ou até piorar um quadro de asma pré-existente. Numerosos estudos populacionais conduzidos em todo o mundo indicam que a prevalência de asma é maior em indivíduos obesos versus magros. Além disso, diversos estudos prospectivos, tanto em adultos quanto em crianças, indicam que o risco relativo da incidência de asma aumenta com o índice de massa corporal (IMC). A obesidade também piora o controle medicamentoso da asma e a gravidade desta doença. Recentemente, diversos dados emergiram indicando que a inflamação associada à obesidade pode aumentar a propensão para o desenvolvimento de asma. Acredita-se que a resistência à insulina associada à obesidade desempenha importante papel no desenvolvimento da asma, explicando, ao menos em parte, a associação da asma com obesidade. Relatos recentes indicam uma alta prevalência de resistência à insulina em pacientes obesos e asmáticos versus obesos não asmáticos, sugerindo que a resistência à insulina possa contribuir com este fenótipo. Baseado nestas informações, o objetivo deste trabalho foi verificar se doenças metabólicas associadas à obesidade, tal como a resistência à insulina, podem estar envolvidas na exacerbação da asma associada à obesidade. No presente estudo observamos que o tratamento de camundongos obesos com metformina corrige a resistência à ação sistêmica da insulina. Além disso, metformina normaliza o trânsito dos eosinófilos da medula óssea até o lúmen em animais obesos e desafiados com OVA. Essa normalização parece ser mediada pela ativação da AMPK no pulmão e diminuição das concentrações de TNF-? e NOx no LBA e inibição da expressão de iNOS induzida pelo fator de transcrição NF-?B no pulmão. Além disso, ao normalizar o tráfego de eosinófilos da região peribronquiolar para a luz das vias aéreas, o tratamento com metformina induz concomitante diminuição do acúmulo de eosinófilos na medula óssea devido à regulação positiva da expressão de moléculas de adesão VLA-4 e Mac-1 na superfície das células e posterior aumento da resposta adesiva à ICAM-1 e VCAM-1. Os resultados descritos neste estudo parecem confirmar a hipótese que a resistência à insulina, resultante da obesidade, medeia a exacerbação da resposta inflamatória pulmonar observada em animais obesos. Dessa forma, ao corrigir a resistência à insulina sistêmica através da ativação da AMPK, camundongos sensibilizados obesos aceleram o início do processo de resolução da inflamação pulmonar alérgica / Abstract: Obesity and asthma are prevalent and increasing diseases, and both have significant impact on global public health. The increase in prevalence of asthma and obesity has led researchers to suggest that obesity may be an important factor in the development of asthma, or even worse the pre-existing asthma. Numerous populational studies conducted around the world indicate that the prevalence of asthma is higher in obese versus lean person. In addition, several prospective studies, both in adults and in children, indicate that the relative risk of incident asthma increases with body mass index (BMI). Obesity also worsens the drug therapy of asthma and the severity of this disease. Recently, several data emerged showing that the inflammation associated with obesity increase the propensity for development of asthma. It is believed that insulin resistance associated with obesity plays an important role in the development of asthma, explaining, at least in part, asthma associated with obesity. Recent reports indicate a high prevalence of insulin resistance in obese asthmatics versus obese non-asthmatics patients, suggesting that insulin resistance may contribute to this phenotype. Based on this information, the purpose of this study was to determine whether metabolic diseases associated with obesity such as insulin resistance, are involved in asthma exacerbation associated with obesity. In the present study we observed that obese mice treated with metformin, impairs the resistantance to the systemic action of insulin. Furthermore, in obese mice challend with OVA, metformin normalizes the transit of eosinophils from bone marrow to the lung lumen. This normalization is mediated by AMPK activation in the lung, as well as decreased concentrations of TNF-? and nitrite and nitrate in BAL fluid accompanied by the inhibition of NF-?B induced iNOS expression in the lung. Furthermore, by normalizing the eosinophils trafficking from peribronchiolar region to airway lumen, metformin treatment induces concomitant reduction in the accumulation of eosinophils in bone marrow through the upregulation of adhesion molecules VLA-4 and Mac-1 on cell surface and subsequent increase in the adhesive response to plates coated with ICAM-1 and VCAM-1. Our data seem to confirm the hypothesis that insulin resistance resulting from obesity mediates the exacerbation of airway inflammation in high fat-diet mice. Thus, by normalizing the systemic insulin resistance through the atictivation of AMPK, obese sensitized mice progress to resolution of allergic airway inflammation / Doutorado / Farmacologia / Doutora em Farmacologia

Orientador: Licio Augusto Velloso / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T02:29:02Z (GMT). No. of bitstreams: 1 Guarilha_AlessandraLiaGasparetti_D.pdf: 7883483 bytes, checksum: cefd0ee77fd363b470280f9b8a380ff9 (MD5) Previous issue date: 2004 / Resumo: A exposição de animais homeotérmicos ao mo é utilizada como um método reprodutível para se obter um modelo animal de hipoinsulinemiaacompanhada por elevada mobilização periférica de glicose. No presente estudo, avaliaram-se as etapas iniciais e intermediárias da via de sinalização da insulina em tecidos periféricos de ratos expostos ao mo. Avaliou-se ainda, a comunicação intracelular entre o receptor (33-adrenérgicoe as vias de sinalização da insulina em tecido adiposo marrom de ratos expostos ao mo e tratados, ou não, com compostos agonista ou antagonista (33-adrenérgicos.A exposição de ratos ao mo promoveu a redução da secreção de insulina, acompanhada de um elevado clearance de glicose e maior captação de glicose por tecido muscular esquelético, adiposo branco e adiposo marrom. Tais fenômenos foram acompanhados por inibição da ativação da maior parte dos componentes da via de sinalização da insulina em tecido muscular esquelético e adiposo branco; por estimulação da maior parte dos componentes da via de sinalização da insulina em tecido adiposo marrom; e por efeitos variados (estímulo, inibição e não-modulação) de componentes da via de sinalização da insulina em figado. Por fim, este estudo demonstrou que a exposição ao mo ativa a sinalização (33-adrenérgicaem tecido adiposo marrom. Tal ativação leva à modulação da atividade de vários componentes da via de sinalização da insulina neste tecido. Entretanto, fatores independentes da sinalização (33-adrenérgica parecem contribuir para a complexa regulação do sinal da insulina obseIVada em tecido adiposo marrom de ratos expostos ao mo. Em conclusão, o presente estudo revelou alguns dos intrincados mecanismos pelos quais a exposição ao mo controla a atividade da insulina em animais homeotérmicos, podendo favorecer a identificação de potenciais alvos para a ação terapêutica em doenças onde a resistência à insulina desempenha papel central / Abstract: Cold exposure provides a reproducible model of improved glucose turnover accompanied by reduced blood levels of insulin. In the present study, the initial and intermediate steps of the insulin-signaling pathway in peripheral tissues of rats exposed to cold environment were evaluated. Also, the intracellular connection between insulin and ~3-adrenergic signaling in brown adipose tissue of cold exposed rats treated, or not, with ~3-adrenergic agonist or antagonist compounds were evaluated. During cold exposure, insulin secretion was significantly impaired, while whole body glucose clearance rates were significantly improved. This was accompanied by an increased glucose uptake by skeletal muscle, white adipose tissue and brown adipose tissue. These phenomena were paralleled by an apparent molecular resistance to insulin in skeletal muscle and white adipose tissue; by improved molecular response to insulin in brown adipose tissue; and by ambiguous effects (stimulation, inhibition and not modulation) of regulation of the insulin-signaling pathway in liver. Finally, cold exposure activated the ~3-adrenergic signaling in brown adipose tissue. It leads to modulation of activity of several components of the insulin signal transduction pathway in this tissue. However, ~3-adrenergic receptor independent mechanisms seem to contribute to the complex regulation of the insulin signaling observed in brown adipose tissue of rats exposed to cold. In conclusion, the present study revealed some of the complex mechanisms that participate in the cold-exposure-induced control of the insulin action in homeothermic animals. These results may favour the identification of novel potential targets for therapeutics in diabetes and related disorders / Doutorado / Medicina Experimental / Doutor em Fisiopatologia Medica

L'obésité est classiquement associée à plusieurs anomalies métaboliques comme l'insulinorésistance, la dyslipidémie et l'inflammation de bas grade, aujourd'hui reconnues comme facteurs de risques cardio-métaboliques. C’est également un composant fondamental du syndrome métabolique, un concept développé pour aider à l'identification des patients à haut risque cardio-métabolique. Pourtant, il existe une sous-population d'obèses dite "métaboliquement saine" qui est associée à un moindre risque. Cette sous-population n'est actuellement toujours pas définie de manière consensuelle mais l'insulinorésistance est essentielle dans les critères d'identification de la "santé métabolique". Une plus forte prévalence de l'insulinorésistance est associée à l'obésité abdominale, principal facteur diagnostique du syndrome métabolique, mais pourtant ces 2 phénotypes ne sont pas synonymes. Nous savons donc qu'il existe une hétérogénéité métabolique chez les patients obèses. Mon projet proposait d'identifier les meilleurs déterminants de l'insulinorésistance chez ces patients. Nous avons mis en évidence que l’inflammation de bas grade était associée aux marqueurs d’adiposité plutôt qu’à l’insulinorésistance, puis que les anomalies des métabolismes des glucides et des lipides, plus particulièrement les triglycérides et l’hémoglobine glyquée A1c, étaient les principaux facteurs associés de l’insulinorésistance chez nos patients obèses. Ceci restaure l’intérêt de ces dosages simples qui, associés à l’indice de masse corporelle, pourraient servir d’outils rapides et peu couteux pour aider le clinicien à identifier les individus insulino-résistants, alors que les nombreuses définitions du phénotype « obèse métaboliquement sain » ne font pas encore consensus. / Obesity is classically associated with a constellation of metabolic pattern including insulin-resistance, dyslipidemia and low-grade inflammation, now clustered as cardio-metabolic risk factors. Obesity is also a main component of the metabolic syndrome, which has become one of the major public health challenges in helping identify individuals at high risk of both type 2 diabetes and cardiovascular diseases. However a subgroup of metabolically healthy individuals with obesity (MHO) who might be at lower risk of cardiovascular events has been clinically recognized but no universally accepted criteria exist to define it.Assessment of insulin resistance phenotype is essential, and for most definitions of metabolic health, insulin sensitivity is taken into account. It is well accepted that a higher prevalence of insulin resistance is associated with abdominal obesity measured by waist circumference in routine. Although abdominal adiposity is a major component of the concept of metabolic syndrome, it appears that metabolic syndrome is not synonymous with the insulin resistance phenotype. We can assume that there is heterogeneity in the metabolic status of patients with obesity. Accordingly, the aim of my project was to explore what are the best determinants of insulin resistance in the obesity condition. We showed that inflammation was associated to fat accumulation rather than insulin resistance and that triglycerides and glycated hemoglobin were the factors best correlated to insulin resistance. Finally, a simple blood test as triglycerides and glycated hemoglobin determination could be an easy and available method to help physicians identify obesity related insulin resistance for appropriate prevention.

Objectives: To study recovery after hysterectomy under Enhanced Recovery After Surgery (ERAS) care, and in relation to different operation techniques. Materials and Methods: An observational study was conducted comparing 85 patients undergoing hysterectomy with ERAS care to 120 patients immediately before establishing ERAS. In a prospective cohort study of 121 consecutive patients undergoing hysterectomy, the outcome was compared for patients with malignant versus benign indications. The main outcome measure was length of stay (LOS). A randomised controlled trial (RCT) of 20 women scheduled for hysterectomy compared robot-assisted laparoscopic with abdominal hysterectomy in terms of the development of insulin resistance, inflammatory reactions, and clinical recovery, and examined the relation to hormonal status. All studies were conducted in 2011--2015, at the Department of Obstetrics and Gynaecology, Örebro University Hospital, Sweden. Results: Implementation of a structured ERAS protocol significantly reduced LOS compared to non-ERAS care. The effect was similar between patients with malignant and benign indications for surgery. No difference in complications was found. There was no difference in development of insulin resistance between robotic and abdominal technique, but clinical outcomes and inflammatory responses significantly favoured robot-assisted hysterectomy. Female sex hormone status was associated with the development of insulin resistance. Conclusions: Recovery after hysterectomy can be influenced. ERAS care seems to be effective and safe. Clinical outcome can also be influenced by operational technique. Hysterectomy triggers a stress reaction in both the metabolic and the inflammatory system. It remains unclear why the reduced inflammatory reaction and favourable clinical outcome in robotic surgery were not mirrored by less insulin resistance. This could not be explained by female sex hormone status.

The global number of obese people has reached pandemic proportions. High caloric diets and reduced physical exercise are to blame for this growing epidemic. Obesity has a very complex association with several other metabolic disorders, such as insulin resistance (IR), diabetes mellitus type 2 (DMT2) and cardiovascular disease. This puts a huge burden on health care systems world wide and claims many lives. Sutherlandia frutescens is a traditionally used herb, which is known to have anti-diabetic properties. However, the direct mode of action of S. frutescens still remains to be elucidated. The aim of this study was to investigate the developmental stages of high fat diet (HFD)-induced IR, to illuminate the pathogenesis of IR with a focal point on modifications in the lipid metabolism. Furthermore, the effects of S. frutescens as a treatment or prevention drug for IR and associated metabolic changes were examined. Two sets of experiments were conducted on male Wistar rats. In the first experiment rats, one week post weaning received a low fat diet (LFD), high fat diet (HFD) or HFD supplemented with S. frutescens (50mg/kg BW/d). Rats were sacrificed at week 0, 1, 2, 4, 8 and 12 in the feeding regime. In a second experiment rats were fed with a LFD or a HFD for 12 weeks and treated thereafter with S. frutescens (50mg/kg BW/d), metformin (13mg/kg BW/d) or water (control) for 28 days. Rats in the second experiment were sacrificed at week 12 to confirm IR while concurrently run rats were sacrificed after 28 days of treatment. For all the experiments rats were anaesthetized, blood was removed and rats were dissected. Plasma samples were analyzed for insulin, glucose, blood lipid parameters and cytokines. Liver, muscle and adipose tissue were analyzed for glucose uptake, total lipid content, lipid profile and fatty acid profile. It was shown that the intake of HFD caused IR and hyperinsulinaemia. The developmental stages in experiment one confirmed that an increase in plasma free fatty acids preceeded the onset of IR. Plasma and tissue lipid parameters (free fatty acid-, triglyceride- and cholesterol concentrations) showed pathological modifications in the HFD group. An ectopic accumulation of fat was observed in muscle and liver, as well as a change in membrane fatty acid profile. The results for circulating cytokines were somewhat inconclusive. Rats supplemented with S. frutescens did not develop HFD-induced IR (study one) or IR was reversed (study two). S. frutescens treatment also resulted in positive changes in plasma and tissue lipid parameters. In summary, an animal model for HFD-induced IR was established and the detrimental effect of elevated plasma FFA on glucose and lipid metabolism was observed. A novel discovery suggests that the anti-diabetic mode of action of S. frutescens is through modulation of lipid metabolism. It was also established that S. frutescens has the potential to prevent IR in vivo.

No description available.

Purpose: The overall objective of this prospective study was to quantify the prevalence of insulin resistance (IR), metabolic syndrome (MetS) and type 2 diabetes (T2D) in women at high risk for breast cancer, stratified by menopausal status. We also aimed to calculate the sample size required for a future case-control study comparing these prevalences to those of the general population. Methods: Participants consisted of 100 Caucasian women above the age of 35 with an estimated 5yr risk of breast cancer ≥1.7%. A comprehensive metabolic profile was obtained for each participant based on a questionnaire, fasting blood sample and biophysical measurements. Results: In comparison to published prevalence’s of IR, MetS and T2D in the general population, the prevalence of IR and MetS is higher in our study sample. High risk postmenopausal women have a higher prevalence of body mass index, waist circumference, MetS and hypertension than premenopausal women. We have shown a significant correlation between Gail score and high-density lipoprotein cholesterol. Conclusions: The sample size calculation, based on the prevalence’s obtained in the present study, support the significance and feasibility of a future case control study comparing the prevalence of IR and MetS in women at high risk and average risk for breast cancer. Further studies are needed to clarify the underlying mechanisms for the association between IR, MetS, T2D and breast cancer risk.

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) and tau pathologies, insulin resistance, neuro-inflammation and dysregulation of cholesterol homeostasis, all of which play a role in neuro-degeneration. The main aim of this study was to determine possible relationships between insulin signaling, cholesterol biosynthesis and their effects on Aβ, and inflammatory response in vitro. Insulin treatment increased cholesterol synthesis in human Neuroblastoma SH-SY5Y (SHY) and mouse neuroblastoma 2a (N2a) and N2a transfected with human APP (N2a-APP) by up-regulating biosynthesis enzymes including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3methyl-glutaryl-CoA reductase (HMGCR) through sterol regulatory element binding protein-2 (SREBP2) up-regulation. Aβ caused insulin resistance in N2a-APP cells by phosphorylating IRS-1 at Ser612, inhibiting signaling to downstream targets. Aβ1-42-treated SHY exhibited similar IRS-1 phosphorylation at Ser612 and inflammatory response of JNK activation. Aβ1-42 caused down-regulation of neuro-protective/anti-inflammatory DHCR24, and an increase in HMGCR levels indicating dysregulation of cholesterol homeostasis in SHY cells. Insulin resistance, Aβ toxicity, neuro-inflammation and dysregulation of cholesterol homeostasis appear to be intertwined processes in AD that should be studied simultaneously.