O câncer é considerado uma das principais causas de morte no mundo. Para o tratamento dessa doença, frequentemente são utilizadas estratégias farmacológicas baseadas na intervenção quimioterápica, no qual a doxorubicina (DOX) é largamente utilizada. Visto que, o músculo esquelético possui importante papel na captação de glicose, o objetivo do presente trabalho foi investigar o efeito da DOX na intolerância à glicose. Para isso foram utilizados ratos Wistar, os quais receberam uma dose única de DOX ou salina intraperitoneal (15mg/kg). Avaliamos a expressão de proteínas envolvidas na sensibilidade à insulina e captação de glicose. Os ensaios captação de glicose foram realizados em cultura de miócitos, no qual foi utilizado o agonista de AMPK. O tratamento com DOX causou resistência à insulina e hiperglicemia. No músculo EDL e em miócitos houve menor expressão de GLUT-4 e de AMPk. Em conclusão, o tratamento com DOX causou intolerância à glicose e redução da expressão de AMPk e GLUT-4. A utilização do agonista de AMPk foi capaz de recuperar à intolerância à glicose. / The cancer is considered a major cause of death worldwide. For the treatment of this disease, with frequency are used pharmacological strategies based in chemotherapeutic intervention, in which doxorubicin (DOX) is widely used. Since the skeletal muscle plays an important role in glucose uptake, the aim of this study was to investigate the effect of DOX in glucose intolerance. For this Wistar rats which received a single dose of DOX or saline intraperitoneally (15mg / kg). We evaluated the expression of proteins involved in insulin sensitivity and glucose uptake. The glucose uptake assays were performed on culture myocytes, which was used in the agonist of AMPK. The treatment with DOX caused insulin resistance and hyperglycemia. In the EDL muscle myocytes and there was less expression of GLUT4 and AMPK. In conclusion, treatment with DOX caused impaired glucose tolerance and reduction of expression of AMPK and GLUT-4. The use of AMPK agonist was able to recover glucose intolerance.

O aumento mundial na incidência da obesidade está associado com um aumento significante com os custos com a saúde. Somente nos Estados Unidos, os gastos com os tratamentos associados a obesidade superam 9% dos custos anuais com a saúde, em torno de $147 bilhões de dólares por ano. Os efeitos da obesidade no músculo esquelético estão relacionados com o desenvolvimento da resistência à insulin (IR), diabetes e piora da qualidade de vida. Trabalhos rescentes tem demonstrado que a dieta hiperlipídica (DHL) diminui a capacidade do músculo esquelético responder a sinais de crescimento. Este efeito negativo relacionado a diminuição na ativação da via Akt/mTOR e aumento nd estresse de retículo endoplasmático (ERE) é denominado de resistência anabólica. Por outro lado, estudos têm demonstrado um possível efeito benéfico da suplementaçãoo com o ácido graxo polinsaturado ômega 3 (Ag-w3) e do treinamento físico aeróbico em diversos parâmetros como, melhora da capacidade oxidativa, sistema imunológico, síntese proteica e degradação em saudáveis ou com alguma patologia associada. Dessa maneira, o presente trabalho demonstra que 8 semanas de DHL contribuíram para o desenvolvimento da obseidade. Por outro lado, o protocolo de TA promoveu um efeito protetor ao ganho de peso nos animais obesos. A suplementação com o AG-w3 foi capaz de prevenir alguns parametros analisados e a associação do óleo de peixe não foi capaz de potencializar os efeitos benéficos encontrados com o TA. / There is a worldwide increase in the incidence of obesity that is associated with significant increases in medical costs. In the United States alone, treatment of obesity related health problems accounts for up to 9% of the total annual cost of healthcare, an estimated $147 billion per year. The effects of obesity on skeletal muscle are correlated with insulin resistance (IR), diabetes and decreased of quality of life. Recent work has demonstrated that a high fat diet (HFD) decreases the ability of skeletal muscle to hypertrophy in a model of increased mechanical load. This negative effect on muscle growth is correlated with a decrease in activation of the Akt/mTOR signaling pathway and an increase in endoplasmic reticulum stress.

A forte associação entre obesidade e resistência à insulina denota a participação do tecido adiposo na patogênese das anormalidades metabólicas encontradas no Diabetes Mellitus (DM). Entretanto, a falta de tecido adiposo também pode desencadear sérias complicações metabólicas. O objetivo deste trabalho foi verificar o papel do tecido adiposo sobre as anormalidades metabólicas apresentadas pelo modelo experimental de DM induzido por estreptozotocina no período neonatal em ratos, caracterizado pela reduzida massa adiposa e presença de resistência à insulina na idade adulta. Cinco grupos de animais foram experimentados: controle não diabético (C); diabéticos tratados com: insulina (I); pioglitazona (P); ou metformina (M) e; grupo diabético não tratado (D). Verificamos que apenas os grupos I e P recuperaram o peso corporal e a massa adiposa, concomitante à uma melhora na responsividade à insulina. A normalização da massa adiposa observada nos grupos I e P está relacionada a aumento na expressão gênica de fatores de transcrição diretamente relacionados à adipogênese, assim como a um aumento na incorporação de glicose em lípides. Assim, a manutenção da massa adiposa exerce um papel-chave no controle metabólico apresentado por este modelo experimental. / A strong relationship between obesity and insulin resistance denotes the participation of adipose tissue in the pathogenesis of metabolic abnormalities seen in Diabetes Mellitus (DM). However, not only the excess, but the lack of adipose tissue can also trigger serious metabolic complications. The present study aimed to verify the role of adipose tissue on metabolic abnormalities seen in a DM experimental model induced by streptozotocin during neonatal period in rats, characterized by reduced adipose mass and presence of insulin resistance during adulthood. Five experimental groups were performed: non-diabetic control (C); treated diabetic with: insulin (I); pioglitazone (P); or metformin (M) and; non-treated diabetic (D). We verified that only I and P groups recovered body weight and adipose mass, concomitant to an improvement of insulin responsiveness The normalization of adipose mass in groups I and P is related to increased gene expression of transcription factors directly related to adipogenesis as well as increase in glucose incorporation into lipids. Therefore the maintenance of adipose mass exerts a key role in the metabolic control presented by this experimental model.

O ácido linoléico conjugado (CLA) é um ácido graxo poliinsaturado, encontrado nos produtos da alimentação. Estudos indicam que o CLA possui ações contra câncer, aterogênese e DM 2 e obesidade. O presente trabalho avaliou os efeitos da suplementação crônica com CLA em ratos Wistar machos e teve como objetivo investigar o desenvolvimento corporal e o perfil metabólico dos animais e dos adipócitos isolados do tecido adiposo branco periepididimal. Após quatro semanas de suplementação os animais apresentaram redução no ritmo de ganho de peso, acompanhado de redução da ingestão alimentar, redução da massa adiposa e do volume celular dos adipócitos. A menor incorporação dos substratos acetato e glicose em lipídeos, o aumento lipólise e diminuição da expressão do PPAR?, também contribuíram para menor adiposidade encontrada. A redução de massa adiposa foi acompanhada por resistência à insulina, elevados níveis de citocinas inflamatórias e desenvolvimento de esteatose hepática. Esses fatores estão relacionados com o desenvolvimento de síndrome lipodistrófica em animais. Portanto, a efetividade do CLA em reduzir massa adiposa foi comprovada no presente estudo, mas os efeitos devem ser considerados. / Conjugated linoleic acid (CLA) is a natural polyunsatured fatty acid found in many dietary sources. Animal studies demonstrated that CLA has properties against cancer, atherogenesis, diabetes and obesity. This work evaluated the effects with chronic CLA supplementation in young adults Wistar male rats for four weeks, aiming to investigate the possible changes in corporal development and metabolic profile as well as the effects in isolated adipocytes of periepidydimal white adipose tissue of these supplemented animals. We observed a reduction of the rhythym of body weight gain, followed by diminished food intake, regression of adipose mass, and also a reduction of adipocyte volume. The findings of low incorporation of acetate and glucose substrates into lipids, elevation on the lipolytic response and reduction of PPAR-gamma gene expression, also contributed to the lower adiposity. This reduction in adipose mass was followed by insulin resistance, high levels of inflammatory citokines and the development of hepatic steatosis, features related to the development of lipodystrophic syndrome. Therefore, this study demonstrated the CLA effect on reduction of adipose mass, although adverse effects associated with CLA chronic supplementation must be considered.

We tested the hypothesis that triacylglycerol (TAG) accumulation in the liver induced by short-term high-fat diet (HFD) in rats leads to the dysregulation of endogenous TAG degradation via lysosomal pathway and is causally linked with the development of hepatic insulin resistance. Lysosomal lipase (LAL) is stored in qualitatively different depots (light and dense lysosomes). In contrast to dense lysosomal fraction, LAL associated with light lysosomes exhibits high activity on intracellular TAG and prandial- or diet-dependent regulation. On standard diet, LAL activity was up-regulated in starved and down-regulated in fed animals. In the HFD group, we demonstrated elevated LAL activity, increased TAG content, enhanced production of diacylglycerol and the abolishment of prandial-dependent LAL regulation in light lysosomal fraction. The impairment of insulin signalling and increased activation of PKCε was found in liver of HFD-fed animals. Lipolysis of intracellular TAG, mediated by LAL, is increased in steatosis probably due to the enhanced formation of phagolysosomes. Consequent overproduction of diacylglycerol may represent the causal link between HFD-induced hepatic TAG accumulation and hepatic insulin resistance via PKCε activation.

Prevalence of obesity and associated diseases like type 2 diabetes has increased rapidly during last years. These diseases closely relate to each other. Obesity leads to insulin resistence, which directly precedes type 2 diabetes. Metformin is the most prescribed medicament for type 2 diabetic patients and insulin resistant people. It improves glucose tolerance and insulin resistance. Enzyme AMP-activated protein kinase (AMPK) is strogly involved in metformin action. The latest studies using transgenic models lacking AMPK suggest, that notable part of mechanisms involved in metformin action is independent on AMPK. n-3 polyunsaturated fatty acids (n-3 PUFA), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are abundant in sea fish, have beneficial effects on metabolism. These fatty acids lower plasma lipids and exert cardioprotective effects. n-3 PUFA also prevent development of insulin resistence and type 2 diabetes in rodents. The aim of this thesis was to characterise acute effects of metformin on glucose homeostasis, impact of short term diet intervention with diet rich in n-3 PUFA on metformin action and the role of insulin stimulated signalling pathways and AMPK. Results suggest that early effect of metformin is dose dependent and that single dose of metformin...

Visceral adipose tissue derived serine protease inhibitor (vaspin) or SERPINA12 according to the serpin nomenclature was identified together with other genes and gene products that  were specifically expressed or overexpressed in the intra abdominal or visceral adipose tissue  (AT) of the Otsuka Long-Evans Tokushima fatty rat. These rats spontaneously develop visceral  obesity, insulin resistance, hyperinsulinemia and ‐glycemia, as well as hypertension and thus represent a well suited animal model of obesity and related metabolic disorders such as type  2 diabetes.  The follow-up study reporting the cloning, expression and functional characterization of  vaspin suggested the great and promising potential of this molecule to counteract obesity induced insulin resistance and inflammation and has since initiated over 300 publications, clinical and experimental, that have contributed to uncover the multifaceted functions and molecular mechanisms of vaspin action not only in the adipose, but in many different cells, tissues and organs. This review will give an update on mechanistic and structural aspects of vaspin with a focus on its serpin function, the physiology and regulation of vaspin expression, and will summarize the latest on vaspin function in various tissues such as the different adipose tissue depots as well as the vasculature, skin, bone and the brain.

While genome‐wide association studies as well as candidate gene studies have revealed a great deal of insight into the contribution of genetics to obesity development and susceptibility, advances in adipose tissue research have substantially changed the understanding of adipose tissue function. Its perception has changed from passive lipid storage tissue to active endocrine organ regulating and modulating whole‐body energy homeostasis and metabolism and inflammatory and immune responses by secreting a multitude of bioactive molecules, termed adipokines. The expression of human vaspin (serpinA12) is positively correlated to body mass index and insulin sensitivity and increases glucose tolerance in vivo, suggesting a compensatory role in response to diminished insulin signaling in obesity. Recently, considerable insight has been gained into vaspin structure, function, and specific target tissue‐dependent effects, and several lines of evidence suggest vaspin as a promising candidate for drug development for the treatment of obesity‐related insulin resistance and inflammation. These will be summarized in this review with a focus on molecular mechanisms and pathways.

Thesis (M.Sc. (Physiology)) -- University of Limpopo, 2019 / Background Type 2 diabetes mellitus (T2DM) is an increasing challenge globally, and is estimated to affect 439 million adults by 2030. This estimate is linked to an unhealthy lifestyle with characteristics such as low physical activity (PA) and high plasma glucose levels (PGLs). Studies associating PA with insulin resistance and diabetes among adults and adolescents have been conducted widely in developed countries. Such studies are scanty among rural populations, especially in Africa. Assessment of the burden of diabetes and associated lifestyle risk factors in developing countries is essential in order to encourage appropriate intervention strategies to counter the increasing prevalence. Aim and objectives The aim of this study was to investigate the relationship between PA and T2DM among rural young adults aged 22 to 30 years in Ellisras area in Limpopo Province, South Africa Methods A total of 713 young adults (349 males and 364 females) who have been part of the Ellisras Longitudinal Study participated in the current study. Physical activity data was collected using a validated questionnaire. After an overnight fast, participants provided fasting venous blood samples for determination of plasma glucose and insulin. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance. Anthropometric measurements (waist circumference and height) were performed using standard procedures. Linear and logistic regressions were used to assess the relationship between PA, pre-diabetes, insulin resistance and T2DM; and the odds of having T2DM with low PA levels. Results The prevalence of physical inactivity was 67.3 and 71.0% for males and females, respectively. That of pre-diabetes was between 45.7% and 50.2%. The prevalence of diabetes was 9.6% for males and 10.1% for females while for insulin resistance was 22.9% for males and 29.3% for females. Linear regression found a significant relationship (p<0.05) between physical activity and blood glucose (ß =5.715; 95% CI 4.545; 6.885), waist circumference (ß = 37.572; 95% CI 25.970; 49.174) and waist-toheight ratio (ß = 0.192; 95% CI 0.087; 0.296). Logistic regression found a significant (p<0.05) relationship between low physical activity and T2DM (Odds ratio = 2.890; 95% CI 1.715; 4.870) and insulin resistance (Odds ratio = 1.819; 95% CI 1.266; 2.614). Conclusion Physical activity is low in this population, and is independently associated with T2DM and insulin resistance. KEY WORDS Type 2 diabetes mellitus; pre-diabetes; insulin resistance; physical activity; young adults; rural South African population. / Vrije University, Amsterdam, The Netherlands, and the University of Limpopo

The prevalence of type 2 diabetes mellitus is increasing worldwide and is considered one of the top health concerns globally. The occurrence of type 2 diabetes is linked to the rapidly increasing trend of obesity in both adults and children, which is proposed to be a contributing factor in the development of insulin resistance and type 2 diabetes. White adipose tissue, an insulin target tissue, is an important endocrine organ involved in the control of energy homeostasis through its direct influence on metabolism, insulin sensitivity and food intake. To better understand these functions, we studied adipocyte differentiation in 3T3-Ll cells, a white adipose tissue cell line. Many mitochondrial proteins exhibit an increase in expression levels during adipogenesis as identified by mass spectrometry. Moreover, increased mitochondrial mass and altered morphology was observed by light microscopy. Qualitative changes in mitochondrial gene expression were also observed during adipogenesis as revealed by Affymetrix GeneChip analysis. Additionally, striking changes in mitochondrial protein expression and morphology were identified following treatment with the insulin sensitizing agent, rosiglitazone. These results suggest that mitochondrial biogenesis and remodeling is inherent to white adipocyte differentiation. To investigate the physiological relevance of these findings, mRNA and protein expression profiles and mitochondrial morphology were studied during the development of insulin resistance and obesity and following treatment with rosiglitazone in ob/ob mice. These studies reveal a marked decrease in transcript levels for over 50% of mitochondrial genes with the onset of obesity in ob/ob mice. Rosiglitazone treatment stimulates enhanced expression in approximately half of these genes, as well as changes in mitochondrial mass and remodeling. Furthermore, these studies reveal that depressed oxygen consumption and fatty acid oxidation occur with obesity development and these alterations can be reversed with rosiglitazone treatment. This work identifies the previously underscored plasticity of mitochondria in white fat and suggests that mitochondrial biogenesis and remodeling in white adipose tissue may lead to systemic changes in insulin sensitivity and energy homeostasis. Lastly, these studies suggest that mitochondria may be an important therapeutic target for antidiabetic drugs.