A Hypercaloric pellet-diet cycle induces obesity and co-morbidities in wistar rats

O objetivo do estudo foi desenvolver um ciclo de dietas hipercalóricas para promover obesidade em ratos. Ratos Wistar foram distribuídos em dois grupos: dieta normal (ND = 32; 3,5 kcal/g) e dietas hipercalóricas (HD; n = 32; 4,6 kcal/g). O grupo ND recebeu ração comercial e os animais HD um ciclo de diferentes dietas hipercalóricas, por 14 semanas. As variáveis analisadas foram peso corporal, parâmetros metabólicos e hormonais, pressão arterial sistólica e teste oral de tolerância à glicose. O nível de significância foi de 5%. O ciclo de dietas hipercalóricas promoveu aumento de peso e gordura corporal, pressão arterial sistólica e níveis séricos de glicose, triacilglicerol, insulina e leptina no grupo HD. Além disso, o grupo HD apresentou tolerância à glicose diminuída. em conclusão, os resultados deste estudo mostram que o ciclo de dietas hipercalóricas promove obesidade e exibe várias características comumente associadas com a obesidade humana, como aumento da pressão arterial, resistência à insulina, hiperglicemia, hiperinsulinemia, hiperleptinemia e dislipidemia.

Glucose Tolerance and Insulin Action in Monosodium Glutamate (MSG) Obese Exercise-trained Rats

The present study was designed to evaluate the effects of chronic aerobic exercise (swimming, 1h/day, 5 days/week, with an overload of 5% body weight) on glucose metabolism in obese male Wistar rats. Hypothalamic obesity was induced through administration of monosodium glutamate (MSG) at 4 mg/g of body weight every other day from birth to 14 days old. Fourteen weeks after drug administration, the rats were separated into two groups: MSG-S (sedentary) and MSG-T (swimming for 10 weeks). Rats of the same age and strain, receiving saline in place of MSG, were used as control (C), and subdivided into two groups: C-S and C-T. At the end of the experimental period, an oral glucose tolerance test was performed and serum glucose (AG) and insulin (AI) were evaluated. A constant for serum glucose decrease (Kitt) in response to exogenous insulin was calculated. Soleus muscle strips and adipose tissue samples were incubated and insulin stimulated glucose uptake determined. No differences were observed in AG among the 4 groups. MSG-S rats showed higher AI (418%) and lower Kitt (92.3%) than C-S rats. T-rats showed higher glucose uptake by muscle (224.0%) and adipose tissues (94.1%) than S-rats. Among trained rats, glucose uptake by muscle was higher in MSG-T (5.4%) than in C-T. while the opposite was observed in adipose tissue (39% higher in C-T). Chronic aerobic exercise was able to improve glucose tolerance and reduce insulin resistance in MSG-obese rats. These effects were associated to an increase in glucose uptake by muscle and adipose tissue in response to insulin.

Low ethanol consumption induces enhancement of insulin sensitivity in liver of normal rats

Moderate amounts of alcohol intake have been reported to have a protective effect on the cardiovascular system and this may involve enhanced insulin sensitivity. We established an animal model of increased insulin sensitivity by low ethanol consumption and here we investigated metabolic parameters and molecular mechanisms potentially involved in this phenomenon. For that, Wistar rats have received drinking water either without (control) or with 3% ethanol for four weeks. The effect of ethanol intake on insulin sensitivity was analyzed by insulin resistance index (HOMA-IR), intravenous insulin tolerance test (IVITT) and lipid profile. The role of liver was investigated by the analysis of insulin signaling pathway, GLUT2 gene expression and tissue glycogen content. Rats consuming 3% ethanol showed lower values of HOMA-IR and plasma free fatty acids (FFA) levels and higher hepatic glycogen content and glucose disappearance constant during the IVITT. Neither the phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), nor its association with phosphatidylinositol-3-kinase (PI3-kinase), was affected by ethanol. However, ethanol consumption enhanced liver IRS-2 and protein kinase B (Akt) phosphorylation (3 times, P < 0.05), which can be involved in the 2-fold increased (P < 0.05) hepatic glycogen content. The GLUT2 protein content was unchanged. Our findings point out that liver plays a role in enhanced insulin sensitivity induced by low ethanol consumption. © 2005 Elsevier Inc. All rights reserved.

Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca2 2+ signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca2 2+signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally,weexplored the status of Ca2 2+-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase Cα as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the β-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity. Copyright © 2010 by The Endocrine Society.

Diet-induced obesity impairs AKT signalling in the retina and causes retinal degeneration

Retinopathy, a common complication of diabetes, is characterized by an unbalanced production of nitric oxide (NO), a process regulated by nitric oxide synthase (NOS). We hypothesized that retinopathy might stem from changes in the insulin receptor substrate (IRS)/PI3K/AKT pathway and/or expression of NOS isoforms. Thus, we analysed the morphology and apoptosis index in retinas of obese rats in whom insulin resistance had been induced by a high-fat diet (HFD). Immunoblotting analysis revealed that the retinal tissue of HFD rats had lower levels of AKT1, eNOS and nNOS protein than those of samples taken from control animals. Furthermore, immunohistochemical analyses indicated higher levels of iNOS and 4-hydroxynonenal and a larger number of apoptotic nuclei in HFD rats. Finally, both the inner and outer retinal layers of HFD rats were thinner than those in their control counterparts. When considered alongside previous results, these patterns suggest two major ways in which HFD might impact animals: direct activity of ingested fatty acids and/or via insulin-resistance-induced changes in intracellular pathways. We discuss these possibilities in further detail and advocate the use of this animal model for further understanding relationships between retinopathy, metabolic syndrome and type 2 diabetes. © 2012 John Wiley & Sons, Ltd.

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation. © 2012 Elsevier B.V.

Pathological and behavioral risk factors for higher serum c-reactive protein concentrations in free-living adults - A Brazilian community-based study

Low-grade chronic systemic inflammation is often associated with chronic non-communicable diseases, and its most frequently used marker, the C-reactive protein (CRP), has become an identifier of such diseases as well as an independent predictor for cardiovascular disorders and mortality. CRP is produced in response to pro-inflammatory signaling and to individual and behavioral factors, leading to pathological states. The aim of this study was to rank the predicting factors of high CRP concentrations in free-living adults from a community-based sample. We evaluated 522 adults (40-84 years old; 381 women) for anthropometric characteristics, dietary intake, clinical and physical tests, and blood analysis. Subjects were assigned to groups, according to CRP concentrations, as normal CRP (G1;<3.0 mg/L; n = 269), high CRP (G2; 3.0-6.0 mg/L; n = 139), and very high CRP (G3; >6.0 mg/dL; n = 116). Statistical comparison between groups used one-way ANOVA or Kruskal-Wallis tests, and prediction of altered values in increasing CRP was evaluated by proportional hazard models (odds ratio). CRP distribution was influenced by gender, body mass index, body and abdominal fatness, blood leukocytes, and neutrophil counts. The higher CRP group was discriminated by the above variables in addition to lower VO2max, serum metabolic syndrome components (triglycerides, glucose, and HDL cholesterol), higher insulin, homeostasis assessment of insulin resistance, uric acid, gamma-GT, and homocysteine. After adjustments, only fatness, blood leukocytes, and hyperglycemia remained as independent predictors for increased serum CRP concentrations. Intervention procedures to treat low-grade chronic inflammation in overweight women would mainly focus on restoring muscle mass and functions in addition to an antioxidant-rich diet. © 2012 Springer Science+Business Media, LLC.

Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats

It is now commonly accepted that chronic inflammation associated with obesity during aging induces insulin resistance in the liver. In the present study, we investigated whether the improvement in insulin sensitivity and insulin signaling, mediated by acute exercise, could be associated with modulation of protein-tyrosine phosphatase 1B (PTP-1B) in the liver of old rats. Aging rats were subjected to swimming for two 1.5-h long bouts, separated by a 45 min rest period. Sixteen hours after the exercise, the rats were sacrificed and proteins from the insulin signaling pathway were analyzed by immunoblotting. Our results show that the fat mass was increased in old rats. The reduction in glucose disappearance rate (Kitt) observed in aged rats was restored 16 h after exercise. Aging increased the content of PTP-1B and attenuated insulin signaling in the liver of rats, a phenomenon that was reversed by exercise. Aging rats also increased the IRβ/PTP-1B and IRS-1/PTP-1B association in the liver when compared with young rats. Conversely, in the liver of exercised old rats, IRβ/PTP-1B and IRS-1/PTP-1B association was markedly decreased. Moreover, in the hepatic tissue of old rats, the insulin signalling was decreased and PEPCK and G6Pase levels were increased when compared with young rats. Interestingly, 16 h after acute exercise, the PEPCK and G6Pase protein level were decreased in the old exercised group. These results provide new insights into the mechanisms by which exercise restores insulin signalling in liver during aging. © 2013 Moura et al; licensee BioMed Central Ltd.

Maternal periodontal disease in rats decreases insulin sensitivity and insulin signaling in adult offspring

Background: Periodontal disease during pregnancy has been recognized as one of the causes of preterm and lowbirth- weight (PLBW) babies. Several studies have demonstrated that PLBW babies are prone to developing insulin resistance as adults. Although there is controversy over the association between periodontal disease and PLBW, the phenomenon known as programming can translate any stimulus or aggression experienced during intrauterine growth into physiologic and metabolic alterations in adulthood. The purpose of the present study is to investigate whether the offspring of rats with periodontal disease develop insulin resistance in adulthood. Methods: Ten female Wistar rats were divided into periodontal disease (PED) and control (CN) groups. All rats were mated at 7 days after induction of periodontal disease. Male offspring were divided into two groups: 1) periodontal disease offspring (PEDO; n = 24); and 2) control offspring (CNO; n = 24). Offspring body weight was measured from birth until 75 days. When the offspring reached 75 days old, the following parameters were measured: 1) plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and tumor necrosis factor-α (TNF-α); 2) insulin sensitivity (IS); and 3) insulin signal transduction (IST) in insulin-sensitive tissues. Results: Low birth weight was not detected in the PEDO group. However, plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and TNF-α were increased and IS and IST were reduced (P <0.05) in the PEDO group compared with the CNO group. Conclusion: Maternal periodontal disease may induce insulin resistance and reduce IST in adult offspring, but such alterations are not attributable to low birth weight.

Manifestações clínicas, bioquímicas, ultrassonográficas e metabólicas da síndrome dos ovários policísticos em adolescentes

PURPOSE: To evaluate the clinical, ultrasonographic, biochemical and metabolic alterations of adolescents with polycystic ovary syndrome (PCOS). METHODS: Retrospective observational study conducted on 44 adolescents aged 12 to 19 years, diagnosed with PCOS according to the Rotterdam Consensus. Metabolic changes were assessed according to the recommendations of the International Diabetes Federation, considering: waist circumference (WC) ≥90th percentile (10-15 years of age) or >80 cm (age >16 years), fasting glucose >100 mg/dL, triglycerides >150 mg/dL, HDL <40 mg/dL, and blood pressure ≥Hg 130/85 mm. RESULTS: Mean age was 16.7±2.2 years and age at menarche was 11.8±1.4 years. The menstrual irregularity most frequently observed was amenorrhea (72.7%) followed by oligomenorrhea (27.3%); hirsutism was observed in 86.4% and acne in 56.8%. Polycystic ovaries were observed by ultrasound only in 27.3%. Mean BMI was 30.3±6.6 kg/m2. According to BMI, 52.3% of adolescents were obese, 13.6% were overweight and 6.8% had a healthy weight. Increased waist circumference (63.6%, 28/44) and the reduction of HDL-C (34.1%, 15/44) were the metabolic changes most frequently observed. Increased triglycerides were observed in 27.3% (12/44) and increased blood pressure and impaired fasting glucose were found in 9.1% (4/44) and 4.5% (2/44) of cases, respectively. Acanthosis nigricans was observed in 52.3% and insulin resistance in 62.8% of the adolescents with PCOS. Metabolic syndrome was identified in six children (13.6%), all of them obese or overweight. CONCLUSION: In the adolescents with PCOS studied here, menstrual irregularity and hirsutism were the most common clinical manifestations, while the sonographic findings consistent with polycystic ovaries were less prevalent. Obesity associated with insulin resistance predisposes these adolescents to a higher frequency of metabolic disorders.

Proposta de modelo experimental para o estudo da síndrome metabólica

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Caracterização do modelo B6D2F1 para obesidade, diabetes e síndrome metabólica e sua potencialidade para terapia celular em lesão aguda

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ingestão habitual do suco de laranja vermelha e fatores de risco para a síndrome metabólica

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Suco de laranja reduz colesterol e insulina no sangue de indivíduos saudáveis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estudo caso-controle em genes polimórficos das vias esteróide (ER-alfa e ER-beta) e da insulina (INSR, PA-1 e IGF2) na síndrome do ovário policístico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)