Black South African (SA) women are disproportionally affected by obesity and insulin resistance, which have been associated with depot-specific alterations in adipose tissue function. This thesis aimed to evaluate the differences in fatty acid (FA) composition and gene expression between abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT), and the changes in response to exercise training in relation to body composition, hepatic fat, inflammatory and oxidative stress markers, and insulin sensitivity (SI) in obese black SA women. This research evaluated the i) FA composition of aSAT and gSAT, and red blood cell total phospholipids (RBC-TPL) and their associations with body composition, hepatic fat and SI, ii) changes in these FA profiles in response to exercise training and the relationship with changes in systemic inflammation, hepatic fat and SI; iii) effects of exercise training on systemic markers and SAT gene expression of inflammation and oxidative stress; and iv) regional differences in transcriptome profiles of aSAT and gSAT pre- and post-exercise training. Forty-five IsiXhosa women (30-40kg/m2 , 20-35 years) were randomized into control (n=22) or exercise groups (n=23; 12-week aerobic-resistance training, 40-60 min/session, 4 days/week). Pre and postintervention measurements included: anthropometry, body composition, cardiorespiratory fitness, dietary intake, SI, hepatic fat, systemic markers and SAT gene expression of adipokines, inflammation and oxidative stress, RBC-TPL and SAT fatty acids profiles, and untargeted SAT gene expression analyses. The main findings showed differences in the circulating (RBC-TPL) and stored (SAT) FA composition, which reflected in different associations between these FA profiles and SI. Moreover, the changes in FA composition in response to exercise training were depot-specific, with the changes in RBC-TPL correlating with a decrease in systemic inflammation and hepatic fat. Exercise training alleviated systemic oxidative stress and induced increased gSAT inflammatory genes, reflecting SAT remodelling. These changes coincided with a reduction in gynoid fat and were not associated with increased SI. Furthermore, there were unique depot-specific gene expression signatures relating to embryonic development at baseline and more diverse functional-related processes at post-training. This generated novel candidate genes potentially implicated in the relationship between body fat distribution and metabolic status in obese black SA women.

Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi- dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n Z 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity among the included studies. Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR values. / Revisión por pares

Introduction: Bariatric surgery is considered the most effective treatment for severe obesity. However, it is not clear if patients with diabetes mellitus or insulin resistance have the same response than patients without those conditions. Our objective was to evaluate association between pre-surgical HOMA-IR index and percentage of excess weight loss (EWL%) one year after bariatric surgery using sleeve gastrectomy. Methods: Retrospective cohort including patients ≥ 18 years old with BMI ≥ 35 kg/m2, who underwent primary sleeve gastrectomy between 2014-2017 at the Avendaño Medical Center, Peru. Only patients with Type 2 Diabetes, Hypertension, or Dyslipidemia were included. EWL% ≥ 60% one year after surgery was considered satisfactory. Crude and adjusted Lineal and Poisson regression with robustness was used to assess statistical associations with EWL%. Results: Ninety-one patients were included with a median of 34 years, and 57.1% were women. 85.7% had insulin resistance as per HOMA-IR. One year after surgery, 76.9% had a satisfactory EWL%. The lineal model showed. 29% less EWL% per each extra year of life (P = .019), and. 93% more EWL% per each extra HOMA-IR point (P = .004). The adjusted Poisson model showed 2% lower risk of having a satisfactory EWL% per each additional year of life (P = .050), and 2% more chance of success per each additional HOMA-IR point (P = .038). Conclusions: There was association between a higher pre-surgical HOMA-IR index and increased EWL% one year after surgery. It is possible that insulin resistance does not affect negatively sleeve gastrectomy outcomes. / Revisión por pares

Resveratrol, a naturally-occurring phytoestrogenic stilbene derivative, has been shown to elicit shifts in physiology of obese animals consuming a high calorie or ad libitum diet toward that of lean counterparts. This study was designed to evaluate effects of oral resveratrol supplementation on parameters of metabolic health and reproductive cyclicity in obese mares on pasture. Seventeen healthy, mares were matched by age and assigned to obese control (OBC; n=5, mean BCS=7.4±0.3), obese supplemented with 5g/d resveratrol (OBR; n=6, mean BCS=7.4±0.2) or non-obese control (NOC; n=6, mean BCS=5.4±0.1) treatments. Control horses received the resveratrol carrier paste. Across three consecutive estrous cycles, morphometric measurements were collected biweekly and follicular dynamics were evaluated via transrectal ultrasonography every other day. Frequently-sampled intravenous glucose tolerance tests were conducted pre- and post- treatment. Insulin and glucose kinetics were analyzed via minimal model. Resveratrol supplementation had no discernible effect on reproductive parameters (P>0.05), however obese mares had more (6 vs. 0) hemorrhagic anovulatory follicles. Neither resveratrol treatment nor time on study influenced morphometric measurements or minimal model parameters (raw data or data adjusted for animal size). As a whole, horses became more insulin resistant over time (Si value < 0.78 (1/[mU/L"min]). NOC horses had lower (P=0.01) acute insulin response to glucose relative to OBC or OBR. Although resveratrol supplementation did not elicit detectable responses in this study, promising results in other species warrant further investigation of the compound in horses, including exploration of bioavailability and possible effects at the tissue or cellular levels. / Master of Science

Background. Bisphenol A (BPA) and BPS are environmental pollutants that are associated with the development of insulin resistance and type 2 diabetes (T2D). Although skeletal muscle and adipose tissue dysfunction are involved the development of insulin resistance, there are few studies that have investigated the effects of bisphenols on their metabolism. In this study, we investigated the effects of BPA and BPS exposure on skeletal muscle and adipose tissue metabolism to determine how they contribute to the development of T2D. Methods. L6 muscle cells were treated with BPA during the last 24 hours of differentiation, and mitochondrial function and glucose metabolism was measured. Human subcutaneous adipose tissue was incubated for 24 or 72 hours with BPA or BPS, and adipokine gene expression and glucose metabolism was measured in adipose tissue. Results. L6 muscle cells treated with high concentrations of BPA (10⁵ nM) had mitochondrial dysfunction and a compensatory increase in glucose metabolism; however, there were no effects at environmentally-relevant concentrations. Adipose tissue treated with BPA for 24 hours had reduced expression of proinflammatory cytokines and adipokines, and reduced insulin-stimulated glucose uptake. Conclusions. BPA exposure for 24 hours did not alter L6 muscle cell mitochondrial function and glucose metabolism at environmentally-relevant concentrations; however, adipose tissue had altered proinflammatory expression and glucose metabolism at low concentrations. This has important implications in regulatory guidelines in the use of BPA in the manufacturing of consumer products.

TGFβ ligands, activin and myostatin have been shown to stimulate insulin production and secretion. Antagonists, Follistatin (FST) and Follistatin like 3 (FSTL3) were partially and fully ablated, respectively, creating hyperinsulinemic mice with fatty liver. Much research has surfaced on the connection between hepatic steatosis and hepatic insulin resistance. We present two different models, each with a different mechanism behind the development of fatty liver. FST288-only mice have increased synthesis of mRNA and proteins responsible for hepatic triglyceride (TG) uptake, while our double mutants have increased synthesis of mRNA and proteins responsible for TG synthesis. This alteration was likely independent of hepatic insulin resistance as livers from both mouse lines were insulin sensitive. Experiments conducted in this study to realize the causal factor of hepatic steatosis can be performed on adipose and muscle tissues in the future to better characterize the phenotype.

Controversy exists concerning the possible involvement of serotonin in the pituitary-adrenocortical response to stress. In the present research, a variety of physiological and pharmacological manipulations were used in male rats to study the role of this neurotransmitter in the adrenocortical response to insulin- induced hypoglycemia. First, the effect of insulin stress on hypothalamic 5-HT metabolism was examined, and an increased turnover was found as determined by an enhanced accumulation of 5-HT following monoamine oxidase inhibition. The corticos terone response to insulin was potentiated by prior administration of L-tryptophan, and blocked by pretreatment with valine, an amino acid that competes with tryptophan for transport across the blood-brain barrier. Treatment with the 5-HT receptor blocker methysergide, or serotonin depletion by intraventricular injection of 5 , 7-dihydroxy tryptamine significantly attenuated the insulin- induced rise in circulating corticosterone.

Introduction: Metabolic syndrome and depression are considered to be important risk factors for the development of cardiovascular diseases. The prevalence of metabolic syndrome is estimated to be around 25% of the adult population in industrialized countries, including the population of Czech Republic. The prevalence of depression is estimated to be around 15% of the same adult population. It is not clear yet on the base of poor literature, which is so far available, whether there is a causal relationship between these factors or not. Objective: To try to find a relationship between metabolic syndrome and depression in a population sample using clinical and metabolic parameters. Methods: The prevalence of depressivity or other psychopathologies was evaluated with the use of self-report questionnaires in a randomly selected population sample of 259 people living in Pilsen. The questionnaires were mailed to the subjects. Those of them who responded were invited to the examination of anthropometric and laboratory parameters defining the metabolic syndrome and to the examination of some other parameters. The occurrence of risk factors of the metabolic syndrome of insulin resistance and the relationship between depression and metabolic syndrome was investigated. Metabolic syndrome of insulin resistance...

Molecular analysis of the cross talk between Angiotensin II (Ang II) and insulin signaling systems reveal that they are multifaceted and occur at cellular level and intracellular level. Experiments were carried out to evaluate the crosstalk between the Ang II receptors-AT1 and AT2 and the Insulin Receptor (IR) to understand the changes in the signaling pathway that could lead to the transition from hypertension to insulin resistance. Transient expression of rat AT2 in CHO cells induced co-immunoprecipitation of the AT2R with IRâ and inhibition of IRâ tyrosine phosphorylation. An AT2-peptide carrying the amino acids 226-363 (that spans 3rd intracellular loop (ICL) and C-terminal cytoplasmic domain) was sufficient for AT2- IRâ interaction in a yeast two-hybrid assay. An orthovanadate-insensitive AT2- IRâ association was also observed in human breast cancer cell line MCF-7. Interestingly, while AT2- IRâ complex formation was insensitive to pertussis toxin (PTX), AT2-mediated inhibition of IRâ phosphorylation was partially sensitive to PTX treatment in MCF-7. To address the mechanism behind the transition of an early hypertensive heart to an insulin resistant status, we investigated the changes that occur at post translational level in the IR and its downstream signaling molecules that modulate insulin signaling. Early hypertension was induced in 10-week old SD rats by 2% NaCl diet in combination with Ang II infusion. Enhanced serine phosphorylation of the IRâ suggestive of dysfunctional insulin signaling was observed in cardiac tissues as a result of the treatment. In addition, an enhanced association of both AT1R and AT2R with IRâ was observed in the heart tissue lysates from hypertensive rat heart. To evaluate the tissue effects of Ang II, we compared the transcriptome of hypertensive rat hearts to the controls. Analysis suggests that the Ang II induces multiple responses in heart tissue that result in changes to the gene expression pattern intended to promote insulin sensitivity and insulin resistance. Taken together our results suggest that exogenous Ang II and moderately high salt diet promote metabolic abnormalities in heart tissue that result in sequestration of IR and modulation of IR signaling, and significant changes in gene expression profile in the hypertensive heart.

No description available.