Masters Degrees (Medical Physiology)

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Browsing Masters Degrees (Medical Physiology) by Author "Boshoff, Anel W."

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    Investigating the onset of insulin resistance and non-alcoholic fatty liver disease in obesity-induced cardiac dysfunction
    (Stellenbosch : Stellenbosch University, 2019-04) Boshoff, Anel W.; Johnson, Rabia; Huisamen, Barbara; Gabuza, Kwazi; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Medical Physiology.
    Introduction: The global obesity epidemic has been associated with various metabolic disorders, including insulin resistance and non-alcoholic fatty liver disease (NAFLD). Insulin resistance is thought be a hallmark of NAFLD, which is an established risk factor for the development of type 2 diabetes mellitus (T2DM) and cardiac dysfunction. Conversely, evidence exists to suggest that NAFLD can develop despite conserved insulin sensitivity, and that it can play a role in the development of insulin resistance. While both insulin resistance and NAFLD are known to contribute to cardiac dysfunction, it is not evident which develops first. With the rising burden of obesity-related heart disease, it is vital to gain a better understanding of the pathophysiology involved in order to better treat or prevent heart failure. Aim: To investigate the order of onset of NAFLD and insulin resistance in obesity-induced cardiac dysfunction. Methods: Six- to fifteen-week-old male leptin receptor deficient (Leprdb/db) mice and their lean littermate controls (Leprdb/+) were monitored weekly to measure fasting blood glucose and body weight. Heart function was determined weekly using TDI echocardiography, after which 8 animals per group were terminated. Serum was collected to measure lipogram and liver enzymes, while muscle, liver and heart tissue were used to investigate insulin resistance, NAFLD, and cardiac dysfunction, respectively. Results: Data obtained showed that Leprdb/db mice had increased body weight (31.75 g ± 0.71 vs. 20.50 g ± 0.55, p < 0.001) and total cholesterol (3.90 mmol/L ± 0.14 vs. 1.90 mmol/L ± 0.04, p < 0.001) by 6 weeks of age. Serum AST/ALT ratio (0.76 ± 0.07) indicated hepatic lipid accumulation by 7 weeks and histological analysis confirmed the presence of NAFLD at this time, as well as its progression in severity with age. Gene expression analysis in the liver showed an increase in lipogenic genes FASN (1.16 ± 0.18 vs. 0.25 ± 0.05, p < 0.01) and SCD1 (1.03 ± 0.08 vs. 0.20 ± 0.05, p < 0.001) by 7 weeks of age. Muscle insulin resistance was not present at the onset of NAFLD, and developed around 10 weeks of age, as confirmed by a decrease in pPI3K and pAKT protein expression (0.17 ± 0.03 vs 0.10 ± 0.01, p < 0.01 and 0.23 ± 0.06 vs 0.12 ± 0.03, p < 0.05, respectively). Gene expression analysis confirmed an increase in oxidative stress NOX4 (1.23 ± 0.30 vs. 0.77 ± 0.09, p < 0.05), inflammation NFκB (1.68 ± 0.09 vs. 0.69 ± 0.04, p < 0.001) and apoptosis CASP3 (1.42 ± 0.10 vs. 1.06 ± 0.06, p < 0.05) in the heart of Leprdb/db mice by 10 weeks. Conclusion: Hepatic steatosis preceded muscle insulin resistance in a genetic model of obesity, and likely contributed to the development of insulin resistance and myocardial dysfunction.