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Investigating the onset of insulin resistance and non-alcoholic fatty liver disease in obesity-induced cardiac dysfunction

dc.contributor.advisorJohnson, Rabiaen_ZA
dc.contributor.advisorHuisamen, Barbaraen_ZA
dc.contributor.advisorGabuza, Kwazien_ZA
dc.contributor.authorBoshoff, Anel W.en_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Medical Physiology.en_ZA
dc.date.accessioned2019-02-05T19:56:34Z
dc.date.accessioned2019-04-17T08:21:20Z
dc.date.available2019-02-05T19:56:34Z
dc.date.available2019-04-17T08:21:20Z
dc.date.issued2019-04
dc.identifier.urihttp://hdl.handle.net/10019.1/105970
dc.descriptionThesis (MMed)--Stellenbosch University, 2019.en_ZA
dc.description.abstractIntroduction: 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.en_ZA
dc.description.abstractInleiding: Die wêreldwye vetsug epidemie is geassosieer met verskeie metabolies afwykings, insluitend insulien weerstandigheid en nie-alkoholiese vetterige lewer siekte (NAFLD). Insulien weerstandigheid word beskou as 'n kenmerk van NAFLD, wat 'n gevestigde risikofaktor is vir die ontwikkeling van tipe 2 diabetes mellitus (T2DM) en kardiale disfunksie. Daarenteen bestaan bewyse dat NAFLD kan ontwikkel ondanks die behoud van insulien sensitiwiteit, en dat dit 'n rol kan speel in die ontwikkeling van insulien weerstandigheid. Alhoewel beide insulienweerstandigheid en NAFLD bekend is om by te dra tot hartafwykings in vetsug, is dit nie duidelik wat eerste ontwikkel nie. Met die stygende las van vetsugverwante hartsiektes is dit noodsaaklik om die risikofaktore wat betrokke is om hartversaking beter te verstaan en in sodoende, beter te behandel of te voorkom. Doelstelling: Om die volgorde van aanvang van NAFLD en insulienweerstandigheid in vetsugverwante hartafwykings te ondersoek. Metodes: Ses tot vyftien week-oue manlike leptien-reseptor-gebrekkige (Leprdb/db) -muise en hul maer beheerkontroles (Leprdb/+) is weekliks gemonitor om bloedglukose en liggaamsgewig te meet. Hartfunksie is weekliks vasgestel met behulp van TDI-ekkokardiografie, waarna 8 diere per groep beëindig is. Serum is ingesamel om lipogram en lewer ensieme te meet, terwyl spier-, lewer- en hartweefsel gebruik is om insulienweerstandigheid, NAFLD en hartafwykings onderskeidelik te ondersoek. Resultate: Die data wat verkry is, het getoon dat Leprdb/db-muise hoёr gewig (31,75 g ± 0,71 vs. 20,50 g ± 0,55, p <0,001) en totale cholesterol (3,90 mmol / L ± 0,14 teenoor 1,90 mmol / L ± 0,04, p <0,001) gehad het teen 6 weke oud. Serum AST/ALT-verhouding (0.76 ± 0.07) het lewer lipiedakkumulasie teen 7 weke aangedui en histologiese analise het die teenwoordigheid van NAFLD op hierdie tydstip bevestig, sowel as die ontwikkelling daarvan in erns met ouderdom. Gene-ekspressie-analise in die lewer het 'n toename in lipogene gene FASN (1.16 ± 0.18 vs. 0.25 ± 0.05, p <0.01) en SCD1 (1.03 ± 0.08 vs. 0.20 ± 0.05, p <0.001) teen 7 weke oud. Spierinsulienweerstand was nie teenwoordig by die aanvang van NAFLD nie, en ontwikkel ongeveer 10 weke oud, soos bevestig deur 'n afname in pPI3K- en pAKT-proteïenuitdrukking (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, onderskeidelik). Gene-ekspressie-analise bevestig 'n toename in oksidatiewe stres NOX4 (1.23 ± 0.30 vs. 0.77 ± 0.09, p <0.05), inflammasie NFκB (1,68 ± 0.09 vs. 0.69 ± 0.04, p <0.001) en apoptose CASP3 (1.42 ± 0.10 vs. 1.06 ± 0.06, p <0.05) in die hart van Leprdb/db muise teen 10 weke. Gevolgtrekking: Lewer steatosis kom voor spier insulien weerstandigheid voor in 'n genetiese model van vetsug, en dra waarskynlik by tot die ontwikkeling van insulien weerstand en miokardiale afwykings.af_ZA
dc.format.extent124 pages : illustrationsen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.subjectUCTDen_ZA
dc.subjectObesityen_ZA
dc.subjectInsulin resistanceen_ZA
dc.subjectFatty liveren_ZA
dc.subjectLiver -- Diseasesen_ZA
dc.subjectCardiac diseasesen_ZA
dc.titleInvestigating the onset of insulin resistance and non-alcoholic fatty liver disease in obesity-induced cardiac dysfunctionen_ZA
dc.typeThesisen_ZA
dc.rights.holderStellenbosch Universityen_ZA


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