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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Insights into the cardiovascular complications of a novel mouse model of diabetes mellitus : a mechanistic view

Gibbons, Stephen January 2011 (has links)
Heart failure (HF) is one of the commonest complications of Diabetes Mellitus (DM) with the prevalence of DM reported at around 30% in many pivotal heart failure studies. However the pathophysiological mechanisms that contribute to HF development in diabetes are poorly understood. To investigate this we used a novel human relevant mouse model of DM (GENA348) in which there is a point mutation in the glucokinase (Gck) gene, the glucose sensor which regulates insulin secretion. A mutation in the same gene is known to underlie Maturity Onset Diabetes of the Young Type 2 (MODY 2) in humans. The mutant mice developed significant hyperglycaemia with normal insulin levels due to the altered glucose sensing. We examined the molecular mechanisms that contribute to the HF phenotype in DM. Mean random blood glucose was found to be increased in the GENA348 mutant(HO) mice compared to wild type (WT) litter mates (WT 6.9±0.3mmol/L vs HO20.6±0.8mmol/L, P<0.001). Serial echocardiography was performed, at 3, 6 and 12 months. No significant changes in echocardiographic parameters were observed at 3 months, although by 6 months development of significant cardiachypertrophy in HO mice was observed characterised by a 20% increase in the diastolic posterior wall thickness (dPW). At 12 months of age left ventricular dilatation was also evident. Systolic function was preserved although significant diastolic dysfunction was evident at 6 and 12 months. Histological staining illustrated significant cellular hypertrophy with real time PCR data demonstrating a relative 150% increase in the hypertrophic marker BNP. Hypertrophic pathways were examined through western blot analysis revealing an age dependent increase in Akt phosphorylation (6 months-140%, 12 months-460%). Serum levels of advanced glycation end products (AGEs) and expression of their receptors RAGE were also elevated. In vitro cellular experiments also revealed AGEs directly activate Akt through phosphorylation and increase levels of the receptor RAGE. AGE induced phosphorylation of Akt is inhibited in the presence of wortmannin, suggesting a PI3K dependent signalling mechanism. Wortmannin blocked the development of cardiac hypertrophy in the diabetic mice. In conclusion we demonstrate that the human relevant GENA348 mouse model of diabetes develops a progressive cardiac phenotype including cardiachypertrophy, LV dilatation and diastolic dysfunction similar to the clinical manifestations of diabetic cardiomyopathy. We propose a novel RAGE/PI3K/Akt pathway that for the first time provides insight into the molecular mechanisms that underlie the development of HF. Moreover, we show raised glucose alone is able to cause cardiotoxicity independently of insulin.
2

Investigation into the underlying mechanisms of diabetic cardiomyopathy using a mouse model of diabetes

Al-Maimani, Riyad Adnan A. January 2016 (has links)
Diabetes Mellitus (DM) is one of the most common metabolic disorders in the world with an estimated prevalence of over 415 million patients. Heart failure (HF) is the most common cardiovascular complication of diabetes. The prevalence of diabetes in patients with HF is reported at approximately 30%. However, the molecular mechanisms that contribute to the development of heart failure in diabetic patients remain uncertain. To study this, a genetic mouse model of diabetes (GENA348) with a point mutation in the glucokinase gene was used. Glucokinase is a glucose sensor that controls insulin release. This mutation in the glucokinase is similar to that found in Maturity Onset Diabetes of the Young Type 2 (MODY2) in humans. Our group has previously shown that GENA348 mice exhibit a diabetic phenotype. At 6 months, the mice developed a diabetic cardiomyopathy analogous to that seen in clinical practice with the development of cardiac hypertrophy and diastolic dysfunction, which progressed to dilatation of the left ventricle and systolic dysfunction at 12 months. The aim of the project was to examine the molecular and pathophysiological mechanisms that contribute to development of this cardiac phenotype in diabetic GENA348 mice in the setting of hypertension and at baseline. To study the mice under hypertensive stress conditions, 6 month old-GENA348 HO and WT mice were infused with angiotensin II (ANG II) via minipump. After ANG II treatment, HO and WT GENA348 mice showed a significantly greater increase in systolic and diastolic blood pressure compared to untreated controls. It was evident that ANG II treatment resulted in cardiac hypertrophy with the same level observed in both HO and WT mice. The diastolic function was generally preserved in the WT and HO mice following the ANG II treatment. Our data indicates that the HO mice have had a blunted hypertrophic response to the hypertension induced by ANG II. At baseline, two hypothesis-generating methods were used. Firstly, gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS) were used on 12-month-old GENA348 mice heart and serum samples. Secondly, diabetes PCR array plates were used on 6- and 12-month-old GENA348 mice heart samples. For the GCMS and UPLC-MS, there were 43 differences in metabolites from tissue samples and 93 from serum samples. The main altered metabolites from tissue samples were sugars and fatty acids. However, fatty acids, phospholipids and sphingolipids were the main altered metabolites from serum samples. After the validation of the array plates the most apparent observation was that only two up-regulated genes, Phosphoenolpyruvate carboxykinase 1 (Pck1)and Glucose-6-Phosphatase, Catalytic Subunit (G6pc) showed a comparable pattern as the array results. Pck1 and G6pc are the main enzymes that play a key role in gluconeogenesis regulation. We also looked at the expression level of one of the main transcriptional regulators of gluconeogenesis, Forkhead boxprotein O1 (FoxO1). It was found that the expression was altered at 12 months. In conclusion, it was clear that hyperglycaemia altered gene expression and the metabolites profiles in 12 month old HO mice, with evident alterations detected in genes involved in the metabolic regulation of the heart. In addition, this study may provide preliminary insight into pathophysiological alterations in the cardiac metabolism that may contribute to the development of diabetic cardiomyopathy.

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