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Title: Investigation into the underlying mechanisms of diabetic cardiomyopathy using a mouse model of diabetes
Author: Al-Maimani, Riyad Adnan A.
ISNI:       0000 0004 5919 2166
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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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.
Supervisor: Cartwright, Elizabeth ; Mamas, Mamas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Hypertension ; Diabetes Mellitus ; Heart Failure ; Cardiac Metabolism ; Metabolomics ; Gene expression ; Gluconeogenesis