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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:549096 |
| Date | January 2011 |
| Creators | Gibbons, Stephen |
| Contributors | Mamas, Mamas ; Cartwright, Elizabeth |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/insights-into-the-cardiovascular-complications-of-a-novel-mouse-model-of-diabetes-mellitus-a-mechanistic-view(d1c68010-8059-4371-a50f-be3614703471).html |
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