Molecular and genetic mechanisms of myocardial insulin resistance in humans and mice

Abstract

Patients with type 2 diabetes mellitus have a greatly increased risk of coronary artery disease and heart failure due to a number of factors such as insulin resistance, hyperglycaemia, arterial hypertension, and obesity. To study the changes seen in hearts of diabetic patients the aim of this project was to generate a clinically relevant diet-induced obese mouse model which could mimic these changes. Male C57BL/6 mice were fed a 45% high fat diet for 8, 11, and 14 weeks. Metabolic and histological changes in animals that responded to the high fat diet (diet-induced obese, DIO) were investigated and the most appropriate feeding period was determined for further studies. DIO animals showed significantly increased body weight gain, elevated fasting serum insulin levels and over time animals developed impaired glucose tolerance. Histological analysis of DIO hearts after 14 weeks of high fat diet showed significantly increased interstitial fibrosis and after all three time points a previously unrecognised coronary microvascular remodelling was observed in DIO mice. Molecular mechanisms involved in insulin resistance and coronary microvascular remodelling were investigated in DIO mice after 11 weeks of high fat diet. Animals showed alterations in coronary flow, endothelial dysfunction and myocardial gene expression analysis revealed differentially expressed genes involved in lipid and carbohydrate metabolism. Validation experiments showed that one of these genes, regulator of G-protein signalling (RGS2), had a significant reduction at both RNA and protein level in total heart lysates. Additionally, RGS2 expression in vascular smooth muscle cells of small vessels in the heart was significantly reduced in DIO mice. After a shift from high fat to a normal rodent chow a reversal of microvascular remodelling as well as a return of RGS2 expression levels back to baseline were observed. In conclusion, this diet-induced mouse model shows features of cardiomyopathy and coronary microvascular remodelling which is closer to the phenotype seen in patients with arterial hypertension or hypertrophic cardiomyopathy compared to other mouse or rat models.