Over the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart... Show moreOver the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart failure and coronary artery disease. Despite remarkable advances in cardiovascular prevention and treatment, heart disease remains a common cause of death and an important contributor to health loss. The aim of this thesis was to characterize cardiovascular remodeling associated with metabolic disturbances, using a variety of magnetic resonance techniques. This thesis demonstrates that reduced diastolic function is a common characteristic of myocardial remodeling in type 2 diabetes and obesity, but also a potential marker for the detection of patients at increased cardiovascular risk after hematopoietic stem cell transplantation and possibly a contributing factor in the pathogenesis of ventricular arrhythmia after myocardial infarction. Also, in this thesis, it was shown that the evaluation of visceral adiposity and myocardial triglyceride content may help to identify distinct cardiometabolic phenotypes and to better understand the cardiometabolic actions of the glucagon-like peptide 1 receptor agonist liraglutide. With the emergence of non-contrast cardiovascular protocols, magnetic resonance techniques may be increasingly used for cardiometabolic phenotyping in population-based cohorts as well as clinical studies. Show less
Cardiometabolic disease such as obesity, type 2 diabetes, and atherosclerosis, are a leading cause of morbidity and mortality in the Western world. Two important risk factors for the development of... Show moreCardiometabolic disease such as obesity, type 2 diabetes, and atherosclerosis, are a leading cause of morbidity and mortality in the Western world. Two important risk factors for the development of cardiometabolic disease are hyperlipidemia and inflammation. Recently, evidence strongly indicates a role for the gut microbiota in the development of cardiometabolic disease. Therapeutic approaches are therefore aimed at modifying the gut microbiota composition and function to beneficially affect the development of cardiometabolic disease and its underlying risk factors. A potential candidate to modify gut microbiota composition are indigestible carbohydrates, or prebiotics. In this thesis, we aimed to understand the interplay between various indigestible carbohydrates, gut microbiota composition and function, and the development of obesity, type 2 diabetes, and atherosclerosis. Together, the studies described in this thesis increased our knowledge on the potential of various indigestible carbohydrates in the modulation of the gut microbiota to affect the development of cardiometabolic disease, suggesting a promising strategy to further pursue with some caution. Show less
Metabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an... Show moreMetabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an irreversible state of diabetes or cardiovascular disease. Much research has been done on the role of insulin signaling in metabolic disease, as well as the resultant disturbed lipid homeostasis present in cardiovascular disease and atherosclerosis. Here we add to existing work by developing new tools and sketching out the pathology of dysregulated adipose insulin signaling. We discuss the mechanism of lipodystrophy by using adipocytes differentiated from patient-derived iPSCs. These cells mimic the clinical phenotype and hint at mechanism that reduced patients’ adipose tissue mass. In mice we find that if we knock out the adipose insulin receptor, there is disrupted adipose and liver metabolism. There is a protection from diet-induced obesity, but a dramatically reduced lifespan. We also establish a relationship between obesity and inflammation by transcriptomically assessing obese human adipocytes. We find that an immune factor is responsible for lipid droplet formation and content. Lastly, we develop a new differentiation and purification strategy for iPSC-derived hepatocytes, which we employ to in vitro model a SNP that protects against cardiovascular disease. Show less
