Center of Excellence: Diabetes & metabolism
Diabetes is a major threat to health care in the Netherlands, with 1 million patients and an expected ~30 percent increase in prevalence in the next 15 years. As obesity figures are expected to double in this period, type 2 diabetes mellitus (DM2), the Metabolic Syndrome (MetSyn) and their co-morbidities will profoundly affect our health and economy. Although it is clear that excess energy intake is the driving force for obesity, little is known about the processes that trigger the transition from the metabolically healthy to the metabolically unhealthy obese phenotype. In addition to the MetSyn, and closely linked to it, is the expanding prevalence of chronic kidney disease, which, like MetSyn has proven to be a key metabolic derangement involved in cardiovascular disease. Both conditions share epidemiological features (like ageing, and increasing prevalence), pathophysiological mechanisms (like disturbed microcirculatory regulation) and clinically important cardiovascular complications.
Pathogenesis of DM2 and diabetes-related syndromes
Chronic low-grade inflammation (resulting from e.g. altered intestinal microbiome composition and nutrient overload) leads to microvascular dysfunction and peripheral insulin resistance in obese subjects. This is followed by complex inter-organ communication involving the brain, endothelium, beta cell (inflammation), bone and bone marrow/immune cells, adipose tissue and symbionts (intestinal microbiome). To disentangle this complex process, we will analyse datasets from different biobank studies (HELIUS, Hoorn and Slotervaart-OLVG Bariatric surgery cohort), and use combinations of computational models, developed in collaboration with the systems biology groups in UvA and VU/VUmc, and tissue-specific animal models.
New DM2 therapies
It is of utmost importance to dissect the underlying mechanisms that induce the comorbidities of the MetSyn and directly test and implement the diagnostic and therapeutic value of these discoveries in clinical diabetes care.
Complications of diabetes
Clearly this requires a thorough understanding of the mechanisms inducing the metabolic imbalance in subjects characterized by malign obesity with insulin resistance as well as Type 2 diabetes. In this regard the pathophysiological mechanisms behind obesity- and diabetes-associated microvascular dysfunction, which predispose to e.g. nephropathy and heart failure, are incompletely understood. The role of obesity and diabetes in diastolic heart failure is investigated in close collaboration with the CoE Heart Failure and Arrhythmias. Early identification of persons at risk and understanding of preclinical pathology will be central to initiate proper treatment strategies and delay or reverse disease progression.
Organ failure-induced cardiovascular disease
Metabolic derangements due to organ failure represent a high risk for cardiovascular disease. However, systemic consequences of metabolic derangements are poorly understood. Impaired kidney function is a strong risk factor for mortality in heart failure patients. Our current studies focus on the mediating effects of both early and advanced renal failure on cardiovascular function. The connection between kidney dysfunction and development of vascular and cardiac dysfunction is studied within (inter)nationally-funded research consortia.