GLP-1 receptors are present in most organ systems of the human body, and pharmacological interventions enhancing GLP-1 activity may influence the function of these organs. The use of GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors (DPP-4i) has been associated with an increased heart rate, acute pancreatitis and acute renal failure. To date, studies in humans detailing the effects of these drugs on these organ systems, biological processes and underlying mechanisms, which could explain these associations, are lacking.~Therefore, as part of the EU-FP7 SAFEGUARD program, the present study will aim to detail the (mechanisms underlying the) actions of GLP-1RA and DPP-4i on the cardiovascular, renal and gastrointestinal system in healthy obese subjects and patients with T2DM.~In the main study, sixty patients with type 2 diabetes will undergo two interventions within the same protocol in order to assess changes in the outcome parameters:~acute study = acute infusion with exenatide or placebo (to assess the cardiovascular and renal effects)~long-term study = 12 weeks of treatment with liraglutide, sitagliptin or placebo (to assess the cardiovascular, renal and gastrointestinal effects)~In a substudy (termed 'acute MRI study'), twelve patients with type 2 diabetes will undergo an additional acute intervention study with exenatide (to assess the pancreatic effects)~In a substudy (termed 'pilot-study'), ten healthy obese subjects will undergo a similar acute study like the patients with type 2 diabetes (to assess the cardiovascular and renal effects). Moreover, in these healthy subjects, the effects of exenatide during L-NMMA infusion will be assessed.
The aim of this study is to detail the (mechanisms underlying the) actions of the GLP-1 receptor agonists and DPP-4 inhibitors on the cardiovascular, renal and gastrointestinal systems in patients with Type 2 Diabetes Mellitus.