The Effect of GLP-1 Receptor Activation on Central Reward and Satiety in Obesity and Diabetes
Condition: Diabetes Mellitus; Diabetes Mellitus, Type 2; Obesity
MeSH terms: Diabetes Mellitus; Obesity; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Glucagon-like peptide 1 (GLP-1) based therapies, such as exenatide, are already successfully
      employed in the treatment of Type 2 Diabetes (T2DM). Exenatide improves glycemic control and
      is associated with reduced food intake and body weight. The investigators hypothesize that it
      affects central reward and satiety circuits and that this may contribute to the weight loss.
    

Detailed description: 
      The aim of the project is to determine 1) whether GLP-1 receptor activation of CNS reward and
      satiety circuits occurs, in the context of food(-related) stimuli; if this effect is altered
      in obese and diabetic compared to lean individuals 2) if it is independent of other
      postprandial metabolic and hormonal changes 3) if this effect is GLP-1-receptor-mediated 4)
      if the CNS changes correlate with subsequent feeding behaviour.

      Methods The investigators will compare 16 obese T2DM-patients, 16 normoglycemic obese and 16
      healthy lean individuals, with respect to food(-related) neuronal activity in central reward
      and satiety circuits by blood oxygen level-dependent (BOLD) fMRI. fMRI will be performed
      during intravenous infusion of a) the GLP-1 receptor agonist exenatide; b) exenatide and a
      GLP-1 receptor antagonist (exendin 9-39)(to investigate whether the exenatide-induced effects
      are GLP-1-receptor mediated) or c) saline; in randomized order, on separate days. To tease
      out concomitant postprandial metabolic and hormonal influences, measurements will be
      performed during a somatostatin pancreatic clamp with replacement of basal insulin, glucagon
      and growth hormone. Finally, to correlate changes in brain activity with subsequent feeding
      behavior, the investigators will measure food intake, self-reported hunger, satiety and mood,
      during a choice-buffet after the scanning.

      Expected Results This project will gain insight into (CNS) mechanisms underlying the observed
      effects of the GLP-1 receptor agonist exenatide on food intake and body weight in obese,
      diabetic and healthy lean individuals. These findings may increase our understanding of the
      development of obesity and weight loss problems in obese and diabetic individuals and the
      role of GLP-1 in the central regulation of feeding behavior/appetite control.
    

Intervention name(s): exenatide; exenatide + exendin (9-39); placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): The loading dose is 50 ng/min during 30 min, followed by a maintenance dose 20 ng/min for the rest of the tests.; The loading dose is 50 ng/min during 30 min, followed by a maintenance dose 20 ng/min for the rest of the tests. Exendin 9-39 will be infused intravenously at doses of 600 pM/kg • min.; saline infusion
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Keywords: Exenatide; Type 2 diabetes mellitus; Incretin hormones; GLP-1 agonist; Satiety; Reward