Diabetes Mellitus, Diabetes Mellitus, Type 2, Obesity
Conditions
Keywords
Exenatide, Type 2 diabetes mellitus, Incretin hormones, GLP-1 agonist, Satiety, Reward
Brief 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.
Interventions
DRUGexenatide
The loading dose is 50 ng/min during 30 min, followed by a maintenance dose 20 ng/min for the rest of the tests.
DRUGexenatide + exendin (9-39)
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.
DRUGplacebo
saline infusion
Sponsors
Eli Lilly and Company
Bristol-Myers Squibb
Amsterdam UMC, location VUmc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
For all 3 study groups: 1. age 18-70 years. 2. Men and women. For women, only postmenopausal women (as ascertained by serum FSH) will be included in order to avoid variations related to the menstrual cycle. 3. To promote comparability and to overcome the interference of lateralization, only right-handed persons will be included. For the healthy lean subjects, inclusion criteria will be: 1. body-mass index (BMI) of \<25 kg/m2 2. stable bodyweight (\<5% reported change during the previous 3 months) 3. Normal fasting and 2-h postload glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) For the normoglycemic obese individuals, inclusion criteria will be: 1. body-mass index (BMI) ≥30 kg/m2 2. stable bodyweight (\<5% reported change during the previous 3 months) 3. Normal fasting and 2-h postload glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) For the obese T2DM individuals, inclusion criteria will be: 1. Diagnosed with T2DM (20) \> 3 months prior to screening 2. BMI ≥30 kg/m2 3. HbA1c 6.2-8.5% 4. Treatment with metformin at a stable dose for at least 3 months.
Exclusion criteria
In the obese T2DM patients, no blood glucose- and weight lowering agents will be allowed within 3 months before screening except for metformin. The normoglycemic lean and obese individuals will not be allowed to take blood glucose-lowering agents at any time before and during the study. For all individuals,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in neuronal activity in CNS reward and satiety circuits | 1 hour | Differences in neuronal activity in CNS reward and satiety circuits (including striatum, amygdala, orbitofrontal cortex, insula, hypothalamus), as represented by BOLD fMRI signal change from baseline (%) in response to food(-related) stimuli, between obese T2DM patients, normoglycemic obese individuals and normoglycemic healthy lean subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feeding behavior | 2 hours | Feeding behavior, measured as quantitative (kcal) and qualitative (energy density as well as nutrient composition; carbohydrate/fat/protein) changes in food choice during a choice-buffet lunch, will be compared between groups and conditions. |
| Self-reported hunger | 2 hours | Self-reported hunger, satiety, fullness and prospective food consumption, will be rated on 100 mm visual analogue scales before and after the meal. |
Countries
Netherlands
Outcome results
None listed