Overall objective:The overall objective is to test the hypothesis that GLP-1 receptor activation of CNS reward and satiety circuits occurs, in the context of food(-related) stimuli, and that this effect is altered in individuals with obesity and…
ID
Source
Brief title
Condition
- Other condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Central nervous system vascular disorders
Synonym
Health condition
obesitas
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
-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, (Appendix 4) between the infusion of exenatide and the infusion of
exenatide in combination with a GLP-1 receptor antagonist.
-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, satiety, fullness and prospective food consumption, will
be rated on 100 mm visual analogue scales before and after the meal.
Background summary
Comparable to the role for central nervous system (CNS) reward and satiety
responses in drug addiction, it has been hypothesized that excessive eating due
to changes in CNS reward and satiety responses to the consummation of food is
crucial in the development of obesity and type 2 diabetes (T2DM). The delivery
of nutrients to the gastrointestinal tract after food ingestion activates the
secretion of several gut-derived mediators, including the incretin hormone
glucagon-like peptide 1 (GLP-1). GLP-1-based therapies, including GLP-1
receptor agonists such as exenatide, are currently successfully employed in the
treatment of patients with T2DM. Exenatide improves glycemic control and
stimulates satiety, leading to a reduction in food intake and body weight. We
hypothesize that GLP-1 and exenatide affect central reward and satiety circuits
and these actions may contribute to the observed GLP-1 receptor agonist-induced
weight loss. It is unknown whether differences in GLP-1 receptor activation
play a role in the previously observed differences between lean and
obese/diabetic individuals in activity of CNS circuits involved in satiety and
reward after food intake. Differences in GLP-1 receptor activation may be due
to a diminished sensitivity for GLP-1 (receptor agonists) and/or, reduced GLP-1
levels in individuals with obesity and type 2 diabetes.
Study objective
Overall objective:
The overall objective is to test the hypothesis that GLP-1 receptor activation
of CNS reward and satiety circuits occurs, in the context of food(-related)
stimuli, and that this effect is altered in individuals with obesity and T2DM.
To this end we will address the following research objectives:
Primary Objective
1)Do the effects of the GLP-1 receptor agonist exenatide on neuronal activity
of CNS reward and satiety circuits, in response to food(-related) stimuli,
differ between obese T2DM patients, normoglycemic obese individuals, and
normoglycemic healthy lean subjects?
Secondary Objectives
2)Are the exenatide-induced effects on the neuronal activity of CNS reward and
satiety circuits effectuated by the GLP-1 receptor agonist per se (i.e.
independent of other postprandial metabolic and hormonal changes)?
3)Are the exenatide-induced effects on the neuronal activity of CNS reward and
satiety circuits mediated via the GLP-1 receptor?
4)How do the GLP-1 receptor agonist-related CNS changes correlate with
subsequent quantitative and qualitative aspects of food intake, including
self-reported hunger, satiety, fullness, prospective food consumption, and
mood, during a choice-buffet in these obese T2DM patients, normoglycemic obese
individuals, and normoglycemic healthy lean subjects?
Study design
This is a randomized, single blind, cross-over mechanistic study in humans in
vivo, addressing important mechanism of action of the GLP-1 receptor agonist
exenatide, using a complex protocol in obese T2DM patients, normoglycemic obese
individuals, and normoglycemic healthy lean subjects.
Intervention
We will investigate and compare all participants with respect to food(-related)
neuronal activity in central reward and satiety circuits by blood oxygen
level-dependent (BOLD) fMRI at 3 different occasions. Neuronal activity will be
expressed as signal change from baseline (%) in response to food(-related)
stimuli. BOLD fMRI assessment will be performed during intravenous infusion of
a) the GLP-1 receptor agonist exenatide; b) the GLP-1 receptor agonist
exenatide in combination with a GLP-1 receptor antagonist (exendin 9-39) or c)
saline. These infusions will be performed in randomized order, on three
separate days. To address the secondary objective, i.e. tease out the role of
GLP-1 receptor agonist per se versus concomitant postprandial metabolic and
hormonal influences on the CNS circuits, the fMRI measurements will be
performed during a somatostatin pancreatic clamp with replacement of basal
insulin, glucagon and growth hormone. Levels of glucose and fore-mentioned
hormones will be kept at levels compatible with the postprandial state. To
investigate whether the exenatide-induced effects on the CNS circuits are
mediated via the GLP-1 receptor (objective 3), we will assess BOLD fMRI signal
alteration of combined infusion of exenatide and a GLP-1 receptor antagonist
(exendin 9-39). Finally, to correlate changes in brain activity with subsequent
feeding behavior (objective 4), we will measure quantitative and qualitative
food intake including self-reported hunger, satiety, fullness, prospective food
consumption, and mood, during a choice-buffet immediately after the scanning
period.
Study burden and risks
We are well aware of the possible demand that may be imposed on the
participants in this mechanistic study. After the screening visit participants
will travel 3 times to the study location. The duration of the visits is
aproximately 4 hours. A total amount of 477.5 mL blood will be withdrawn in the
total study (during 3 months). The risks associated with participation are the
risks of venous blood drawing. Exenatide, a GLP-1 receptor agonist, will be
infused according to a predefined algorithm. The only known side-effects of
exenatide infusion are nausea and vomiting, however we have specifically chosen
infusion rates at which the risk of the development of these undesired effects
is kept to an absolute minimum. We will try to make this study as bearable as
possible for our participants. All tests will be done by one researcher.
De Boelelaan 1117
1007MB
NL
De Boelelaan 1117
1007MB
NL
Listed location countries
Age
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 6.5*8.5% (48-69 mmol/mol)
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, exclusion criteria will be:
1.congestive heart failure (NYHA II-IV)
2.chronic renal failure (glomerular filtration rate < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease (MDRD)) or serious liver impairment
3.a history of gastrointestinal disorders, including gastroparesis, pancreatitis and cholelithiasis
4.neurological illness
5.malignancy
6.pregnancy or breast feeding
7.implantable devices
8.substance abuse
9.addiction
10.contra-indication for MRI, such as claustrophobia or pacemaker
11.any psychiatric illness, including eating disorders and depression
12.hypersensitivity to the active substance or to any of the excipients
13.chronic use of glucocorticoids or centrally acting drugs within 2 weeks immediately prior to screening
14.use of cytostatic or immuno-modulatory agents
15.participation in other studies
16.individuals who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
17.individuals who are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted
18.individuals who have previously completed or withdrawn from this study or any other study investigating GLP-1 receptor agonist or dipeptidyl peptidase (DPP)-4 within 6 months
19.individuals, who in the opinion of the investigator, are unsuitable in any other way to participate in this study
20.individuals who are employed by Amylin Pharmaceutical Inc. or Eli Lilly & company (that is, employees, temporary contract workers, or designees responsible for conducting the study). Immediate family of Amylin or Lilly employees may participate in sponsored clinical trials, but are not permitted to participate at an Amylin or Lilly facility. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted
21.poor commandment of the Dutch language or any (mental) disorder that precludes full understanding the purpose, instruction and hence participation in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023635-42-NL |
| CCMO | NL34552.029.11 |