The Effect of GLP-1 Receptor Activation on Central Reward and Satiety in Obesity and Diabetes (Braini-Ex)

This study has been completed.
Sponsor:
Collaborators:
Eli Lilly and Company
Bristol-Myers Squibb
Information provided by (Responsible Party):
M. Diamant, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01281228
First received: January 20, 2011
Last updated: October 14, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention
Diabetes Mellitus
Diabetes Mellitus, Type 2
Obesity
Drug: exenatide
Drug: exenatide + exendin (9-39)
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Official Title: The Effect of GLP-1 Receptor Activation on Central Reward and Satiety Circuits in Response to Food Stimuli in Obesity and Diabetes

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • Differences in neuronal activity in CNS reward and satiety circuits [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
    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 Measures:
  • Feeding behavior [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
    Self-reported hunger, satiety, fullness and prospective food consumption, will be rated on 100 mm visual analogue scales before and after the meal.


Enrollment: 48
Study Start Date: September 2011
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: exenatide
Infusion of exenatide; loading dose 50 ng/min during 30 min, followed by a maintenance dose 20ng/min for the rest of the tests.
Drug: exenatide
The loading dose is 50 ng/min during 30 min, followed by a maintenance dose 20 ng/min for the rest of the tests.
Other Name: Byetta
Experimental: exenatide + exendin (9-39)
exenatide infusion: loading dose 50 ng/min during 30 min, followed by a maintenance dose 20 ng/min for the rest of the test. And infusion of exendin(9-39) 600pM/kg/min.
Drug: exenatide + 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.
Placebo Comparator: saline
saline infusion, with the same infusion speed
Drug: placebo
saline infusion

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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, 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01281228

Locations
Netherlands
VU University Medical Center
Amsterdam, De Boelelaan 1117, Netherlands, 1007MB
Sponsors and Collaborators
VU University Medical Center
Eli Lilly and Company
Bristol-Myers Squibb
Investigators
Principal Investigator: Michaela Diamant, MD PhD VU University Medical Center, Diabetes Center
  More Information

No publications provided

Responsible Party: M. Diamant, Professor, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01281228     History of Changes
Other Study ID Numbers: DC2010Exbrain001, 2010-023635-42
Study First Received: January 20, 2011
Last Updated: October 14, 2013
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
Exenatide
Type 2 diabetes mellitus
Incretin hormones
GLP-1 agonist
Satiety
Reward

Additional relevant MeSH terms:
Diabetes Mellitus
Obesity
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Exenatide
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on October 01, 2014