Effects of Glucagon Like Peptide-1(GLP-1) and Liraglutide on Brain Satiety and Reward Circuits and Feeding Behavior in Diabetes (LIBRA)

Central Effects of Endogenous Glucagon Like Peptide-1 (GLP-1) and the GLP-1 Analog Liraglutide on Brain Satiety and Reward Circuits and Feeding Behavior in Diabetes

The aim of this study is to investigate if endogenous Glucagon Like Peptide -1 (GLP-1) has an effect on brain satiety and reward systems and if there are alterations in obese patients with type 2 diabetes (T2DM). Secondly, the aim is to investigate whether treatment with a GLP-1 analog, liraglutide, restores these signals in obese patients with type 2 diabetes. Finally, also the endogenous GLP-1 effects will be investigated in obese individuals before and after gastric bypass surgery on brain satiety and reward systems.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: Drug: Liraglutide treatment 12 weeks; Drug: insulin glargine treatment; Drug: GLP-1 receptor antagonist

Detailed Description

First aim will be addressed in a cross-sectional randomized study. 20 healthy, lean and 20 obese individuals with type 2 diabetes (T2DM) will be exposed to food cues and with concomitant infusion of glucagon Like peptide-1 (GLP-1) receptor antagonist or saline, to assess the involvement of endogenous GLP-1, secreted in response to a meal. Measurements activation of CNS circuits involved in satiety and reward will be performed using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI).

The second aim will be addressed in cross-over randomized-controlled trial (RCT) in the T2DM patients only. Patients will be randomly assigned liraglutide vs insulin glargine treatment, during a treatment period of 12 weeks each with a 12-week washout period in between. The investigators will perform the same fMRI protocol.

The third aim will be addressed in a study with obese individuals who are scheduled for a gastric bypass surgery. The same protocol as for the first aim will be performed and this will be before and after the surgery in the same individuals.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• For the healthy, lean individuals:
• Age 18-65 years
• Women: post menopausal (excluding possible menstruation cycle effects)
• Body-mass index (BMI) of <25 kg/m2,
• Stable bodyweight (<5% reported change during the previous 3 months).
• Normal fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) (34)
• Right handed

For the obese T2DM individuals:

• Age 18-65 years
• Women: post menopausal (excluding possible menstruation cycle effects)
• BMI 25-40 kg/m2
• Stable bodyweight (<5% reported change during the previous 3 months).
• Diagnosed with T2DM > 3 months prior to screening
• HbA1C 6.5-8.5%
• Treatment with metformin at a stable dose for at least 3 months.
• Right handed

For the obese individuals scheduled for gastric bypass surgery:

• Age 18-65 years
• Women: preferably post menopausal (excluding possible menstruation cycle effects)
• Body-mass index (BMI) of >30 kg/m2,
• Stable bodyweight (<5% reported change during the previous 1 months).
• Normal or impaired fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) (defined as glucose fasting < 7.1 mmol/l and after OGTT t=120min < 11.0 mmol/l) (39)
• Right handed

Exclusion Criteria:

• GLP-1 based therapies, thiazolidinediones, sulphonylurea or insulin within 3 months before screening
• Weight-lowering agents within 3 months before screening.
• Congestive heart failure (NYHA II-IV)
• Chronic renal failure (glomerular filtration rate < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease (MDRD))
• Liver disease
• History of gastrointestinal disorders (including gastropareses, pancreatitis and cholelithiasis)
• Neurological illness
• Malignancy
• Other type of bariatric surgery (Redo-GBP, sleeve, distal GBP, adj banding, Scopinaro)
• History of major heart disease
• History of major renal disease
• Pregnancy or breast feeding
• Implantable devices
• Substance abuse
• Addiction
• Contra-indication for MRI, such as claustrophobia or pacemaker
• Any psychiatric illness; including eating disorders and depression
• Chronic use of centrally acting agents or glucocorticoids within 2 weeks immediately prior to screening.
• Use of cytostatic or immune modulatory agents
• History or known allergy for acetaminophen.
• History of allergy for insulin analog
• History of allergy for liraglutide
• Participation in other studies
• 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
• Individuals who are investigator site personnel, directly affiliated with the study, or are immediate family

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liraglutide; 12 week treatment with liraglutide in fixed dosage	Drug: Liraglutide treatment 12 weeks; liraglutide will be started with a titration period of 2 weeks: week 1 0.6mg once daily, week 2 1.2mg once daily. If well tolerated, treatment will be continued for 10 more weeks in dosage of 1.8mg once daily
Active Comparator: Insulin glargine; 12 week treatment, once daily, with insulin glargine. Dosage based on fasting blood glucose measurements	Drug: insulin glargine treatment; Insulin glargine treatment consist a treatment period of 12 weeks. Treatment will start with a dosage of 10 IU once daily. Patient will self-titrate the insulin glargine dosage based on self-monitored fasting blood glucose (FBG) concentrations for the previous 3 days using the following guideline: If FBG levels are above 5.6 mmol/L (100-153 mg/dL) on 3 consecutive mornings, the daily dose is to be increased by 2 IU/day. If hypoglycemia documented by glucose concentration < 3.3 mmol/L (60 mg/dL) or requiring assistance occurs without an easily identifiable reason (skipped meal, excessive physical activity), the daily dose is to be downregulated, with -2 IU/day
Other: before start of treatment period; before start of the treatment period, one day with tests will be performed. During this test a GLP-1 receptor antagonist will be administered In the group with obesity and planned gastric bypass surgery, the GLP-1 receptor agonist will be administered during 1 test before and 1 test after the surgery	Drug: GLP-1 receptor antagonist; Exendin 9-39 will be infused intravenously at doses of 600 pM/kg • min. This will only be during one of the visit for the healthy lean controls and the T2DM group, and during two visits in the group with obesity planned for gastric bypass surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%)	differences between obese T2DM patients and healthy lean subjects food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%); the involvement of endogenous GLP-1 food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%); Effects of treatment with the GLP-1 analog liraglutide in obese patients with type 2 diabetes in food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%); - To investigate the involvement of the increased meal-related endogenous GLP-1 levels after gastric bypass surgery in these food-stimuli related CNS satiety and reward responses and to investigate whether pharmacological blocking of endogenous GLP-1 receptor activation, using a GLP-1 antagonist, differentially affects these responses before and after gastric bypass surgery in obese individuals.	approximately 3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in self-reported hunger, satiety, fullness	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in basal metabolic rate and post-prandial energy expenditure	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in microvascular function and vasomotion	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in cardiovascular autonomic nervous balance	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in concomitant changes in metabolic and humoral markers	approximately 3 years
Alterations in resting state brain activity networks in obese patients with type 2 diabetes compared to lean, healthy individuals and the involvement of endogenous GLP-1	approximately 3 years
Alterations in brain arterial blood flow in obese patients with type 2 diabetes compared to lean, healthy individuals and the involvement of endogenous GLP-1	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in resting state brain activity networks.	approximately 3 years
GLP-1 analog treatment related changes in obese patients with type 2 diabetes in brain arterial blood flow.	approximately 3 years

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Ten Kulve JS, Veltman DJ, Gerdes VEA, van Bloemendaal L, Barkhof F, Deacon CF, Holst JJ, Drent ML, Diamant M, IJzerman RG. Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues. Diabetes Care. 2017 Nov;40(11):1522-1529. doi: 10.2337/dc16-2113.
• ten Kulve JS, Veltman DJ, van Bloemendaal L, Barkhof F, Deacon CF, Holst JJ, Konrad RJ, Sloan JH, Drent ML, Diamant M, IJzerman RG. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia. 2015 Dec;58(12):2688-98. doi: 10.1007/s00125-015-3754-x. Epub 2015 Sep 18.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: May 26, 2011
• First Submitted That Met QC Criteria: May 31, 2011
• First Posted (Estimate): June 1, 2011

Study Record Updates

• Last Update Posted (Estimate): February 18, 2015
• Last Update Submitted That Met QC Criteria: February 17, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide; Insulin Glargine
• Other Study ID Numbers: DC2011LiBrain001