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

Condition(s) targeted: Obesity; Type 2 Diabetes

Intervention: Liraglutide treatment 12 weeks (Drug); insulin glargine treatment (Drug); GLP-1 receptor antagonist (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: VU University Medical Center

Overall contact:
Jennifer S ten Kulve, MD, Phone: +31 20 4442974, Email: js.tenkulve@vumc.nl

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.

Official title: 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

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label

Primary outcome: food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%)

Secondary outcome:

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in self-reported hunger, satiety, fullness

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in basal metabolic rate and post-prandial energy expenditure

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in microvascular function and vasomotion

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in cardiovascular autonomic nervous balance

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in concomitant changes in metabolic and humoral markers

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

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

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in resting state brain activity networks.

GLP-1 analog treatment related changes in obese patients with type 2 diabetes in brain arterial blood flow.

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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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

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

- 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

Jennifer S ten Kulve, MD, Phone: +31 20 4442974, Email: js.tenkulve@vumc.nl

VU University Medical Center, Amsterdam 1081 HV, Netherlands; Recruiting
Jennifer S ten Kulve, MD, Phone: +31 20 4442974, Email: js.tenkulve@vumc.nl

Starting date: October 2011
Last updated: May 9, 2012