Effects of Glucagon Like Peptide-1(GLP-1) and 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.

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.

Eligibility 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

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