To Determine the Effect of GLP1 on Cognitive Function, Brain Glucose Metabolism and Neuroplasticity.

The Effect of Glucagon-like Peptide-1 (GLP-1) on Cognitive and Non-cognitive Function in Human

To test the hypothesis that GLP1 can exert favourable effects on multiple aspects of brain function. To this purpose, the investigator determine whether chronic increase in GLP1 concentration as it occurs after bariatric surgery (Roux-en- Y Gastric Bypass) is associated with improvement in:

• cognitive function measured by Mini Mental State Examination (MMSE) and Mental Deterioration Battery(MDB).
• brain glucose metabolism measured by FDG-CT/PET
• neuroplasticity measure by binocular rivalry and saccadic adaptation tests in morbid obese subjects. In order to discern the effect of GLP1 irrespective of changes in the metabolic milieu the investigator will test whether short-term GLP-1 infusion can modulate the same parameters in healthy subjects.

The research project will include two separate studies:

1. In obese subjects undergoing RYGB to test the effect of chronic elevation of GLP1 levels, and
2. In normal volunteers to test the acute effect of GLP1, irrespective of changes in the metabolic milieu In several aspects of brain function as detailed below:.

Morbid Obese Subjects Group:

This study will consist in a single arm, non randomized, uncontrolled, single center before-and after RYGB in 15 morbid obese subjects.

Healthy Subjects Group:

This study will consist in a single arm, non randomized, uncontrolled, single center study in 8 healthy subjects.

The primary endpoint are the changes in:

• cognitive function measured by Mini Mental State Examination (MMSE) and Mental Deterioration Battery (MDB)
• brain glucose metabolism measured by FDG-CT/PET
• neuroplasticity measure by binocular rivalry and saccadic adaptation tests six months after RYGB in morbid obese subjects and with elevation of circulating GLP1 levels in healthy subjects.

Morbid obese subjects participating in this study will be evaluated before and 6 months after bariatric surgery which is routinely performed to treat morbid obesity. For the purpose of baseline assessment subjects will undergo 3 visits at 1 week interval. All test procedures will be repeated in two subsequent visits 6 months after surgery with body weight being stable. Therefore, participation in the study will require a total of 5 visit with a post-trial phone contact 2 weeks after completion for safety assessment.

Healthy subjects will be recruited for determining the acute effect of GLP1 on brain function irrespective of changes in the metabolic milieu. The study will require participation in a total of 3 visits.

Inclusion Criteria:(Morbid Obese Subjects Group)

1. Males and females undergoing bariatric surgery as per clinical management
2. Age = 18-60 years
3. BMI>35 Kg/m 2 and stable weight (± 3 lbs) over the preceding three months
4. Normal Glucose Tolerance (HbA1c > 4.5 % and < 5.7%) or Type 2 diabetes (HbA1c >5.7 % and <10.0%)
5. Stable eGFR (>60 ml/min/1.73 m2 )
6. Drug naive for type 2 diabetes treatment or on stable dose more than 3 months with anti-diabetic agents other than DPP4-inhibitors, GLP1 receptor agonists, and insulin.
7. Subjects are capable of giving informed consent

Inclusion Criteria (Healthy Subjects Group)

1. Males and females
2. Age = 18-60 years
3. BMI 22-35 Kg/m 2 and stable weight (± 3 lbs) over the preceding three months
4. Stable eGFR (&gt;60 ml/min/1.73 m 2 )
5. Normal Glucose Tolerance (HbA1c>4.5 % and< 5.7%)
6. Subjects are capable of giving informed consent.

Exclusion Criteria:(both groups)

1. Steroids treatment
2. Psychiatric Disorders
3. Mental Retardation
4. Severe cognitive Impairment
5. Neurodegenerative diseases
6. Epilepsy
7. Depression Treatment
8. Traumatic Brain Injury over the preceding six months
9. Liver function enzymes higher more than two times the upper limit
10. Heart Failure (NYHA III-IV)
11. Type 1 Diabetes
12. Diabetic Ketoacidosis
13. GFR<60 ml/min/1.73 m 2
14. Donation of blood to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of &gt; 400 mL of blood during the 8 weeks prior to the enrollment visit and at least 8 weeks thereafter
15. Women who are pregnant or breastfeeding
16. Patient with a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose an unacceptable risk to the patient or interfere with trial procedures.