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.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Obesity; Degenerative Brain Disorder
• Intervention / Treatment: Procedure: RYGB; Drug: GLP-1

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Pisa, Italy
    • Dept.Clinical and Experimental Medicine.Section of Diabetes.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 (>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 > 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Roux-en- Y gastric bypass (RYGB); Roux-en- Y gastric bypass (RYGB) is the most popular bariatric procedure and it has been associated with improvements in glycemic control and cognitive function. It works by decreasing the amount of food you can eat at one sitting and by changing the hormones released at the bottom of the stomach and duodenum.we propose that RYGB is a model of chronic elevation of GLP-1 providing an opportunity to explore relationship between changes in the circulating hormone and brain glucose metabolism, cognitive function and neuroplasticity.	Procedure: RYGB; RYGB is associated with a increase of circulating GLP-1 (up to ten-fold) especially in response to meal ingestion. This increased availability of GLP1 has been claimed to contribute to restoration of some of the beta-cell function.
Active Comparator: GLP-1; GLP-1 is an intestinal hormone secreted in response to nutrients.	Drug: GLP-1; GLP-1 is an hormone secreted by gut in response to nutrients ingestion.; Other Names: gut hormone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sustained Weight Loss	normalizing obesity-related comorbidities.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
glycemic Control	GLP-1 level controled	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
cognitive Function	cognitive function measured by Mini Mental State Examination (MMSE).	6 months

Collaborators and Investigators

• Sponsor: University of Pisa

Publications and helpful links

General Publications

• Dardano A, Aghakhanyan G, Moretto C, Ciccarone A, Bellini R, Sancho Bornez V, Ceccarini G, Santini F, Volterrani D, Del Prato S, Daniele G. Brain effect of bariatric surgery in people with obesity. Int J Obes (Lond). 2022 Sep;46(9):1671-1677. doi: 10.1038/s41366-022-01162-8. Epub 2022 Jun 21.

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2016
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: January 15, 2018
• First Submitted That Met QC Criteria: January 22, 2018
• First Posted (Actual): January 29, 2018

Study Record Updates

• Last Update Posted (Actual): July 19, 2018
• Last Update Submitted That Met QC Criteria: July 18, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: obesity; cognitive dysfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Brain Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: PRA 2016

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No