Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients (LEPTOB)

Study of the Communication of the Hypothalamus With the Periphery: Impact of Metformin on Leptin Transport in the Cerebrospinal Fluid of Obese Patients. A Monocentric Prospective Study

Obesity, a major health problem, is gradually transforming into a global epidemic. The current obesity treatment with long term efficacy is the bariatric surgery, however, the operative risk of this procedure is high and the post-operative iotrogeny may be important. Obesity is most often associated to the feeding behavior which depends on hypothalamic integration of peripheral signals such as leptin and glucose. High levels of circulating leptin are detected in obese patients. These elevated leptin levels fail to reduce appetite or increase energy expenditure. The mechanism underlying this non-integration of peripheral signals remains to be identified. The ratio of leptin levels in the cereprospinal fluid (CSF) and in the periphery is drastically decreased in obese patients when compared to lean individuals, therefore a defective transport of circulating leptin into the brain via the CSF is maybe linked to obesity.

Study Overview

• Status: Recruiting
• Conditions: Obesity Without Type 2 Diabetes, With BMI>30
• Intervention / Treatment: Drug: Metformin Oral Tablet

Detailed Description

We hypothesize that the alteration of leptin transport into the CSF of obese patients could be modulated by drugs such as metformin which is widely used worldwide to treat diabetes. This study is monocentric, prospective, one-arm type and interventional. The main objective isto evaluate the impact of metformin on the transport of leptin into the CSF of obese patients.

We propose to show a variation of CSF leptin / serum leptin before and after metformin treatment and study its association with changes in hypothalamic metabolic activity, cognitive and appetite-related behaviors and ratio of other metabolic signals. This would support the hypothesis of modulation of resistance to peripheral leptin by metformin and thus uncover a new indication for metformin treatment towards the management of obesity.

For this purpose, volunteers will be subjected to blood sampling via venipuncture, CSF collection via lumbar puncture, MRI assessments and questionnaires (cognitive tests, food survey and feeding behavior) before and after a 3-month metformin treatment.

• Study Type: Interventional
• Enrollment (Estimated): 31
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Amélie Lansiaux, MD, PhD; Phone Number: 0033320225741; Email: lansiaux.amelie@ghcl.net
• Study Contact Backup: Name: Melody Plets, MSc; Phone Number: 0033320225733; Email: plets.melody@ghicl.net

Study Locations

• France
  • Arras, France, 62022
    • Recruiting
    • Centre Hospitalier D'arras
    • Contact: Vincent Florent, MD, MSc, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults between 18 and 40 years old
• Body mass index >30
• For childbearing age women: use of an effective contraceptive method for the duration of the study
• Patients willing to participate in the study and who have signed the informed consent form
• Patients with health insurance

Exclusion Criteria:

• Genetic obesity
• Type 2 diabetes defined by 2 fasting blood glucose >1,26g/L or blood glucose >2 g/L at 120 min of oral glucose tolerance test with 75 g of glucose
• Patients already treated with metformin
• Type 1 diabetes
• Active neoplastic pathology, diagnosed < 5 years, or in treatment
• Neurological pathology (demyelinating, tumor, vascular)
• Adipose tissue pathology (lipodystrophy)
• History of bariatric surgery
• Contraindication to metformin
• Lumbar puncture contraindication
• MRI contraindication
• Person unable to consent, or benefiting from a legal protection regime (guardianship/curatorship/guardianship of justice)
• Pregnant or breastfeeding woman
• Contra-indication to impedance measurement
• Contraindication to indirect calorimetry: claustrophobia
• Taking a psychotropic drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Obese patients; Patients with body mass index >30	Drug: Metformin Oral Tablet; Day 1 to day 3: 500 mg/day Day 4 to day 6: 500 mg/twice a day Day 7 to day 9: 500 mg three times a day Day 10 until next lumbar puncture : 850 mg three times a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
cerebrospinal fluid /plasma leptin ratio	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cerebrospinal fluid /plasma glucose ratio		at day 0, 3 months
cerebrospinal fluid /plasma glucagon like peptide 1 (GLP1) ratio		at day 0, 3 months
cerebrospinal fluid /plasma insulin ratio		3 months
cerebrospinal fluid /plasma ghrelin ratio		at day 0, 3 months
Cerebrospinal fluid levels of Agouti-Related Peptide (AgRP)		at day 0, 3 months
Plasma levels of Agouti-Related Peptide (AgRP)		at day 0, 3 months
Cerebrospinal fluid levels of proopiomelanocortin (POMC)		at day 0, 3 months
Plasma levels of proopiomelanocortin (POMC)		at day 0, 3 months
Cerebrospinal fluid levels of neuropeptide Y (NPY)		at day 0, 3 months
Plasma levels of neuropeptide Y (NPY)		at day 0, 3 months
Cerebrospinal fluid levels of leptin soluble receptor		at day 0, 3 months
Plasma levels of leptin soluble receptor		at day 0, 3 months
Apparent diffusion coefficient (ADC)	Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue, and is commonly clinically calculated using Magnetic resonance imaging (MRI). An ADC of a tissue is expressed in units of mm2/s	at day 0, 3 months
Hypothalamic concentration of N-acetyl-aspartate (NAA)	This concentration will be measure by spectroscopy	at day 0, 3 months
Hypothalamic concentration of creatine	This concentration will be measure by spectroscopy	at day 0, 3 months
Hypothalamic concentration of Choline	This concentration will be measure by spectroscopy	3 months
Hypothalamic concentration of Glutamine / glutamate	This concentration will be measure by spectroscopy	at day 0, 3 months
Hypothalamic concentration of gamma-aminobutyric acid (GABA)	This concentration will be measure by spectroscopy	at day 0, 3 months
Weight		at day 0, 3 months
Abdominal circumference		3 months
Percentage of body fat	This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body.	at day 0, 3 months
Fat free mass (Kg)	This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body.	at day 0, 3 months
Energy expenditure	This parameter will measure by indirect calorimetry (kCal / 24h)	at day 0, 3 months
Score of the Three Factor Eating Questionnaire (TFEQ)	The TFEQ contains 51 items and measures three dimensions of eating behavior: cognitive restraint of eating' (Factor I - 21 items); disinhibition (Factor II - 16 items); hunger (Factor III - 14 items) Each item scores either 0 or 1 point. The minimum score for factors I-II-III is therefore 0-0-0, the possible maximum score 21-16-14	3 months
Score of the Dutch Eating Behaviour Questionnaire (DEBQ)	This is a 33-item self-report questionnaire to assess three distinct eating behaviors in adults: (1) emotional eating, (2) external eating, and (3) restrained eating. Items on the DEBQ range from 1 (never) to 5 (very often), with higher scores indicating greater endorsement of the eating behavior.	at day 0, 3 months

Collaborators and Investigators

• Sponsor: Lille Catholic University
• Collaborators: Centre Hospitalier Arras
• Investigators: Study Director: Vincent Prévot, PhD, Institut National de la Santé Et de la Recherche Médicale, France; Principal Investigator: Vincent Florent, MD, MSc, PhD, Centre Hospitalier d'Arras, INSERM

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2020
• Primary Completion (Estimated): June 15, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: May 28, 2019
• First Submitted That Met QC Criteria: June 3, 2019
• First Posted (Actual): June 4, 2019

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: leptin; metformin; cerebrospinal fluid
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: RC-P0054

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No