Effect of GLP1 Receptor Agonist on Brain Insulin Responsiveness

Impact of the Incretin System on Brain Insulin Sensitivity in Humans with Normal Weight, Overweight and Obesity

The overarching goal of the current study is to investigate the effect of GLP-1 on brain insulin responsiveness in a randomized, single-blinded, within subject cross-over study design. To this end, investigators will compare the effect of the administration of semaglutide versus placebo, followed by an fMRI with administration of intranasal insulin or placebo.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Overweight and Obesity; Insulin Sensitivity; Normal Weight
• Intervention / Treatment: Other: Subcutaneous GLP1-RA; Other: Subcutaneous placebo

Detailed Description

Investigate the effect of the GLP1 receptor agonist (i.e. 0.25 mg semaglutide) vs. placebo on the brain using functional magnetic resonance imaging (fMRI) in combination with 160IU intranasal insulin vs. placebo administration in healthy male and female participants of normal-weight and overweight/obesity. Participants will furthermore undergo tasks that assess cognitive functions and eating behavior. Brain insulin responsiveness (primary outcome) is defined as the cerebral response to intranasal insulin compared to placebo by means of cerebral blood flow and resting-state BOLD measurements. Secondary outcomes include diffusion weighted imaging, neural food cue reactivity, cognitive functions and metabolic predictors.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stephanie Kullmann, PhD; Phone Number: 87703 0049707129; Email: stephanie.kullmann@med.uni-tuebingen.de

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • Recruiting
    • University Clinic Tubingen, Department of Internal Medicine IV
    • Contact: Stephanie Kullmann, PhD; Phone Number: 87703 0049707129; Email: stephanie.kullmann@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• BMI between 18.5 and 24.9 kg/m2; and between 27.5 kg/m2 and 40 kg/m2
• Written consent to participate in the study
• Written consent to be informed about incidental findings

Exclusion Criteria:

• Type 1 or type 2 diabetes, LADA, MODY, or cardiovascular diseases such as chronic heart failure, myocardial infarction, status post stroke
• BMI < 18.5 or > 40 kg/m2
• Persons who cannot legally give consent
• Pregnancy or lactation
• History of severe mental or somatic disorders including neurological diseases (incl. epileptic seizures)
• Taking psychotropic drugs
• Chronic diseases or medication that influence glucose metabolism
• Regular use of analgesic drugs
• Previous bariatric surgery
• Known allergy against one or more of the used agents
• Acute infection and/or antibiotic treatment within the last 4 weeks
• Hemoglobin values less than 10.5 g/dl for women, less than 11.5 g/dl for men
• Other diseases that in the opinion of the investigator may jeopardize the success of the study or indicate a risk to the volunteer
• Participation in a lifestyle intervention study or a pharmaceutical study within the last 30 days
• Metal implants which cannot be removed as pacemakers, artificial heart valve, electrical devices as insulin pumps, large tattoos, retainer over more than 4 teeth, contraceptive coil, implanted magnetic metal parts as screws or plates after a surgery
• Persons with claustrophobia
• Persons with tinnitus
• Weight loss or gain of >5% in the last 3 months
• Pancreatic diseases
• History or family history of multiple endocrine neoplasia (MEN2) or medullary thyroid cancer
• History of malignant thyroid disease
• History of malignant disease in the past 5 years
• Surgery in the last three months
• Chronic tobacco use of more than 10 cigarettes/day
• Women who do not consent to refrain from breastfeeding until 2 months after the end of the study
• Women of childbearing age who do not consent to use safe method of contraception from 28 days before until 2 months after the end of the study or refrain from heterosexual intercourse during this time
• Women of childbearing age who do not consent to take a pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GLP-1; Acute administration of 0.25 mg semaglutide (0.19 ml)	Other: Subcutaneous GLP1-RA; Subcutaneous administration of semaglutide
Placebo Comparator: Placebo; Acute administration of 0.19 ml NaCl	Other: Subcutaneous placebo; Subcutaneous administration of NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral response after insulin compared to placebo nasal spray	Resting-state cerebral blood flow and BOLD-fMRI response from before to 30 min after nasal spray administration	24 hours after semaglutide or placebo administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neural food-cue reactivity after insulin compared to placebo nasal spray	BOLD-fMRI response to food cues 30 min after nasal spray administration	24 hours after semaglutide or placebo administration
Diffusion-weighted imaging (DWI)	Diffusion weighted parameter based on MRI measurements	24 hours after semaglutide or placebo administration
Heart rate variability (HRV)	HRV based on ECG measurements	24 hours after semaglutide or placebo administration
Change in subjective feeling of hunger and food craving	On a visual analogue scale, subjective feeling of hunger and food craving will be assessed using questionnaires.	24 hours after semaglutide or placebo administration
Change in mood	Using a questionnaire, positive and negative affect state will be assessed.	24 hours after semaglutide or placebo administration
Performance during cognitive tests	Cambridge Cognition Tests Battery	24 hours after semaglutide or placebo administration

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Investigators: Study Director: Andreas L. Birkenfeld, MD, Institute for Diabetes research and Metabolic Diseases at the University of Tubingen

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: June 27, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): July 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: functional magnetic resonance imaging; GLP-1; Semaglutide; Brain
• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Immune System Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Overweight; Obesity; Hypersensitivity; Insulin Resistance
• Other Study ID Numbers: 065/2024BO1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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