Characterization of Metabolic and Brain Effects of Rising Glucagon During an Oral Glucose Challenge

Study Overview
=================
Brief Summary
-----------------
The investigators previously characterized a phenotype with non-suppressed glucagon at 120 minutes after standardized oral glucose load. This phenotype is associated with healthy metabolic traits such as lower BMI, higher insulin sensitivity and lower liver fat content. Glucagon is a pleiotropic hormone that, besides its main action on increasing endogenous glucose production, also reduces appetite and increases basal energy expenditure. The aims of this study are to i. detect functional differences in the appetite-related central nervous system (CNS) areas between the suppressed and non-suppressed glucagon phenotype ii. mimick the non-suppressed glucagon phenotype in those participants who suppress glucagon by administering a very-low-dose glucagon infusion and retest them.

Official Title
-----------------
Metabolic and Central Nervous System Characterisation of the Phenotype of Non-suppressed (Rising) Glucagon After Glucose Challenge

Conditions
-----------------
Metabolic Syndrome, Diabetes

Intervention / Treatment
-----------------
* Drug: Intravenous glucagon
* Drug: Intravenous saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: BMI 18.5- 29.9 kg/m2 written informed consent Exclusion Criteria: Current febrile infection with temperatures> 38.5 ° C in the last 14 days Blood donation within the last 12 weeks Pre-study Inclusion Chronic diseases: Diabetes mellitus Known liver diseases (hepatitisB/C, hemochromatosis, NASH) Chronic inflammatory diseases (rheumatoid arthritis, Crohn's disease, ulcerative colitis) chronic renal insufficiency Cancer (known malignant disease) psychiatric diagnoses (bipolar disorder, schizophrenia, psychoses, depression, agoraphobia) Persons with non-removable metal parts, e.g: pacemaker artificial heart valves metal prostheses implanted magnetic metal parts (screws, plates of operations) spiral metal slivers / garnet splinters fixed braces Acupuncture needle Insulin pump totally implantable venous access device (port) tattoos, metallic eye shadows Persons with impaired sensitivity and / or increased sensitivity to heating of the body Medical history of venous thromboembolism alcohol consumption of more than 50g / day In physical examination: blood pressure > 160/100 mmHg pathologic cardiac murmurs (diastolic or systolic louder than 2/6) in the blood test: fasting glucose ≥ 125 mg/dl or HbA1c ≥ 6.5% AST or ALT> 2.5x upper limit of the reference range (> 125 U/l) Hb <12 g/dl C reactive protein (CRP) > 5 mg / dL or leukocytes> 15000/μl

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous glucagon<br>Low-dose glucagon infusion (0.5 pmol/min/kg body weight) over 150 minutes during a standardized 75 g oral glucose tolerance test | Drug: Intravenous glucagon<br>* Randomized application of glucagon or saline during oral glucose tolerance test<br>|
| Placebo Comparator: Intravenous saline<br>Saline infusion over 150 minutes during a standardized 75 g oral glucose tolerance test | Drug: Intravenous saline<br>* Randomized application of glucagon or saline during oral glucose tolerance test<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain activity | Resting-state brain activity assessed by fMRI | change from baseline to 120 minutes after oral glucose challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hunger rating | On visual analogue scale | before and 150 minutes after oral glucose challenge and start of glucagon/saline infusion | 
| Brain response to food cues | Assessed by functional magnetic resonance imaging (fMRI) | before, 30 minutes and 120 minutes after oral glucose challenge and start of glucagon/saline infusion | 
| Glucose tolerance | Assessed by 75 g oral glucose tolerance test | 0-120 minutes | 
| Insulin sensitivity | Assessed during 75 g oral glucose tolerance test | 0-120 minutes | 
| Basal energy expenditure | Assessed by indirect calorimetry | 150 minutes after oral glucose challenge | 
| Change in hormone levels | Change in adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), fibroblast growth factor 21(FGF-21) after oral glucose challenge and start of glucagon/saline infusion. | 0-150 minutes |