Amino Acid Change, Glucagon Resistance, Healthy
Conditions
Keywords
interleukin-6, gluagon, pancreatic clamp
Brief summary
The goal of this proof-of-concept study is to learn if interleukin-6 changes the effect of glucagon in healthy volunteers. The main question it aims to answer is: Does IL-6 influence how effectively glucagon lowers the concentration of amino acids in blood? Researchers will compare the infusion of normal saline and a blocker of the receptor for interleukin-6 to see if blocking interluekin-6 changes how effectively glucagon lowers the concentration of amino acids in blood. Participants will be asked to * receive either an infusion of normal saline or the interleukin-6 receptor blocker * participate in a study visit three weeks later at which they will receive infusions of hormones and amino acids to mimic the concentrations of the hormones insulin and glucagon during fasting or fed conditions * labelled glucose, glycerol and amino acids will also be infused continuously to track the fate of these molecules * during the hormone infusions blood samples will be taken repeatedly
Interventions
DRUGTocilizumab
Blockade of the interleukin-6 receptor
OTHERPlacebo
Infusion of 100 ml normal saline
Sponsors
University Hospital, Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind
Intervention model description
Randomized, double-blind, parallel
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18 to 50 years * BMI 18.5 - 25 kg/m2 * Stable body weight in the past 6 months before study initiation * Women should be anovulatory on non-cyclic hormone replacement or hormonal contraception
Exclusion criteria
* Previous medical history for any chronic condition in the last three months, active disease or abnormal physical examination as verified by a qualified physician * Body weight unstable in the past 6 months * Use of tobacco/nicotine * Alcohol consumption \>30g/day * Participation in an investigational drug trial within the past two months * Current intake of any drugs (prescribed, over the counter or recreational) * Known allergy to tocilizumab * Pregnant or lactating women, * Inability or unwillingness to provide informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in maximum glucagon-induced reduction in total plasma amino acid concentrations | At visit 2 during high glucagon phase (80-120 minutes) |
Secondary
| Measure | Time frame |
|---|---|
| AUC of total amino acids | At visit 2 during high glucagon phase (80-120 minutes) |
| rate of phenylalanine oxidation | At visit 2 (15, 30, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300 minutes) |
| urea concentrations | At visit 2 (15, 30, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300 minutes) |
| rate of gluconeogenesis from amino acids | At visit 2 (15, 30, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300 minutes) |
| fractional synthesis rate of plasma proteins | At visit 2 (60, 180, 300 minutes) |
| Amino acid uptake by PBMCs ex vivo | At visit 1 and visit 2 (-120 minutes) |
| Change in fractional synthesis rate of lipoproteins | At visit 2 (60, 180, 300 minutes) |
| Cytokine plasma concentrations (IL-6, IL-1RA, TNF-alpha, IL-8, IL-10, CRP) | At visit 2 (15, 30, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300 minutes) |
| Plasma concentrations of insulin, c-peptide, glucagon, GH, IGF-1, cortisol, catecholamines, fT4, fT3, FGF21, follistatin, AGPTL4, ketones | At visit 2 (15, 30, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300 minutes) |
| Blood pressure diastolic | At visit 2 (-120 minutes) |
| Heart rate | At visit 2 (-120minutes) |
| Energy expenditure kcal/24 hours | At visit 2 (40, 160, 280 minutes) |
| Respiratory exchange rate | At visit 2 (40, 160, 280 minutes) |
| Oxygen consumption (VO2 ml/minutes) | At visit 2 (40, 160, 280 minutes) |
| Carbondioxid production (VCO2 ml/minutes) | At visit 2 (40, 160, 280 minutes) |
| Body composition (lean body mass kg) | At visit 1 and 2 (-120 minutes) |
| Body composition (fat bodymass kg) | At visit 1 and 2 (-120 minutes) |
| Blood pressure systolic | At visit 2 (-120 minutes) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in protein profiles | At visit 2 (60, 180, 300 minutes) | Using untargeted and targeted proteomic platforms, the changes in protein profiles in the plasma will be measured |
| Changes in metabolite profiles | At visit 2 (60, 180, 300 minutes) | Using untargeted and targeted metabolomic platforms, the changes in metabolite profiles in the plasma serum will be measured |
Countries
Switzerland
Outcome results
None listed