Role of Adrenaline in in the Inflammatory Response in Diabetes

Study Overview
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Brief Summary
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The primary aim of the present study is to study the effect of adrenaline administration on inflammatory parameters (e.g. leukocyte phenotype, cytokines, inflammatory proteins). Secondary objectives consist of the effect of adrenaline on atherogenic parameters. All participants will receive intravenous infusion of adrenaline for an hour We will draw blood at 7 time points, not including screening Participants will be asked to return for a total of 4 times Researchers will compare 2 groups, healthy individuals versus people with diabetes type 1 to see if the inflammatory reaction to adrenaline differs between these two groups.

Detailed Description
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Objective: The primary aim of the present study is to study the effect of adrenaline administration on inflammatory parameters (e.g. leukocyte phenotype, cytokines, inflammatory proteins). Secondary objectives consist of the effect of adrenaline on atherogenic parameters. Potentially eligible adult ( 16 - 75 years) participants will be recruited from the diabetes clinic at the department of internal medicine from the Radboud University Medical Center. Healthy participants will be recruited through social media and other advertisements. Researchers will recruit a total of 30 individuals, i.e. 15 healthy participants and 15 people with type 1 diabetes. Participants with type 1 diabetes will be equipped with a blinded continuous glucose monitoring device (CGM) during the test, which will measure interstitial glucose levels for a total of 10 days. Intervention: All participants will receive intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. We will draw blood at baseline, 30 minutes, 60 minutes, 180 minutes, 24 hours 72 hours and a week after start of infusion. The blood samples will be used for phenotyping of the innate immune system and measuring inflammatory and atherogenic parameters. Throughout the infusion, vital parameters will be monitored.

Official Title
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Role of Adrenaline in the Inflammatory Response in People With Diabetes Mellitus Type 1, and Healthy Individuals

Conditions
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Inflammatory Response, Diabetes type1, Hypoglycemia

Intervention / Treatment
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* Drug: Adrenaline


Participation Criteria
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Eligibility Criteria
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Overall inclusion criteria: Ability to provide written informed consent Body-Mass Index: 19-30kg/m2 Age ≥16 years, ≤ 75 years Blood pressure: <140/90 mmHg Non-smoking Electrocardiogram not showing any serious arrythmia's (PVC's and PAC's accepted) Diabetes group specific criteria: Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump) Duration of diabetes > 1 year HbA1c < 100 mmol/mol, Exclusion Criteria: - Any event of cardiovascular disease in the past 5 years (e.g. myocardial infarction, stroke, heart failure, symptomatic peripheral arterial disease) Pregnancy or breastfeeding or unwillingness to undertake measures for birth control Epilepsy, Current treatment with Alpha or beta blockers ( doxazosin, propranolol) History of panic disorders History of Arrhythmias Use of immune-modifying drugs or antibiotics Use of tricyclic antidepressants or MAO inhibitors Use of statins (e.g. stop statins >2 weeks before performing blood sampling. Any infection with systemic symptoms in past 2 weeks Previous vaccination in the past 2 weeks Proliferative retinopathy Nephropathy with an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2 Overt impaired hypoglycaemic awareness assed by the Clarke Questionnaire 4 or higher

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: All participants will receive intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. We will draw blood at baseline, 30 minutes, 60 minutes, 180 minutes, 24 hours 72 and a week after start of infusion. These samples will be used for phenotyping of the innate immune system and measuring inflammatory and atherogenic parameters. Throughout the infusion vital parameters will be monitored.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: People with type 1 diabetes<br>The participants with type 1 diabetes will receive an intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. | Drug: Adrenaline<br>* Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.<br>* Other names: Adrenaline infusion;|
| Active Comparator: Healthy individuals<br>The participants without type 1 diabetes will receive an intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. | Drug: Adrenaline<br>* Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.<br>* Other names: Adrenaline infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte count | The amount of monocytes following 60 minutes of adrenaline infusion compared to baseline to asses the adrenaline effect on the inflammatory response. | Change from baseline compared to after 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukocyte count | Measurement of the amount of leukocytes | Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion | 
| Leukocyte phenotype | Measuring several phenotypes by using a pre-defined panel of interest with flow-cytometry ( e.g. NK-cells, granulocytes) | Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion | 
| Pro-inflammatory proteins | Pro-inflammatory proteins using Olink Proteomics AB inflammation panel with 92 circulating inflammatory proteins ( e.g. EN-rage, FIT3L) | Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion | 
| Inflammation plasma parameters | Inflammatory plasma protein using ELISA, ( e.g high sensitive-crp) | Change from baseline at 30, 60 and 180 minutes day 1, day 3 and day 7 after adrenaline infusion | 
| Atherogenic parameters | Atherogenic parameters using ELISA method including but not limited to, VCAM-1, ICAM-1, E-Selectin, P-selectin, PAI-1, Plasma Endothelin | Change from baseline at 30, 60 and 180 minutes day 1, day 3 and day 7 after adrenaline infusion | 
| Insulin | Plasma levels of insulin | Change from baseline at, 60 and 180 minutes | 
| Adrenaline | Plasma levels of adrenaline | Change from baseline at 30, 60 and 180 minutes | 
| Noradrenaline | Plasma levels of noradrenaline | Change from baseline at 30, 60 and 180 minutes | 
| Glucose variability | Glucose variability measured by the blinded continuous glucose monitor including but not limited to, measuring time within range, amount of hypoglycaemic events, amount of hyperglycaemic events. | 2 weeks | 
| Ex vivo cytokines | Ex vivo production of pro- and anti-inflammatory cytokines and chemokines after ex vivo stimulation of isolated monocytes, including TNF-α, IL-6, IL-10 and IL-1β. | Change from baseline at 30, 60 and 180 minutes, day 1, day 3 and day 7 after adrenaline infusion | 
| Distribution of monocyte subset | Distribution of pro- and anti-inflammatory monocyte subsets using FACS (Fluorescence-activated Cell Sorting) | Change from baseline at 30, 60 and 180 minutes, day 1, day 3 and day 7 after adrenaline infusion |