Role of Adrenaline in in the Inflammatory Response in Diabetes (RAID)

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

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.

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Inflammatory Response; Diabetes Type1
• Intervention / Treatment: Drug: Adrenaline

Detailed Description

Objective: The aim of the present study is to study the effect of increased adrenaline levels on the inflammatory response (e.g. leukocyte phenotype, cytokines, inflammatory proteins) by administering exogenous adrenaline in participants with type 1 diabetes and healthy participants.

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. We 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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboud UMC

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: People with type 1 diabetes; 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; Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.; Other Names: Adrenaline infusion
Active Comparator: Healthy individuals; 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; Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.; Other Names: Adrenaline infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cees Tack
• Investigators: Principal Investigator: Cees Tack, MD. PHD., Radboud University Medical Center (Radboudumc)

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2023
• Primary Completion (Actual): September 3, 2024
• Study Completion (Actual): September 3, 2024

Study Registration Dates

• First Submitted: August 2, 2023
• First Submitted That Met QC Criteria: August 10, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Estimated): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Hypoglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-Agonists; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Epinephrine; Racepinephrine; Epinephryl borate
• Other Study ID Numbers: 114664

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: WE will share the study protocol using a data respository accesible through the research team on demand. Starting around 6 months after publication.
• IPD Sharing Time Frame: 6 months after publication
• IPD Sharing Access Criteria: The coordinating researcher will review acces requests. Seeing as the data are all anonimised acces will be granted for additional research in the field of inflammation or diabetes.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

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