The Role of the Adrenergic System in Hypoglycaemia Induced Inflammatory Response in People With Type 1 Diabetes and People Without Type 1 Diabetes-RAID-II

NCT06422494 | Active Not Recruiting

• 1 other identifier: 115142
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this trial is to study the effect that adrenaline has on the immune reaction seen during a low blood sugar. People with type 1 diabetes do not produce their own insulin. The cells in the pancreas that produce insulin are destroyed. People with type 1 diabetes require daily insulin administration. As a consequence of this insulin therapy the blood sugar can dip too low, causing symptoms such as confusion, irritation and tiredness. This is called hypoglycaemia. Hypoglycaemia has been associated with an increased risk for cardiovascular disease such as heart attacks. During hypoglycaemia the immune system is activated. The immune system consists of white blood cells which produce cytokines, these are proteins used to kill pathogens such as bacteria. During hypoglycaemia there are no pathogens but the cytokines are still produced, leading to unwanted damage. A previous study performed by our research group showed that the immune system activation caused by hypoglycaemia is associated with the stress hormone adrenaline. Adrenaline is released by the body in moments of stress such as during running or bungee jumping. Adrenaline is also released by the body during hypoglycaemia to increase the sugar level. Our hypothesis is that adrenaline activates the immune system during hypoglycaemia. Adrenaline acts in the body through two receivers, these are called alpha and beta receptors. These are present on almost all cells in the body especially on the immune cells. With the study we want to study the situation where there is a hypoglycaemia without the adrenaline. We will achieve this by lowering the blood sugar in participants. During the low blood sugar we will administer two drugs, which will attach themselves to the adrenaline receivers, the alpha and beta receptor. With this method we hope to block the adrenaline effects and with that block the immune response caused by adrenaline.

Conditions

Diabetes Mellitus, Type 1; Inflammation

Outcome Measures

Primary Outcomes (1)

• Monocyte count after 60 minutes of hypoglycaemia and adrenergic blockade

  The number of monocytes following 60 minutes hypoglycaemia and adrenergic blockade compared to baseline. Adrenergic blockade using Phentolamine and Propranolol intravenously. Expressed in 10\^3/µl measured using a sysmex machine.

  After 60 minutes of hypoglycaemia and adrenergic blockade

Secondary Outcomes (18)

• Leukocyte count at the time points

  0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia, +1 day, +3 days and 1 week after of hypoglycaemia

• Ex vivo production of pro- and anti-inflammatory cytokines and chemokines

  0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia, +1 day, +3 days and 1 week after of hypoglycaemia

• 92 circulating inflammatory proteins

  0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia

• Inflammatory plasma protein ( e.g. high-sensitive crp)

  0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia

• Atherogenic parameters

  0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia

Other Outcomes (7)

• HbA1c expressed in mmol/L

  At screening

• Serum creatinine for kidney function expressed in umol/L

  Once at the screening at least 1 week before the hypoglycaemia

• Vitals ( blood pressure and heart rate)

  At both investigational days, every 15 minutes during each investigational day for a total of 8 hours.

Study Arms (2)

Participants without type 1 diabetes

ACTIVE COMPARATOR

The participants without type 1 diabetes

Drug: hyperinsulinaemic hypoglycaemic clamp; Drug: Propranolol Hydrochloride 1 MG/ML; Drug: Phentolamine

Participants with type 1 diabetes

ACTIVE COMPARATOR

Participants with type 1 diabetes

Drug: hyperinsulinaemic hypoglycaemic clamp; Drug: Propranolol Hydrochloride 1 MG/ML; Drug: Phentolamine

Interventions

hyperinsulinaemic hypoglycaemic clamp DRUG

Insulin will be infused at a continuous rate of 60 mU∙m-2 ∙min-1 and glucose 20% will be infused at a variable rate, aiming for stable plasma glucose levels of 5.0 mmol/L. The infusion rate of glucose will be adjusted by plasma glucose levels, measured at 5-minute intervals. After 30 minutes of stable euglycaemia, plasma glucose levels will be allowed to drop gradually to 2.8 mmol/L and will be maintained at this level for 60 minutes. Then, insulin infusion and adrenergic blockade infusions will be stopped. Glucose infusion will be increased and then tapered until stable euglycaemia plasma levels are reached.

Participants with type 1 diabetes; Participants without type 1 diabetes

Propranolol Hydrochloride 1 MG/ML DRUG

When euglycaemic level of 5.0mmol/L is achieved we will start the adrenergic blockade which will continue throughout euglycaemia and hypoglycaemia. The participants will be administered a bolus of phentolamine of 70µg/kg followed by a dose of 7.0µg/kg/min continuous infusion and a bolus of propranolol of 14µg/kg followed by a dose of 1.4µg/kg/min.

Participants with type 1 diabetes; Participants without type 1 diabetes

Phentolamine DRUG

When euglycaemic level of 5.0mmol/L is achieved we will start the adrenergic blockade which will continue throughout euglycaemia and hypoglycaemia. The participants will be administered a bolus of phentolamine of 70µg/kg followed by a dose of 7.0µg/kg/min continuous infusion and a bolus of propranolol of 14µg/kg followed by a dose of 1.4µg/kg/min.

Participants with type 1 diabetes; Participants without type 1 diabetes

Eligibility Criteria

• Age: 16 Years - 75 Years
• Gender Eligibility Details: We aim to match our participants with each other to have comparable groups. So we aim to have the same amount of males and females.
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to provide written informed consent
• Body-Mass Index: 18,5-35 kg/m2
• Age ≥16 years, ≤ 75 years
• Blood pressure: \<140/90 mmHg
• Non-smoking
• Electrocardiogram not showing any serious arrythmias (premature ventricular complexes and premature atrial complexes 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,

You may not qualify if:

• Any event of cardiovascular disease in the past 5 years (e.g. myocardial infarction, stroke, symptomatic peripheral arterial disease)
• Pregnancy or breastfeeding or unwillingness to undertake measures for birth control
• Active epilepsy ( with the need for treatment)
• Allergy for sulphite
• Active asthma with use of β2-bronchodilators or obstructive lung disease
• Current treatment with Alpha- or beta-blockers (e.g. doxazosin, propranolol)
• History of clinical significant Arrhythmias
• Use of immune-modifying drugs or antibiotics
• Use of antidepressants ( Including monoamine oxidase inhibitors, tricyclic antidepressants and serotonin-reuptake inhibitors)
• Use of antipsychotics
• Use of statins with the inability to stop statins \>2 weeks before the investigational day.
• Proliferative retinopathy
• Nephropathy with an estimated glomerular filtration rate (by Chronic Kidney Disease Epidemiology Collaboration equation, CKD-EPI) ˂60ml/min/1.73m2

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Medical Center, Nijmegen, Netherlands

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Inflammation

Interventions

Propranolol; Phentolamine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Cees Tack, MD, PhD

  Radboud University Medical Center (Radboudumc)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will be blinded tot the co-infusion during hypoglycaemia. This will be achieved by similar labelling, with phentolamine having the label infusion A and the propranolol infusion having the label infusion B. When administering saline the 50 milliliter syringes will be filled with saline instead of the solution containing either phentolamine or propranolol. Both saline syringes will still have the labels infusion A and infusion B. The investigators will not be blinded as they will be preparing the adrenergic solutions and the saline solutions. The participants will receive the same amount of millilitres during both infusions, determined by the amount infused during adrenergic blockade. Participants will be block-randomized with blocks of 2 using a randomisation list allocated to receive either the adrenergic blockade or the saline first. The coordinating investigator will have access to this list.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Potentially eligible adult ( 16 - 75 years) participants will be recruited through social media, the Radboudumc outpatient clinic and other advertisements. We will recruit a total of 24 individuals, i.e. 12 healthy participants and 12 participants with type 1 diabetes. Participants with type 1 diabetes will be twice ( as there are two investigational days) equipped with a blinded continuous glucose monitoring device (CGM) during the test, which will measure interstitial glucose levels for a total of 10 days.

Study Record Dates

• First Submitted: May 8, 2024
• First Posted: May 21, 2024
• Study Start: January 1, 2025
• Primary Completion: September 1, 2025
• Study Completion: October 1, 2025
• Last Updated: July 24, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 6 months after publication
• Access Criteria: The coordinating researcher will review access requests. Seeing as the data are all anonymized access will be granted for additional research in the field of inflammation or diabetes.

Locations

NL (1)