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
Overview
- Phase
- Not Applicable
- Status
- Active, not recruiting
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Monocyte count after 60 minutes of hypoglycaemia and adrenergic blockade
Overview
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.
Detailed Description
Rationale: Hypoglycaemia has shown to cause a sustained pro-inflammatory response which could promote a pro-atherogenic state and explain the association between hypoglycaemia and cardiovascular events. This pro-inflammatory response has been linked to the adrenaline response to hypoglycaemia. Adrenergic blockade with α and β adrenergic receptor antagonists (ARA) has shown to blunt the leukocyte response after hypoglycaemia induction and adrenaline administration. Whether and to what degree a combined blockade blunts the hypoglycaemia induced pro-inflammatory response is unknown.
Objective
to examine the effect of adrenergic inhibition on the hypoglycaemia induced inflammatory response (e.g. leukocyte phenotype, cytokines, inflammatory proteins) by performing a hyperinsulinaemic hypoglycaemic glucose clamp alongside infusion of α-ARA and β-ARA. Secondary objectives consist of the effect of adrenergic blockade during hypoglycaemia on atherogenic parameters and glucose metrics ( e.g. time in range).
Study design: Intervention study with a cross-over design
Study population: 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.
Intervention: All participants will undergo a hyperinsulinaemic hypoglycaemic glucose clamp ( nadir 2.8 mmol/L). During the clamp the participants will be randomized to receive an infusion of saline or an infusion of phentolamine and propranolol. This will be done using a cross-over design. The participants will undergo both the saline and adrenergic blockade.
Main study parameters/endpoints: The main study parameter will be the monocyte count after 60 minutes hyperinsulinaemic hypoglycaemic clamp and adrenergic blockade during the clamp.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
Masking Description
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.
Eligibility Criteria
- Ages
- 16 Years to 75 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Overall inclusion criteria:
- •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
Exclusion Criteria
- •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
Arms & Interventions
Participants without type 1 diabetes
The participants without type 1 diabetes
Intervention: hyperinsulinaemic hypoglycaemic clamp (Drug)
Participants without type 1 diabetes
The participants without type 1 diabetes
Intervention: Propranolol Hydrochloride 1 MG/ML (Drug)
Participants without type 1 diabetes
The participants without type 1 diabetes
Intervention: Phentolamine (Drug)
Participants with type 1 diabetes
Participants with type 1 diabetes
Intervention: hyperinsulinaemic hypoglycaemic clamp (Drug)
Participants with type 1 diabetes
Participants with type 1 diabetes
Intervention: Propranolol Hydrochloride 1 MG/ML (Drug)
Participants with type 1 diabetes
Participants with type 1 diabetes
Intervention: Phentolamine (Drug)
Outcomes
Primary Outcomes
Monocyte count after 60 minutes of hypoglycaemia and adrenergic blockade
Time Frame: 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.
Secondary Outcomes
- Variability measured by the blinded continuous glucose monitor(During the full study, 3 days before and 7 days after each investigational day)
- Average glucose measured by the blinded continuous glucose monitor(During the full study, 3 days before and 7 days after each investigational day)
- Amount of plasma glycerol(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Amount of Non-esterified fatty acids(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Untargeted metabolomics profiling(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Functional changes in monocytes(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Adrenergic symptoms assessed using the validated Edinburgh Hypoglycaemia Score(0, 30 minutes after euglycaemia, 30 minutes and 60 minutes during hypoglycaemia)
- Hypoglycaemia awareness using the modified Clarke score(At screening)
- Plasma levels of hormones(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Amount of hypoglycaemic events measured by the blinded continuous glucose monitor(During the full study, 3 days before and 7 days after each investigational day)
- Time in range measured by the blinded continuous glucose monitor(During the full study, 3 days before and 7 days after each investigational day)
- 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)
- Inflammatory plasma protein ( e.g. high-sensitive crp)(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- 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)
- 92 circulating inflammatory proteins(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Atherogenic parameters(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Gene expression changes in leukocytes(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)
- Epigenetic changes in leukocytes(0, 30 minutes after euglycaemia, 60 minutes during hypoglycaemia)