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

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.

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: \ 1 year * HbA1c \< 100 mmol/mol, 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 * 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