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

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.

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
• 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