Cardiovascular Effects of Exercise-related Hypoglycaemia in Patients With Type 1 Diabetes (Hypo Heart Exercise)

Cardiovascular Effects of Exercise-related Hypoglycaemia in Patients With Type 1 Diabetes (Hypo Heart Exercise)

Patients with type 1 diabetes are recommended to perform at least 150 minutes of accumulated physical activity each week, however fear of hypoglycaemia is a well-known barrier to exercise in these patients. Previous experimental studies have almost exclusively focused on investigating cardiovascular effects of hypoglycaemia under resting conditions, however other underlying circumstances prior to or during a hypoglycaemic event, (e.g. exercise) are rarely discussed in the literature but might, nevertheless, be of significant clinical importance. In this study, the investigators aim to investigate the QT interval dynamics and prothrombotic factors during exercise-related hypoglycaemia in comparison with hypoglycaemia under resting conditions, in patients with type 1 diabetes. Fifteen patients with type 1 diabetes will be recruited for a crossover study including two test days, a combined euglycaemic- hypoglycaemic clamp combined with an exercise session and an euglycaemic- hypoglycaemic clamp during bed rest, respectively. Furthermore, the participants will be schedueled for a 24-hours followup visit after each test day for the purpose of investigating prolonged prothrombotic effects of hypoglycaemia. Patients will be randomised 1:1 to start with the combined exercise-clamp or the resting-clamp. The two test days will be separated by at least 4 weeks to minimise carry-over effects. A group of fifteen healthy individuals with normal glucose tolerance matched for age, gender and body mass index, will be recruited for a single blood test aiming to compare baseline coagulation status with patients with type 1 diabetes.

A 180 minutes hyperinsulinaemic euglycaemic-hypoglycaemic clamp in combination with an exercise session. The participants will be monitored with Holter-ECG throughout the entire clamp and plasma glucose will be measured every 5 minutes. Blood samples will be drawn and analysed for changes in electrolytes, counterregulatory hormones, coagulation status, inflammation, endothelial damage and oxidative stress.

A 180 minutes hyperinsulinaemic euglycaemic-hypoglycaemic clamp in combination with bed rest. The participants will be monitored with Holter-ECG throughout the entire clamp and plasma glucose will be measured every 5 minutes. Blood samples will be drawn and analysed for changes in electrolytes, counterregulatory hormones, coagulation status, inflammation, endothelial damage and oxidative stress.

Mean QTc interval prolongation from baseline during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in whole blood coagulability and fibrinolysis (measured by thrombelastography) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in QTd, during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions

Changes in sympathetic/parasympathetic balance (measured by HRV) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in non-clinically significant bradycardia (≤45 bpm for 5 seconds) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in number of atrial ectopic beats (prematurity threshold 30%) and ventricular premature beats respectively, during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in plasma markers of endothelial activation and damage (ng/ml) (including Syndecan-1, Soluble thrombomodulin and PECAM-1) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in markers of vascular oxidative stress (tetrahydrobiopterin/dihydrobiopterin ratio, dehydroascorbic acid/ascorbic acid ratio, asymmetric dimethylarginine/arginine ratio, malondialdehyde) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in electrolyte concentrations including potassium and ionised calcium during exercise-related hypoglycaemia compared insulin-induced hypoglycaemia under resting conditions.

Differences in hormonal response (plasma glucagon, cortisol, catecholamines and growth hormone) during exercise-related hypoglycaemia compared insulin-induced hypoglycaemia under resting conditions.

Differences in inflammatory response (including interleukin 6 and TNFα) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in High-sensitive C-reactive peptide (HsCRP) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Differences in mean absolute relative difference (MARD) between Dexcom G6®, Abbot Flash Libre® and Yellow Springs Instrument (YSI) reference throughout both experimental days.

Differences in whole blood coagulability and fibrinolysis (measured by thrombelastography) between patients with type 1 diabetes and healthy control subjects.

Inclusion Criteria: Informed and written consent Type 1 diabetes diagnosed according to the criteria of the World Health Organization (WHO) Age ≥ 18 years Insulin treatment for ≥1 year Exclusion Criteria: Arrhythmia diagnosed prior to the screening visit. Ischaemic heart disease or myocardial infarction diagnosed prior to the screening visit. Implantable cardioverter defibrillator (ICD) or pacemaker at the time of inclusion Heart failure (left ventricular ejection fraction <45%) diagnosed prior to the screening visit. Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) ECG with left or right bundle branch block diagnosed prior to the screening visit. Thyroid dysfunction (except for well-regulated levothyroxine-substituted myxoedema) Anaemia (male: haemoglobin <8.0; female: haemoglobin <7.0 mmol/l) Treatment with anticoagulant or antiplatelet treatment. Bleeding disorder diagnosed prior to the screening visit. Withdrawal criteria - The participants may withdraw at will at any time