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

Sponsor

Steno Diabetes Center Copenhagen (Other)

Overall Status

Completed

CT.gov ID

NCT04650646

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1 Arrhythmia	Other: Exercise-related hypoglycaemia Other: Hypoglycaemia under resting conditions	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Cardiovascular Effects of Exercise-related Hypoglycaemia in Patients With Type 1 Diabetes

Actual Study Start Date :

Sep 1, 2020

Actual Primary Completion Date :

Jun 3, 2021

Actual Study Completion Date :

Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hypoglycaemic clamp i combination with exercise 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.	Other: Exercise-related hypoglycaemia Hypoglycaemia induced by intravenous insulin and exercise on a vertical cycle ergometer.
Experimental: Hypoglycaemic clamp in combination with bed rest 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.	Other: Hypoglycaemia under resting conditions Hypoglycaemia induced by intravenous insulin during bed rest.

Arm

Intervention/Treatment

Experimental: Hypoglycaemic clamp i combination with exercise

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.

Other: Exercise-related hypoglycaemia

Hypoglycaemia induced by intravenous insulin and exercise on a vertical cycle ergometer.

Experimental: Hypoglycaemic clamp in combination with bed rest

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.

Other: Hypoglycaemia under resting conditions

Hypoglycaemia induced by intravenous insulin during bed rest.

Outcome Measures

Primary Outcome Measures

Hypoglycaemia and QTc interval prolongation [0-180minutes]
Mean QTc interval prolongation from baseline during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.

Secondary Outcome Measures

Key secondary outcome: Hypoglycaemia and coagulation and fibrinolysis [0-24hours]
Differences in whole blood coagulability and fibrinolysis (measured by thrombelastography) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and QT dispersion (QTd) [0-180minutes]
Differences in QTd, during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions
Hypoglycaemia and heart rate variability (HRV) [0-180minutes]
Changes in sympathetic/parasympathetic balance (measured by HRV) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and bradycardia [0-180minutes]
Differences in non-clinically significant bradycardia (≤45 bpm for 5 seconds) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and ectopic beats [0-180minutes]
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.
Hypoglycaemia and endothelial activation and damage [0-24hours]
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.
Hypoglycaemia and vascular oxidative stress [0-24hours]
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.
Hypoglycaemia and electrolytes [0-180minutes]
Differences in electrolyte concentrations including potassium and ionised calcium during exercise-related hypoglycaemia compared insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and counterregulatory hormonal response [0-180minutes]
Differences in hormonal response (plasma glucagon, cortisol, catecholamines and growth hormone) during exercise-related hypoglycaemia compared insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and markers of inflammation [0-24hours]
Differences in inflammatory response (including interleukin 6 and TNFα) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and inflammation [0-24hours]
Differences in High-sensitive C-reactive peptide (HsCRP) during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.
Hypoglycaemia and continuous glucose monitoring (CGM) accuracy [0-180min]
Differences in mean absolute relative difference (MARD) between Dexcom G6®, Abbot Flash Libre® and Yellow Springs Instrument (YSI) reference throughout both experimental days.
Type 1 diabetes, healthy controls and coagulability [0minutes]
Differences in whole blood coagulability and fibrinolysis (measured by thrombelastography) between patients with type 1 diabetes and healthy control subjects.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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.