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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1; Arrhythmia
• Intervention / Treatment: Other: Exercise-related hypoglycaemia; Other: Hypoglycaemia under resting conditions

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2900
    • Clinical Research, Steno Diabetes Center Copenhagen-Gentofte

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypoglycaemia and QTc interval prolongation	Mean QTc interval prolongation from baseline during exercise-related hypoglycaemia compared to insulin-induced hypoglycaemia under resting conditions.	0-180minutes

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Investigators: Principal Investigator: Tina Vilsbøll, MD, DMSc, Steno diabetic centre (SDCC)

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): June 3, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: November 12, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 2, 2020

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: January 5, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Type 1 diabetes; Hypoglycaemia; Exercise-related hypoglycaemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia
• Other Study ID Numbers: H-20023688

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No