Type 1 Diabetes
Conditions
Keywords
Plasma glucose decline rate, Cardiovascular disease, Sudden cardiac death, Glycaemic variability
Brief summary
Type 1 diabetes (T1D) is an autoimmune metabolic disease characterised by impaired lack of endogenous insulin causing elevated plasma glucose levels and increased risk of microvascular and macrovascular complications. With respect to the cardiovascular system, patients with T1D have an up to 10-fold increased risk of sudden cardiac death compared to healthy individuals. Furthermore, diabetes constitutes a hypercoagulable state, which to some extent may explain why cardiovascular disease still is a major cause of mortality in patients with T1D. Due to treatment with exogenously delivered insulin, glycaemic variability with intra-day and inter-day plasma glucose concentrations fluctuating between high levels (peaks) and low levels (nadirs), are inevitable in patients with T1D. A potentially important factor in development of cardiovascular disease, associated with glycaemic variability, is the rate of increase and/or decline of plasma glucose. The aim of this study is to test the hypothesis that a rapid plasma glucose decline from a hyperglycaemic level to an euglycaemic level can induce changes in QT-interval and blood coagulation in a proarrhythmogenic and prothrombotic way. Twenty patients with T1D with a 1:1 distribution with chronic hyperglycaemia (HbA1C ≥63 mmol/mol) and with well-controlled diabetes (HbA1C ≤53 mmol/mol) will be recruited for a crossover study including two test days (protocols), P-rapid, a combined hyperglycaemic and euglycaemic clamp with rapidly declining plasma glucose and P-slow, a combined hyperglycaemic and euglycaemic clamp with slowly declining plasma glucose. Patients will be randomised 1:1 to start with P-rapid or P-slow. The cardiovascular effects will be investigated using Holter-ECG, Thrombelastography, Echocardiography and blood sampling. Given that cardiovascular disease is a major cause of death in patients with T1D and that patients with diabetes may be more susceptible for cardiac arrhythmias and thrombotic events compared to healthy individuals, it is important to identify cardiovascular risk factors related to acute changes in plasma glucose in order to improve prevention strategies and therapy.
Interventions
OTHERRapidly declining plasma glucose
Acute plasma glucose decline, divided into the following three phases: 1) Hyperglycaemic phase (plasma glucose 15 mmol/l), 2) Rapid plasma glucose decline phase and 3) Euglycaemic phase (plasma glucose 4.5-5.5 mmol/l).
OTHERSlowly declining plasma glucose
Acute plasma glucose decline, divided into the following three phases: 1) Hyperglycaemic phase (plasma glucose 15 mmol/l), 2) Slow plasma glucose decline phase and 3) Euglycaemic phase (plasma glucose 4.5-5.5 mmol/l).
Sponsors
University Hospital, Gentofte, Copenhagen
Rigshospitalet, Denmark
Steno Diabetes Center Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- chronic hyperglycaemia cohort * Informed and written consent * Type 1 diabetes * Age ≥18 years * C-peptide negative (\<0.2 nmol/l) * Insulin treatment for ≥1 year * HbA1C ≥63 mmol/mol Inclusion criteria - well-controlled cohort * Informed and written consent * Type 1 diabetes * Age ≥18 years * C-peptide negative (\<0.2nmol/l) * Insulin treatment for ≥1 year * HbA1C ≤53 mmol/mol
Exclusion criteria
- both cohorts * Arrhythmia diagnosed prior to or at the time of the screening visit * ECG with left or right bundle branch block diagnosed prior to the screening visit. * Implantable cardioverter defibrillator or pacemaker at the time of inclusion * Heart failure diagnosed prior to the screening visit (left ventricular ejection fraction \< 45%) * Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) * Thyroid dysfunction (except for well-regulated myxoedema) * Anaemia (male: haemoglobin \<8.0 mmol/l; 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| QTc interval | 0-255 minutes | Difference in mean QTc (ms) interval from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart rate variability | 0-255 minutes | Difference in the sympathetic/parasympathetic balance (measured by heart rate variability) during a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Haemostatic balance | 0-255 minutes | Difference in activation of coagulation and fibrinolysis (measured by TEG) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Endothelial activation and damage | 0-255 minutes | Difference in endothelial activation and damage (measured by Syndecan-1, Soluble thrombomodulin and sVE-cadherin) (ng/ml) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Cardiac function | 0-255 minutes | Difference in ventricular systolic function (measured by echocardiography) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Plasma glucose decline rate and oxidative stress | 0-255 minutes | Difference in vascular oxidative stress (Tetrahydrobiopterin/dihydrobiopterin ratio, Dehydroascorbic acid/Ascorbic acid ratio, Asymmetric dimethylarginine/Arginine ratio, Malondialdehyde) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Plasma glucose decline rate and potassium | 0-255 minutes | Difference in plasma potassium concentration during a rapid plasma glucose decline compared to a slow plasma glucose decline from a hyperglycaemic level to an euglycaemic level. |
| Plasma glucose decline rate and symptomatic response | 0-255 minutes | Difference in symptomatic response (Edinburgh hypoglycaemia symptom scale) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
| Plasma glucose decline rate and counterregulatory hormonal response | 0-255 minutes | Difference in counterregulatory hormonal response (plasma glucagon, catecholamines, cortisol, and growth hormone) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively. |
Countries
Denmark
Outcome results
None listed