Cardiovascular Effects of Rapidly Declining Plasma Glucose in Patients With Type 1 Diabetes

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.


Eligibility Criteria:
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