Acute Changes in Plasma Glucose and Cardiovascular Disease in Diabetes

Myocardial Work and Left Ventricular Mechanical Dyssynchrony During Acute Changes in Plasma Glucose in Individuals With Type 1 Diabetes, Type 2 Diabetes and Without Diabetes

Patients with diabetes have an increased risk of sudden cardiac death compared to the general population. Severe hypoglycemia is associated with an increased risk of cardiovascular (CV) disease (CVD) and events, including cardiac arrhythmias and sudden cardiac death; likewise, increased glycemic variability is associated with macrovascular complications and increased mortality. The physiological mechanisms linking hypoglycemia and glycemic variability to CVD and CV events remain unclear. Myocardial work and mechanical dyssynchrony will be measured by speckle tracking echocardiography during euglycemia, hypoglycemia and hyperglycemia in individuals with type 1 diabetes, type 2 diabetes, and without diabetes. Echocardiographic images from three experimental clamp studies - Hypo-Heart 1 (sub-study 1), Hypo-Heart 2 (sub-study 2) and Rapid-Heart - will be included in this study.

The results of this study may be compiled into one or more manuscripts for publication. Study ID's: Hypo-Heart 1 (sub-study 1): NCT03956173 Hypo-Heart 2 (sub-study 2): NCT03150030 Rapid-Heart: NCT04800536

The present echocardiographic study includes participants from three experimental clamp studies; the Hypo-Heart 1 (Study 1), Hypo-Heart 2 (Study 2) and Rapid-Heart (Study 3).

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).

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).

Includes three steady state phases in plasma glucose, 1) euglycemic phase (5-8 mmol/L), 2) hyperinsulinemic hypoglycemic phase (PG: 2.5 mmol/L), 3) recovery phase in hyperglycemia (20.0 mmol/L)

Includes three steady state phases in plasma glucose, 1) euglycemic phase (5-8 mmol/L), 2) hyperinsulinemic hypoglycemic phase (PG: 2.5 mmol/L), 3) recovery phase in euglycemia (PG: 5-8 mmol/L).

Includes three steady state phases in plasma glucose, 1) euglycemic phase (5-8 mmol/L), 2) hyperinsulinemic hypoglycemic phase (PG: 2.5 mmol/L), 3) recovery phase in hyperglycemia (20.0 mmol/L) or euglycemia (PG: 5-8 mmol/L)

Includes three steady state phases in plasma glucose, 1) euglycemic phase (fasting PG), 2) hyperglycemic phase (fasting PG + 10 mmol/L), 3) hyperinsulinemic hypoglycemic phase (PG < 3.0 mmol/L).

Includes three steady state phases in plasma glucose, 1) euglycemic phase (fasting PG), 2) hyperglycemic phase (fasting PG + 10 mmol/L), 3) hyperinsulinemic hypoglycemic phase (PG < 3.0 mmol/L).

Includes three steady state phases in plasma glucose, 1) euglycemic phase (fasting PG), 2) hyperglycemic phase (fasting PG + 10 mmol/L), 3) hyperinsulinemic hypoglycemic phase (PG < 3.0 mmol/L).

Includes three steady state phases in plasma glucose, 1) euglycemic phase (fasting PG), 2) hyperglycemic phase (fasting PG + 10 mmol/L), 3) hyperinsulinemic hypoglycemic phase (PG < 3.0 mmol/L).

Change in the global work during hypoglycemia in individuals with type 1 diabetes, type 2 diabetes, and without diabetes, respectively.

Absolute change in the global work index measured by pressure-strain loop analysis during insulin-induced hypoglycemia compared to euglycemia in individuals with type 1 diabetes, type 2 diabetes, and without diabetes, respectively (Hypo-Heart 1 and Hypo-Heart 2). Study outcomes will be analyzed separately for each included study.

Primary secondary outcome: Change in mechanical dyssynchrony during hypoglycemia in individuals with type 1 diabetes, type 2 diabetes, and without diabetes, respectively.

Absolute change in mechanical dyssynchrony (defined as the standard deviation of regional time to peak strain) measured by speckle tracking echocardiography measured by pressure-strain loop analysis during insulin-induced hypoglycemia compared to euglycemia in individuals with type 1 diabetes, type 2 diabetes, and without diabetes, respectively (Hypo-Heart 1 and Hypo-Heart 2). Study outcomes will be analyzed separately for each included study.

Absolute change in the global work index measured by pressure-strain loop analysis during recovery (post-hypoglycemic euglycemia and hyperglycemia) compared to euglycemia in individuals with type 1 diabetes (Hypo-Heart 1). Study outcomes will be analyzed separately for each included study.

Absolute change in mechanical dyssynchrony (defined as the standard deviation of regional time to peak strain) measured by speckle tracking echocardiography measured by pressure-strain loop analysis during recovery (post-hypoglycemic euglycemia and hyperglycemia) compared to euglycemia in individuals with type 1 diabetes (Hypo-Heart 1). Study outcomes will be analyzed separately for each included study.

Change in the global work during hyperglycemia in individuals with type 1 diabetes, type 2 diabetes and without diabetes, respectively.

Absolute change in the global work index measured by pressure-strain loop analysis during hyperglycemia compared to euglycemia in individuals with type 1 diabetes, type 2 diabetes and without diabetes, respectively (Rapid Heart and Hypo-Heart 2). Study outcomes will be analyzed separately for each included study.

Change in mechanical dyssynchrony during hyperglycemia in individuals with type 1 diabetes, type 2 diabetes and without diabetes, respectively.

Absolute change in mechanical dyssynchrony (defined as the standard deviation of regional time to peak strain) measured by speckle tracking echocardiography measured by pressure-strain loop analysis during hyperglycemia compared to euglycemia in individuals with type 1 diabetes, type 2 diabetes and without diabetes, respectively (Rapid Heart and Hypo-Heart 2). Study outcomes will be analyzed separately for each included study.

The present echocardiographic study includes 86 participants from three experimental clamp studies; the Hypo-Heart 1 (Study 1), Hypo-Heart 2 (Study 2) and Rapid-Heart (Study 3), including patients with type 1 diabetes (Hypo-Heart 1 and Rapid-Heart), patients with type 2 diabetes (Hypo-Heart 2) and healthy controls (Hypo-Heart 2). Hypo-Heart 1: Inclusion Criteria: Informed and written consent Type 1 diabetes diagnosed according to the criteria of the World Health Organization (WHO) Age 18-70 years Insulin treatment for ≥3 years Exclusion Criteria: Arrhythmia diagnosed prior to the screening visit Implantable cardioverter defibrillator (ICD) or pacemaker at the time of inclusion Severe heart failure (left ventricular ejection fraction <25%) Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) Thyroid dysfunction (except for well-regulated eltroxin substituted myxoedema) Anemia (male: hemoglobin <8.0; female: hemoglobin <7.0 mmol/l) Hypo-Heart 2: Inclusion Criteria: Patients with type 2 diabetes Informed and written consent Type 2 diabetes diagnosed according to the criteria of the World Health Organization (WHO) Treatment with insulin Glycated haemoglobin A1c (HbA1c) ≤58 mmol/mol Inclusion Criteria: Healthy individuals HbA1c ≤42 mmol/mol Fasting plasma glucose ≤6.1 mmol/l Exclusion Criteria: Patients with type 2 diabetes Arrhythmia diagnosed prior to or at the time of inclusion Implantable cardioverter defibrillator (ICD) or pacemaker at the time of inclusion Severe heart failure (left ventricular ejection fraction <25%) Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) Insulin naïve patients with type 2 diabetes Thyroid dysfunction (except for well-regulated eltroxine substituted myxoedema) Unable to comply with daily CGM during run-in period Anemia (male: hemoglobin < 8.0; female: hemoglobin < 7.0 mmol/l) Exclusion Criteria: Healthy individuals Type 1 or type 2 diabetes Prediabetes (HbA1c >42 mmol/l and/or fasting plasma glucose >6.1 mmol/l) Family history of diabetes (type 1 og type 2 diabetes) Arrhythmia diagnosed prior to or at the time of inclusion ICD or pacemaker at the time of inclusion Severe heart failure (left ventricular ejection fraction <25%) Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) Thyroid dysfunction (except for well-regulated eltroxine substituted myxoedema) Anemia (male: hemoglobin < 8.0; female: hemoglobin < 7.0 mmol/l) Rapid-Heart: 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