Aim
To investigate changes in cardiac repolarization abnormalities (heart rate‐corrected QT QTc primary endpoint, T‐wave abnormalities) and heart‐rate variability measures in people with type 1 ...diabetes during insulin‐induced hypoglycaemia followed by recovery hyperglycaemia versus euglycaemia.
Methods
In a randomized crossover study, 24 individuals with type 1 diabetes underwent two experimental clamps with three steady‐state phases during electrocardiographic monitoring: (1) a 45‐minute euglycaemic phase (5‐8 mmol/L), (2) a 60‐minute insulin‐induced hypoglycaemic phase (2.5 mmol/L), and (3) 60‐minute recovery in either hyperglycaemia (20 mmol/L) or euglycaemia (5‐8 mmol/L).
Results
All measured markers of arrhythmic risk indicated increased risk during hypoglycaemia. These findings were accompanied by a decrease in vagal tone during both hyperglycaemia and euglycaemia clamps. Compared with baseline, the QTc interval increased during hypoglycaemia, and 63% of the participants exhibited a peak QTc of more than 500 ms. The prolonged QTc interval was sustained during both recovery phases with no difference between recovery hyperglycaemia versus euglycaemia. During recovery, no change from baseline was observed in heart‐rate variability measures.
Conclusions
In people with type 1 diabetes, insulin‐induced hypoglycaemia prolongs cardiac repolarization, which is sustained during a 60‐minute recovery period independently of recovery to hyperglycaemia or euglycaemia. Thus, vulnerability to serious cardiac arrhythmias and sudden cardiac death may extend beyond a hypoglycaemic event, regardless of hyperglycaemic or euglycaemic recovery.
Aims
To investigate changes in cardiac repolarisation during exercise‐related hypoglycaemia compared to hypoglycaemia induced at rest in people with type 1 diabetes.
Material and methods
In a ...randomised crossover study, 15 men with type 1 diabetes underwent two separate hyperinsulinaemic euglycaemic‐hypoglycaemic clamp experiments during Holter‐ECG monitoring. One experiment included a bout of moderate‐intensity cycling exercise (60 min) along with declining plasma glucose (PG; Clamp‐exercise). In the other experiment, hypoglycaemia was induced with the participants at rest (Clamp‐rest). We studied QTc interval, T‐peak to T‐end (Tpe) interval and hormonal responses during three steady‐state phases: (i) baseline (PG 4.0–8.0 mmol/L); (ii) hypoglycaemic phase (PG <3.0 mmol/L); and (iii) recovery phase (PG 4.0–8.0 mmol/L).
Results
Both QTc interval and Tpe interval increased significantly from baseline during the hypoglycaemic phase but with no significant difference between test days. These changes were accompanied by an increase in plasma adrenaline and a decrease in plasma potassium on both days. During the recovery phase, ΔQTc interval was longer during Clamp‐rest compared to Clamp‐exercise, whereas ΔTpe interval remained similar on the two test days.
Conclusions
We found that both exercise‐related hypoglycaemia and hypoglycaemia induced at rest can cause QTc‐interval prolongation and Tpe‐interval prolongation in people with type 1 diabetes. Thus, both scenarios may increase susceptibility to ventricular arrhythmias.
Aim
To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes.
Materials and Methods
Thirty adults with type 1 ...diabetes were included in a 12‐month observational exploratory study. Daytime and night‐time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose IG <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation).
Results
Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 95% CI: 0.99‐1.18 per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 95% CI: 1.21‐3.40 and IRR 1.07 95% CI: 1.02‐1.13 per 5 minutes, respectively). Night‐time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night‐time.
Conclusions
Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night‐time, indicating diurnal differences in arrhythmia susceptibility.
Hypoglycemia is common in individuals with type 1 diabetes, especially during exercise. We investigated the accuracy of two different continuous glucose monitoring systems during exercise-related ...hypoglycemia in an experimental setting.
Fifteen individuals with type 1 diabetes participated in two separate euglycemic-hypoglycemic clamp days (Clamp-exercise and Clamp-rest) including five phases: 1) baseline euglycemia, 2) plasma glucose (PG) decline ± exercise, 3) 15-minute hypoglycemia ± exercise, 4) 45-minute hypoglycemia, and 5) recovery euglycemia. Interstitial PG levels were measured every five minutes, using Dexcom G6 (DG6) and FreeStyle Libre 1 (FSL1). Yellow Springs Instruments 2900 was used as PG reference method, enabling mean absolute relative difference (MARD) assessment for each phase and Clarke error grid analysis for each day.
Exercise had a negative effect on FSL1 accuracy in phase 2 and 3 compared to rest (ΔMARD = +5.3 percentage points (95% CI): 1.6, 9.1 and +13.5 percentage points 6.4, 20.5, respectively). In contrast, exercise had a positive effect on DG6 accuracy during phase 2 and 4 compared to rest (ΔMARD = -6.2 percentage points -11.2, -1.2 and -8.4 percentage points -12.4, -4.3, respectively). Clarke error grid analysis showed a decrease in clinically acceptable treatment decisions during Clamp-exercise for FSL1 while a contrary increase was observed for DG6.
Physical exercise had clinically relevant impact on the accuracy of the investigated continuous glucose monitoring systems and their ability to accurately detect hypoglycemia.
The impact of hypoglycemia, hyperglycemia and glycemic variability on cardiac arrhythmia susceptibility in people with type 1 diabetes is uncertain. We performed a 12-month prospective observational ...study employing continuous glucose monitoring and implantable loop recorders to investigate potential associations between glycemia and cardiac arrhythmias. Thirty adults with type 1 diabetes (mean ± SD age 63 ± 8 years, BMI 26 ± 5 kg/m2, HbA1c 7.3 ± 1.1% 56.9 ± 11.9 mmol/mol) and without any history of cardiac arrhythmias were included. Daytime and nighttime incidence rate ratios (IRR) of arrhythmias were determined for hypoglycemia (interstitial glucose (IG) < 3.9 mmol/L), hyperglycemia (IG > 10.0 mmol/L), and glycemic variability (standard deviation and coefficient of variation). Hypoglycemia was not associated with an increased risk of cardiac arrhythmias in comparison with euglycemia (IG 3.9 - 10.0 mmol/L) and hyperglycemia. However, during daytime, a trend of increased risk of arrhythmias was observed when comparing hypoglycemia with euglycemia (IRR 1.08 95% CI 0.99 - 1.18). Furthermore, during daytime both the occurrence of hyperglycemia and time spent in hyperglycemia within the same hour of an arrhythmia were associated with an increased risk of arrhythmias compared to euglycemia (IRR 2.03 95% CI 1.21 - 3.40 and IRR 1.07 95% CI 1.02 - 1.13, respectively). Nighttime hypoglycemia and hyperglycemia were not associated with increased risk of arrhythmias. Increased glycemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during nighttime. In conclusion, daytime hypoglycemia and hyperglycemia may contribute to an increased risk of cardiac arrhythmias compared to euglycemia, in people with type 1 diabetes. No associations were found between glycemic levels and cardiac arrhythmias during nighttime, indicating diurnal differences in arrhythmogenic susceptibility.
Disclosure
P.G.Hagelqvist: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. A.Andersen: None. K.Maytham: None. C.R.Andreasen: None. S.Engberg: Employee; Novo Nordisk A/S. T.B.Lindhardt: None. J.Forman: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.
Funding
Novo Nordisk Foundation (28300)
People with type 1 diabetes (T1D) are at increased risk of thrombosis, however, the underlying mechanisms remain unclear. Hypoglycemia induced at rest can induce coagulation activation, but little is ...known about the hemostatic effects of exercise-related hypoglycemia in people with T1D.
We compared hemostatic profiles of individuals with T1D with healthy controls and explored hemostatic effects of hypoglycemia, induced with or without exercise, in participants with T1D.
Thrombelastography (TEG) was used for a baseline hemostatic comparison between fifteen men with T1D and matched healthy controls. In addition, the participants with T1D underwent two euglycemic-hypoglycemic clamp days in a randomized, crossover fashion. Hypoglycemia was induced with the participants at rest (Hypo-rest) or during exercise (Hypo-exercise). TEG provides data on the rate of coagulation activation (R-time), the rate of clot formation (K-time, α-Angle), the maximum clot amplitude (MA), the functional fibrinogen contribution to the clot strength (MA-FF) and the fibrinolysis (LY-30).
The T1D group exhibited shorter R-time and K-time and a greater α-Angle compared to the controls. During the clamp experiments, Hypo-exercise induced an increased clot strength (MA) with a mean difference from baseline of 2.77 mm 95% confidence interval 2.04; 3.51 accompanied with a decreased fibrinolysis (LY-30) of -0.45 percentage points -0.60; -0.29. Hypo-rest resulted in increased functional fibrinogen (MA-FF) of 0.74 mm 0.13; 1.36 along with an increased fibrinolysis (LY-30) of 0.54 percentage points 0.11; 0.98.
Individuals with T1D exhibit a hypercoagulable hemostatic profile compared to healthy controls and exercise-related hypoglycemia may increase the susceptibility to thrombosis via both procoagulant and antifibrinolytic effects.
Mechanical dispersion (MD) describes heterogeneity in ventricular contraction patterns, and myocardial work (MW) indices quantify ventricular performance. Investigating the myocardial and functional ...response to acute hypoglycemia and hyperglycemia may aid in identifying putative mechanisms linking glycemia and cardiovascular disease (CVD). From echocardiography performed during euglycemic, hyperglycemic and hypoglycemic clamps, we explored the relationship between glycemia and MD and MW indices in individuals with type 1 diabetes, type 2 diabetes and without diabetes. MD was measured by speckle-tracking echocardiography, and MW measures were derived from pressure-strain loop analyses. We analyzed data (mean±SD) from 84 individuals: 20 young individuals with type 1 diabetes (age: 30±8 years); 24 middle-aged individuals with type 1 diabetes (age: 53±12 years); 21 older individuals with type 2 diabetes (63±7 years), and 21 controls (62±8 years). Results for MD and MW indices are illustrated in Figure 1. In conclusion, acute hyperglycemia leads to an energy-effective myocardium with homogeneous left ventricular contractions. Hypoglycemia increases constructive myocardial work, followed by a less energy-efficient myocardium and more heterogeneous left ventricular contractions, perhaps alluding to a possible link between hypoglycemia and CVD.
Disclosure
C.R.Andreasen: None. A.Andersen: None. P.G.Hagelqvist: None. K.Maytham: None. M.Sengeløv: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. F.J.Olsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company.
Funding
Danish Diabetes Academy (17SA0031406); Novo Nordisk Foundation (16230)
Diabetes is a hypercoagulable state predisposing to cardiovascular disease. Physical exercise can improve cardiovascular health but may also cause hypoglycemia in insulin-treated patients. We ...compared hemostatic profiles of patients with type 1 diabetes (T1D) with healthy controls and delineated hemostatic changes of hypoglycemia, induced with or without exercise, in patients with T1D.
Thromboelastography (TEG®6s) was used to compare hemostatic profiles of patients with T1D (N=15, (mean±SD) age 29.4±8.1 years, HbA1c 6.8±0.5%, diabetes duration 13.1±6.2 years, BMI 23.7±2.0 kg/m2) with individually matched healthy controls (N=15) . In addition, the patients with T1D underwent (randomized, crossover design) two separate hyperinsulinemic euglycemic-hypoglycemic clamp days. During decline in plasma glucose and the initial 15 min of hypoglycemia, the subjects were either resting or performing moderate-intensity exercise. TEG was performed at baseline euglycemia and after 15 min and 60 min of hypoglycemia.
Compared with healthy controls, patients with T1D were more hypercoagulable with shorter R-time (P<0.001) and K-time (P=0.019) and an increased Angle-value (P=0.009) . Clot maximum amplitude (MA) , functional fibrinogen (MA-FF) , and fibrinolysis (LY-30) were similar in the two groups. In patients with T1D, exercise-related hypoglycemia induced hypercoagulable changes with decreased K-time (P=0.005) , increased Angle-value (P=0.049) , and increased MA (P<0.001) after 15 min of hypoglycemia. These changes were not compensated by an increased fibrinolysis. In contrast, hypoglycemia induced at rest resulted in decreased K-time (P=0.03) and increased MA-FF (P=0.02) only after 60 min, along with increased LY-30 (P=0.02) .
In conclusion, patients with T1D have a more hypercoagulable profile than healthy controls, and exercise-related hypoglycemia induces coagulation without a compensatory fibrinolytic activity, which may increase susceptibility for thrombosis.
Disclosure
P.G.Hagelqvist: None. A.Andersen: n/a. K.Maytham: None. S.Engberg: Employee; Novo Nordisk A/S. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. P.I.Johansson: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.
Funding
Independent research fund Denmark (1030-00256B) Grosserer L.F. Foghts Fund (21.761)
