Cardiac Autonomic Regulation and Repolarization During Acute Experimental Hypoglycemia in Type 2 Diabetes

Abstract

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes mellitus (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in patients with T2DM. We examined changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and 11 age- and BMI-matched control participants without diabetes underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0 mmol/L) or hypoglycemia (2.5 mmol/L) for 1 h. Heart rate, blood pressure, and heart rate variability were assessed every 30 min and corrected QT intervals and T-wave morphology every 60 min. Heart rate initially increased in participants with T2DM but then fell toward baseline despite maintained hypoglycemia at 1 h accompanied by reactivation of vagal tone. In control participants, vagal tone remained depressed during sustained hypoglycemia. Participants with T2DM exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T-wave symmetry and principal component analysis ratio compared with control participants. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears to be time dependent. Individuals with T2DM demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes.

Figure 1

Arterialized blood glucose during hyperinsulinemic-euglycemic and hypoglycemic clamps. Data are mean (SE). EU control, euglycemic clamp, control participants without diabetes; EU DM, euglycemic clamp, patients with T2DM; HYPO control, hypoglycemic clamp, control participants without diabetes; HYPO DM, hypoglycemic clamp, patients with T2DM.

Figure 2

Heart rate and change in HRV during hypoglycemia (HYPO) in patients with T2DM and control participants without diabetes. ○, EU clamp, control participants without diabetes; □, EU clamp patients with T2DM; ●, HYPO clamp, control participants without diabetes; ■, HYPO clamp, patients with T2DM. Data are mean (SE). *P < 0.05, **P < 0.01 compared with baseline; †P < 0.05 euglycemia (EU) vs. HYPO. HR, heart rate.

Figure 3

Blood pressure during hypoglycemia (HYPO) and euglycemia (EU) in patients with T2DM and control participants without diabetes. ○, EU clamp, control participants without diabetes; □, EU clamp patients with T2DM; ●, HYPO clamp, control participants without diabetes; ■, HYPO clamp, patients with T2DM. Data are mean (SE). *P < 0.05, **P < 0.01, ****P < 0.0001 compared with baseline; †P < 0.05, ††††P < 0.0001 EU vs. HYPO at equivalent time points.

Figure 4

Changes in cardiac repolarization during hypoglycemic (HYPO) and euglycemic (EU) clamps in patients with T2DM and control participants without diabetes. The T-wave symmetry (TS) is an index of T-wave morphology. The PCA ratio is the index of complexity of the T-wave morphology among the 12 leads. Data are mean (SE). Data from 9 control participants and 10 patients. *P < 0.05, **P < 0.01 compared with baseline; †P < 0.05, ††P < 0.01 EU vs. HYPO at equivalent time points.