title: 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.
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, U.K.
authors.forename: Elaine
authors.initials: E
authors.lastname: Chow
authors.affiliation: INSIGNEO Institute for In Silico Medicine, University of Sheffield, Sheffield, U.K.|Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.
authors.forename: Alan
authors.initials: A
authors.lastname: Bernjak
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.
authors.forename: Emma
authors.initials: E
authors.lastname: Walkinshaw
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lubina-Solomon
authors.affiliation: Leeds Institute of Health Sciences, University of Leeds, Leeds, U.K.
authors.forename: Jenny
authors.initials: J
authors.lastname: Freeman
authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham, U.K.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Macdonald
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, U.K.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Sheridan
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K. s.heller@shef.ac.uk.
authors.forename: Simon R
authors.identifier: 0000-0002-2425-9565
authors.initials: SR
authors.lastname: Heller
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004562:Electrocardiography; D004837:Epinephrine / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D004837:Epinephrine