title: High-Intensity Exercise as a Dishabituating Stimulus Restores Counterregulatory Responses in Recurrently Hypoglycemic Rodents.
abstract: Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (high-intensity exercise) to demonstrate two classic features of a habituated response, namely dishabituation and response recovery. We demonstrate that after recurrent hypoglycemia the introduction of a novel dishabituating stimulus (a single burst of high-intensity exercise) in male Sprague-Dawley rats restores the defective hypoglycemia counterregulatory response. In addition, the rats showed an enhanced response to the novel stimulus (response recovery). We make the further observation using proteomic analysis of hypothalamic extracts that high-intensity exercise in recurrently hypoglycemic rats increases levels of a number of proteins linked with brain-derived neurotrophic factor signaling. These findings may lead to novel therapeutic approaches for individuals with T1D and IAH.
authors.affiliation: Division of Molecular and Clinical Medicine, University of Dundee, Dundee, U.K.
authors.forename: Alison D
authors.initials: AD
authors.lastname: McNeilly
authors.affiliation: Division of Molecular and Clinical Medicine, University of Dundee, Dundee, U.K.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gallagher
authors.affiliation: Division of Molecular and Clinical Medicine, University of Dundee, Dundee, U.K.
authors.forename: Jeffrey T-J
authors.initials: JT
authors.lastname: Huang
authors.affiliation: Division of Molecular and Clinical Medicine, University of Dundee, Dundee, U.K.
authors.forename: Michael L J
authors.initials: MLJ
authors.lastname: Ashford
authors.affiliation: Division of Molecular and Clinical Medicine, University of Dundee, Dundee, U.K. r.mccrimmon@dundee.ac.uk.
authors.forename: Rory J
authors.identifier: 0000-0002-3957-1981
authors.initials: RJ
authors.lastname: McCrimmon
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001364:Awareness; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015309:Glucose Clamp Technique; D006185:Habituation, Psychophysiologic; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000009:adverse effects; D008297:Male; D008568:Memory; D010468:Perceptual Disorders / Q000378:metabolism* / Q000523:psychology; D010805:Physical Conditioning, Animal; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D007328:Insulin