title: Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport.
abstract: A common complication of type 1 diabetes mellitus is diabetic ketoacidosis (DKA), a state of severe insulin deficiency. A potentially harmful consequence of DKA therapy in children is cerebral edema (DKA-CE); however, the mechanisms of therapy-induced DKA-CE are unknown. Our aims were to identify the DKA treatment factors and membrane mechanisms that might contribute specifically to brain cell swelling. To this end, DKA was induced in juvenile mice with the administration of the pancreatic toxins streptozocin and alloxan. Brain slices were prepared and exposed to DKA-like conditions in vitro. Cell volume changes were imaged in response to simulated DKA therapy. Our experiments showed that cell swelling was elicited with isolated DKA treatment components, including alkalinization, insulin/alkalinization, and rapid reductions in osmolality. Methyl-isobutyl-amiloride, a nonselective inhibitor of sodium-hydrogen exchangers (NHEs), reduced cell swelling in brain slices elicited with simulated DKA therapy (in vitro) and decreased brain water content in juvenile DKA mice administered insulin and rehydration therapy (in vivo). Specific pharmacological inhibition of the NHE1 isoform with cariporide also inhibited cell swelling, but only in the presence of the anion transport (AT) inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid. DKA did not alter brain NHE1 isoform expression, suggesting that the cell swelling attributed to the NHE1 was activity dependent. In conclusion, our data raise the possibility that brain cell swelling can be elicited by DKA treatment factors and that it is mediated by NHEs and/or coactivation of NHE1 and AT.
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada;
authors.forename: Keeley L
authors.initials: KL
authors.lastname: Rose
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Watson
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada; Department of Paediatrics, Western University, London, Ontario, Canada;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drysdale
authors.affiliation: Centre for Critical Illness Research, London, Ontario, Canada;
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada;
authors.forename: Melissa
authors.initials: M
authors.lastname: Chan
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada; Department of Paediatrics, Western University, London, Ontario, Canada;
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Rupar
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada; Centre for Critical Illness Research, London, Ontario, Canada; Department of Paediatrics, Western University, London, Ontario, Canada; Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada; and Translational Research Centre, London, Ontario, Canada douglas.fraser@lhsc.on.ca.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fraser
mesh_terms: D000496:Alloxan; D000818:Animals; D000838:Anions / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D005440:Fluid Therapy / Q000009:adverse effects; D007328:Insulin / Q000009:adverse effects; D017136:Ion Transport / Q000502:physiology*; D051379:Mice; D009924:Organ Culture Techniques; D009994:Osmolar Concentration; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism / Q000502:physiology*; D013311:Streptozocin
chemical_list: D000838:Anions; D007328:Insulin; D017923:Sodium-Hydrogen Exchangers; D013311:Streptozocin; D000496:Alloxan
keywords: anion transport; cell swelling; children; diabetic ketoacidosis; sodium-hydrogen exchangers; treatment