title: Severe hypoglycemia in a juvenile diabetic rat model: presence and severity of seizures are associated with mortality.
abstract: It is well accepted that insulin-induced hypoglycemia can result in seizures. However, the effects of the seizures, as well as possible treatment strategies, have yet to be elucidated, particularly in juvenile or insulin-dependent diabetes mellitus (IDDM). Here we establish a model of diabetes in young rats, to examine the consequences of severe hypoglycemia in this age group; particularly seizures and mortality. Diabetes was induced in post-weaned 22-day-old Sprague-Dawley rats by streptozotocin (STZ) administered intraperitoneally (IP). Insulin IP (15 U/kg), in rats fasted (14-16 hours), induced hypoglycemia, defined as <3.5 mM blood glucose (BG), in 68% of diabetic (STZ) and 86% of control rats (CON). Seizures occurred in 86% of STZ and all CON rats that reached hypoglycemic levels with mortality only occurring post-seizure. The fasting BG levels were significantly higher in STZ (12.4 ± 1.3 mM) than in CON rodents (6.3 ± 0.3 mM), resulting in earlier onset of hypoglycemia and seizures in the CON group. However, the BG at seizure onset was statistically similar between STZ (1.8 ± 0.2 mM) and CON animals (1.6 ± 0.1 mM) as well as between those that survived (S+S) and those that died (S+M) post-seizure. Despite this, the S+M group underwent a significantly greater number of seizure events than the S+S group. 25% glucose administered at seizure onset and repeated with recurrent seizures was not sufficient to mitigate these continued convulsions. Combining glucose with diazepam and phenytoin significantly decreased post-treatment seizures, but not mortality. Intracranial electroencephalograms (EEGs) were recorded in 10 CON and 9 STZ animals. Predictive EEG changes were not observed in these animals that underwent seizures. Fluorojade staining revealed damaged cells in non-seizing STZ animals and in STZ and CON animals post-seizure. In summary, this model of hypoglycemia and seizures in juvenile diabetic rats provides a paradigm for further study of underlying mechanisms. Our data demonstrate that severe hypoglycemia (<2.0 mM) is a necessary precondition for seizures, and the increased frequency of these seizures is associated with mortality.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: Maheandiran
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shanthini
authors.initials: S
authors.lastname: Mylvaganam
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Chiping
authors.initials: C
authors.lastname: Wu
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Youssef
authors.initials: Y
authors.lastname: El-Hayek
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sugumar
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario Canada.
authors.forename: Lili
authors.initials: L
authors.lastname: Hazrati
authors.affiliation: Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: del Campo
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada ; Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Carlen
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000401:mortality; D003975:Diazepam / Q000627:therapeutic use; D004569:Electroencephalography; D005947:Glucose / Q000627:therapeutic use; D007003:Hypoglycemia / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000150:complications* / Q000188:drug therapy / Q000401:mortality
chemical_list: D001786:Blood Glucose; D005947:Glucose; D003975:Diazepam