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.
Highlights
The brain stores minimal glucose, mainly in the form of astrocytic glycogen [1,2,3] and is dependent upon a regular supply of glucose from circulating blood [4]
Optimization of STZ dosage in Juvenile Rodents While the STZ model of diabetes induction has been widely demonstrated in adult rodents [46] and more recently in younger animals [43,44], a model of hypoglycemic seizures in young diabetic animals has not been established
Diabetes was confirmed through blood glucose (BG) measurement from a tail vein blood sample after STZ administration
Summary
The brain stores minimal glucose, mainly in the form of astrocytic glycogen [1,2,3] and is dependent upon a regular supply of glucose from circulating blood [4]. Hypoglycemia is the major limiting factor in the management of Type 1 diabetes [5,6,7,8] with patients experiencing an average of 2 episodes per week [9]. Hypoglycemia can lead to seizures and coma, with generalized seizures being the major acute complication [10] occurring in children [11] and adolescents [12]. Devastating effects, such as the ‘‘dead in bed’’ syndrome, possibly due to hypoglycemic seizures [13], occur approximately 3 times more frequently in young people with diabetes than in those without [14]. Studies evaluating the relationship between hypoglycemia and cognitive dysfunction have yielded conflicting results. Some studies have suggested that hypoglycemia results in cognitive decline [15–
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