Abstract
Recurrent hypoglycemia (RH) is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp), a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and prefrontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e., less time spent in the open arms of the plus-maze). The results show that RH has widespread effects on subsequent brain function, which vary by neural system.
Highlights
The opening paragraph of a recent commentary [1] describes the significance of recurrent hypoglycemia (RH) vividly: “[RH] is the limiting factor in the glycemic management of diabetes
The majority of work studying RH and the brain has been in the context of RH-induced hypoglycemiaassociated autonomic failure (HAAF): unawareness of and inability to respond to hypoglycemia that can in extremes lead to coma and death, focusing on detection of glucose levels in the ventromedial hypothalamus (VMH) [5,6,7,8]
That hypothesis is supported by the findings reported here: we show using an elevated plus-maze task that after RH, rats show no change in anxiety or amygdala norepinephrine (NEp) release when measured at euglycemia, but are significantly more anxious during subsequent hypoglycemia, accompanied by elevated amygdala NEp release
Summary
The opening paragraph of a recent commentary [1] describes the significance of recurrent hypoglycemia (RH) vividly: “[RH] is the limiting factor in the glycemic management of diabetes. It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. Cognitive impairment is especially prevalent during subsequent hypoglycemia, which can have profound consequences: for instance, car accidents are a leading cause of death among diabetic patients, linked to impaired judgment during hypoglycemia [10,11,12,13, 18]
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