Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Abstract

Intensive insulin therapy in patients with type 1 diabetes mellitus reduces long-term complications; however, intensive therapy is also associated with a three-fold increase in hypoglycemic episodes. The present study in conscious rats characterizes the physiologic and neuropathologic consequences of a single episode of moderate hypoglycemia. In this model, intravenous insulin is used to reduce plasma glucose to 30 to 35 mg/dL for 75 mins. This single hypoglycemic insult acutely induces hypoglycemia-associated autonomic failure (HAAF), with epinephrine responses to hypoglycemia reduced more than 36% from control. Neuropathology after this insult includes the appearance of dying cells, assessed with the marker Fluoro-jade B (FJ). After hypoglycemic insult, FJ þ cells were consistently seen in subdivisions of the medial prefrontal cortex, the orbital cortex, and the piriform cortex. There was a significant correlation between depth of hypoglycemia and number of FJ þ cells, suggesting that there is a critical threshold below which vulnerable cells begin to die. These data suggest that there is a population of cells that are vulnerable to moderate levels of hypoglycemia commonly experienced by patients with insulin-treated diabetes. These cells, which may be neurons, are primarily found in cortical regions implicated in visceral perception and autonomic control, raising the possibility that their loss contributes to clinically reported deficits in autonomic and perceptual responses to hypoglycemia.

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

“…According to the present data, noncoma hypoglycemia leads to cell death in the parietal and frontal cortices, showing the parietal cortex the highest number of degenerating neurons. In contrast to previous studies, 28,29 we were unable to detect a significant number of FJB-positive neurons in the piriform cortex. This discrepancy, might be possibly attributed to some variations in the experimental protocols or to differences in strain vulnerability to hypoglycemic neuronal damage.…”

“…The present results agree with previous findings showing that prolonged noncoma hypoglycemia induces neuronal death mainly in the cerebral cortex 22,28,29 and add new information about the distribution of degenerating and ROS-producing cells. According to the present data, noncoma hypoglycemia leads to cell death in the parietal and frontal cortices, showing the parietal cortex the highest number of degenerating neurons.…”

From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease

“…This treatment was associated with significantly reduced epinephrine and norepinephrine elevations to hypoglycemic clamp, whereas glucagon and corticosterone were not significantly suppressed (Flanagan et al, 2003). In general, this phenomenon has been reproduced in several research laboratories studying rat responses to recurrent hypoglycemia (de Vries, Lawson, & Beverly, 2004;Evans et al, 2001;Shum et al, 2001;Tkacs et al, 2005).…”

“…The substantial advantage of the rodent model is the ability to follow up the hormone sampling phase of an experiment with euthanasia and postmortem examination of the brain and other relevant tissues to study correlated neuropathology and associated alterations (Tkacs et al, 2000(Tkacs et al, , 2005Yamada et al, 2004). An additional advantage is the ability to induce consistent and significantly low levels of hypoglycemia.…”

Severe Hypoglycemic Coma Event on MRI Specific Brain Necrosis

“…Experiments confirmed that some of the neuronal apoptosis can occur after hypoglycemic coma lasting 30 minutes [8], whereas glucose levels in the range of 1.7-1.9 mmol/l can lead to a prolonged coma due to irreversible neuronal death. In studies of insulininduced hypoglycemia in monkeys, 5-6 hours of blood glucose concentrations of less than 1.1mmol/L were required for the regular production of neurological damage [9]. Profound, prolonged hypoglycemia can cause brain death [8].…”