Cortical Fluoro-Jade staining and blunted adrenomedullary response to hypoglycemia after noncoma hypoglycemia in rats

• Published in: Journal of cerebral blood flow and metabolism Vol. 25; no. 12; pp. 1645 - 1655
• Main Authors: Tkacs, Nancy C, Pan, Yanhua, Raghupathi, Ramesh, Dunn-Meynell, Ambrose A, Levin, Barry E
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.12.2005; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Adrenal Medulla - physiopathology; Animals; Antihypertensive agents; Autonomic Nervous System - physiopathology; Biological and medical sciences; Biomarkers; Blood Glucose; Cardiovascular system; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Consciousness; Fluoresceins; Hypoglycemia - chemically induced; Hypoglycemia - pathology; Hypoglycemia - physiopathology; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacology; Insulin - blood; Insulin - pharmacology; Lactic Acid - blood; Male; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Organic Chemicals; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Vascular diseases and vascular malformations of the nervous system; visceral cortex; neuron death; insulin; central autonomic regulation; hypoglycemia; Nervous system diseases; Rat; Rodentia; Metabolic diseases; Hypoglycemia; Insulin; Cerebral disorder; Vertebrata; Mammalia; Animal; Central nervous system disease; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/sj.jcbfm.9600152

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 75mins. 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+ 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+ 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.