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Diabetes 53:1230-1236, 2004
© 2004 by the American Diabetes Association, Inc.

Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses

Nicole M. Sanders1, Ambrose A. Dunn-Meynell1,2, and Barry E. Levin1,2

1 Department of Neurology and Neurosciences, New Jersey Medical School, Newark, New Jersey
2 Neurology Service, Veterans Affairs Medical Center, Neurology Service, East Orange, New Jersey

Glucokinase (GK) is hypothesized to be the critical glucosensor of pancreatic ß-cells and hypothalamic glucosensing neurons. To understand the role of GK in glucoprivic counterregulatory responses, we injected alloxan, a GK inhibitor and toxin, into the third ventricle (3v) to target nearby GK-expressing neurons. Four and 6 days after 3v, but not 4v, alloxan injection, alloxan-treated rats ate only 30% and their blood glucose area under the curve was only 28% of saline controls’ after systemic 2-deoxy-D-glucose. In addition, their hyperglycemic response to hindbrain glucoprivation induced with 5-thio-glucose was impaired, whereas fasting blood glucose levels and food intake after an overnight fast were elevated. These impaired responses were associated with the destruction of 3v tanycytes, reduced glial fibrillary acidic protein-immunoreactivity surrounding the 3v, neuronal swelling, and decreased arcuate nucleus neuropeptide Y (NPY) mRNA. Nevertheless, hypothalamic GK mRNA was significantly elevated. Two weeks after alloxan injection, 3v tanycyte destruction was reversed along with restoration of feeding and hyperglycemic responses to both systemic and hindbrain glucoprivation. At this time there were significant decreases in GK, NPY, and proopiomelanocortin mRNA. Thus, neural substrates near and around the 3v affected by alloxan may be critically involved in the expression of these glucoprivic responses.

Address correspondence and reprint requests to Barry E. Levin, MD, Neurology Service (127C), VA Medical Center, 385 Tremont Ave., E. Orange, NJ 07018-1095. E-mail: levin{at}umdnj.edu


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Copyright © 2004 by the American Diabetes Association.