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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/R784    most recent 00645.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Google Scholar Articles by Kang, L. Articles by Levin, B. E. PubMed PubMed Citation Articles by Kang, L. Articles by Levin, B. E.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Departments of ¹Neurology and Neurosciences and ⁵Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry, Newark; ⁴Neurology Service, Veterans Affairs Medical Center, East Orange, New Jersey; ²Division of Endocrinology/Metabolism, Veterans Affairs Puget Sound Health Care System, and ³Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington

Submitted 7 September 2007 ; accepted in final form 17 December 2007

Antecedent insulin-induced hypoglycemia (IIH) reduces adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia. The ventromedial hypothalamus [VMH: arcuate (ARC) + ventromedial nuclei] contains glucosensing neurons, which are thought to be mediators of these AMR. Since type 1 diabetes mellitus often begins in childhood, we used juvenile (4- to 5-wk-old) rats to demonstrate that a single bout of IIH (5 U/kg sc) reduced plasma glucose by 24% and peak epinephrine by 59% 1 day later. This dampened AMR was associated with 46% higher mRNA for VMH glucokinase, a key mediator of neuronal glucosensing. Compared with neurons from saline-injected rats, ventromedial nucleus glucose-excited neurons from insulin-injected rats demonstrated a leftward shift in their glucose responsiveness (EC₅₀ = 0.45 and 0.10 mmol/l for saline and insulin, respectively, P = 0.05) and a 31% higher maximal activation by glucose (P = 0.05), although this maximum occurred at a higher glucose concentration (saline, 0.7 vs. insulin, 1.5 mmol/l). Although EC₅₀ values did not differ, ARC glucose-excited neurons had 19% higher maximal activation, which occurred at a lower glucose concentration in insulin- than saline-injected rats (saline, 2.5 vs. insulin, 1.5 mmol/l). In addition, ARC glucose-inhibited neurons from insulin-injected rats were maximally inhibited at a fivefold lower glucose concentration (saline, 2.5 vs. insulin, 0.5 mmol/l), although this inhibition declined at >0.5 mmol/l glucose. These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR.

glucokinase; counterregulatory response; hypoglycemia-associated autonomic failure; calcium imaging; arcuate nucleus; ventromedial nucleus; ventromedial hypothalamus

This article has been cited by other articles:

				B. E. Levin, T. C. Becker, J.-i. Eiki, B. B. Zhang, and A. A. Dunn-Meynell Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia Diabetes, May 1, 2008; 57(5): 1371 - 1379. [Abstract] [Full Text] [PDF]