Circulating glucose concentration is monitored and maintained at appropriate concentrations by the central nervous system (CNS). Physiological and behavioral responses to glucose imbalances have been described, but the key mechanism by which fluctuations in glucose status are recognized and appropriate counter-regulatory responses initiated is not known. The immediate objective of the proposed research is to identify underlying neurochemical mechanisms in the ventral hypothalamus that sense changes in plasma glucose and initiate counterregulatory responses to restore glucose status. Noradrenergic activity in the ventromedial hypothalamus (VMH) has been demonstrated to influence blood glucose through effects on the autonomic nervous system, behavior, and neuroendocrine system. We have reported a consistent activation of noradrenergic systems in the VMH during hypoglycemia.
The specific aims of this application are to determine the glycemic thresholds for the activation of noradrenergic systems in the VMH, to evaluate the effect of changes in interstitial fluid glucose concentrations in the VMH on noradrenergic activation, to determine if the activation of noradrenergic systems in the VMH is mediated through local intrinsic neurons within the VMH, to the effect of recurrent hypoglycemia on the noradrenergic activation in the VMH, and determine if increased levels of circulating leptin alter sensitivity of noradrenergic response to hypoglycemia. Intravenous catheters and microdialysis probes will be used to simultaneously monitor plasma glucose and concentrations of extracellular neurotransmitters in the VMH. Our hypothesis is that glucose responsive neurons in the VMH respond to changes in extracellular glucose concentrations that reflect circulating plasma glucose and activates noradrenergic inputs to the hypothalamus. The activation of these neurons is dynamic, so that the glycemic threshold for activating NE systems in the VMH will be altered by recurrent episodes of hypoglycemia. Further, we propose that leptin affects the sensitivity of glucose response neurons to interstitial glucose concentrations thereby altering the glycemic threshold for activation of glucoregulatory systems in the VMH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059755-03
Application #
6524527
Study Section
Special Emphasis Panel (ZNS1-SRB-W (02))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$229,500
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Barnes, Meredith B; Lawson, Marcus A; Beverly, J Lee (2011) Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 301:R1815-20
Fugo, Kelly R; Lawson, Marc A; Lee Beverly, J (2006) Ibotenic acid lesions reduce noradrenergic activation in ventromedial hypothalamus during hypoglycemia. Brain Res 1111:105-10
de Vries, Martin G; Lawson, Marcus A; Beverly, J Lee (2005) Hypoglycemia-induced noradrenergic activation in the VMH is a result of decreased ambient glucose. Am J Physiol Regul Integr Comp Physiol 289:R977-81
de Vries, Martin G; Lawson, Marcus A; Beverly, J Lee (2004) Dissociation of hypothalamic noradrenergic activity and sympathoadrenal responses to recurrent hypoglycemia. Am J Physiol Regul Integr Comp Physiol 286:R910-5
de Vries, Martin G; Arseneau, Linda M; Lawson, Marcus E et al. (2003) Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes 52:2767-73