This proposal investigates the effects of recurrent hypoglycemia on glucose sensing neurons in the ventromedial hypothalamic nucleus (VMN). The overall objective is to gain a clearer understanding of (a) how changes in glucose are transduced into neuronal signals, and (b) how those neuronal signals are integrated to initiate the counterregulatory response to hypoglycemia. The two hypotheses in this proposal directly address these issues. HYPOTHESIS I is that VMN glucose sensing neurons have the potential to sense impending hypoglycemia and signal for the initiation of the counterregulatory response. This hypothesis derives from our knowledge of the ability of VMN glucose sensing neurons to respond to physiologically relevant changes in extracellular glucose. HYPOTHESIS II is that VMN glucose sensing neurons receive information from and project to brain regions important to the regulation of glucose homeostasis. The first set of experiments proposed herein will define the responsiveness of physiologically relevant subtypes of VMN glucose sensing neurons over physiological glucose concentrations. We will then determine whether or how the responses are altered by recurrent hypoglycemia sufficient to induce hypoglycemia associated autonomic failure. We will also explore the cellular mechanism of glucose sensing transduction so that the mechanisms that underlie any change in responsiveness can be understood. The second set of experiments will provide the basis for understanding the potential integrative role of VMN glucose sensing neurons. This will be accomplished by identifying presynaptic inputs and transmitters to the VMN from other glucose sensing neurons and identifying the hypothalamic targets of VMN glucose sensing neurons. These studies will provide important information regarding the way that the brain regulates glucose homeostasis and the way that perturbations in glucose homeostasis alter these central mechanisms. This will facilitate the development of new and effective treatments for Type I diabetes mellitus and its major modern complication hypoglycemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064566-02
Application #
6668526
Study Section
Special Emphasis Panel (ZNS1-SRB-R (03))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2002-09-30
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$349,875
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Fioramonti, Xavier; Deak, Adam; Deshpande, Srinidhi et al. (2013) Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia. PLoS One 8:e68709
Fioramonti, Xavier; Marsollier, Nicolas; Song, Zhentao et al. (2010) Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation. Diabetes 59:519-28
Routh, Vanessa H (2010) Glucose sensing neurons in the ventromedial hypothalamus. Sensors (Basel) 10:9002-25
Kang, Ling; Sanders, Nicole M; Dunn-Meynell, Ambrose A et al. (2008) Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. Am J Physiol Regul Integr Comp Physiol 294:R784-92
Fioramonti, Xavier; Contie, Sylvain; Song, Zhentao et al. (2007) Characterization of glucosensing neuron subpopulations in the arcuate nucleus: integration in neuropeptide Y and pro-opio melanocortin networks? Diabetes 56:1219-27
Canabal, Debra D; Song, Zhentao; Potian, Joseph G et al. (2007) Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 292:R1418-28
Canabal, Debra D; Potian, Joseph G; Duran, Ricardo G et al. (2007) Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 293:R592-600
Song, Zhentao; Routh, Vanessa H (2006) Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus. Am J Physiol Regul Integr Comp Physiol 291:R1283-7
Wang, R; Cruciani-Guglielmacci, C; Migrenne, S et al. (2006) Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels. J Neurophysiol 95:1491-8
Kang, Ling; Dunn-Meynell, Ambrose A; Routh, Vanessa H et al. (2006) Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes 55:412-20

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