Abstract

This proposal investigates the effects of insulin and leptin on the glucose sensitivity of glucose sensing neurons (GSNs) in the hypothalamic arcuate nucleus (ARC). The overall objective is to gain a clear understanding of (a) how the glucose sensitivity of ARC GSNs is regulated by ambient levels of insulin and leptin and (b) how the dysfunctional signaling pathways for these neuronal signals seen in obesity and type 2 diabetes mellitus (T2DM) alter the function of ARC GSNs. The 2 hypotheses in this proposal directly address these issues. Hypothesis I is that insulin and leptin modulate the glucose sensitivity of ARC GSNs. The corollary to hypothesis I is that the dysfunctional insulin and leptin signaling which occurs during obesity and T2DM contributes to the impaired glucose sensitivity of ARC GSNs. Hypothesis II is the nitric oxide (NO) signal transduction pathway is a point of convergence in the regulation of ARC GSNs by glucose, insulin and leptin. The first set of experiments proposed herein will define the glucose concentration response relationships for ARC GNSs in the presence of insulin and leptin. We will also explore the cellular pathways underlying the interactions between glucose, insulin and leptin so that the mechanisms that underlie any change in responsiveness can be understood. We will then determine whether or how the responses are altered during obesity and T2DM. The second set of experiments will examine the hypotheis that NO provides a novel signal transduction pathway at which glucose, insulin and leptin signaling converges. We will also test the hypothesis that NO provides a mechanism for the glucose-induced presynaptic modulation of neuronal activity which we have observed. These studies will provide important information regarding the way that the brain integrates signals of overall energy status and how this system is altered during obesity and T2DM. This will facilitate the development of new and effective treatments for these serious diseases of the modern world.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK055619-06
Application #
6875269
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Sato, Sheryl M
Project Start
2000-02-01
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
6
Fiscal Year
2005
Total Cost
$280,092
Indirect Cost

  Institution

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

  Publications

Reno, Candace M; Puente, Erwin C; Sheng, Zhenyu et al. (2017) Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation. Diabetes 66:587-597
Vazirani, Reema P; Fioramonti, Xavier; Routh, Vanessa H (2013) Membrane potential dye imaging of ventromedial hypothalamus neurons from adult mice to study glucose sensing. J Vis Exp :
Fioramonti, Xavier; Song, Zhentao; Vazirani, Reema P et al. (2011) Hypothalamic nitric oxide in hypoglycemia detection and counterregulation: a two-edged sword. Antioxid Redox Signal 14:505-17
Diggs-Andrews, Kelly A; Zhang, Xuezhao; Song, Zhentao et al. (2010) Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes 59:2271-80
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
Cotero, V E; Zhang, B B; Routh, V H (2010) The response of glucose-excited neurones in the ventromedial hypothalamus to decreased glucose is enhanced in a murine model of type 2 diabetes mellitus. J Neuroendocrinol 22:65-74
Routh, Vanessa H (2010) Glucose sensing neurons in the ventromedial hypothalamus. Sensors (Basel) 10:9002-25
Murphy, Beth Ann; Fakira, Kurt A; Song, Zhentao et al. (2009) AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297:C750-8
Murphy, Beth Ann; Fioramonti, Xavier; Jochnowitz, Nina et al. (2009) Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose. Am J Physiol Cell Physiol 296:C746-56
Cotero, Victoria E; Routh, Vanessa H (2009) Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab 296:E1101-9

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