Abstract

This proposal examines the effects of diet-induced obesity (DIO) and non-insulin dependent diabetes mellitus (NIDDM) on the ATP-sensitive K+ (K-ATP) channel located on neurons in the arcuate nucleus (ARC) which integrate metabolic signals concerning energy balance. The overall objective is to investigate the mechanisms by which arcuate glucosensing neurons sense and respond to changes in glucose homeostasis. To achieve this objective the following two hypotheses will be tested using a rodent model of DIO and NIDDM. HYPOTHESIS I is that the K-ATP channel regulates the generation of action potentials on ARC neurons by responding to changes in intracellular ATP. This hypothesis derives from our knowledge of the pancreatic beta-cell in which ATP is a critical regulator of K-ATP channel activity and insulin secretion. HYPOTHESIS II is that central and peripheral signals which regulate energy homeostasis will also regulate the ARC K-ATP channel via their effects on phosphorylation. These hypotheses will be tested using whole cell and single channel patch clamp recordings of ARC K-ATP channel currents in isolated cells as well as intact brain slices. These studies will provide new insights into the way in which the brain controls and is controlled by changes in glucose metabolism in obesity and diabetes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055619-04
Application #
6626977
Study Section
Metabolism Study Section (MET)
Program Officer
Sato, Sheryl M
Project Start
2000-02-01
Project End
2004-11-30
Budget Start
2003-01-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2003
Total Cost
$211,208
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

Showing the most recent 10 out of 21 publications