Vanessa H. Routh, Ph.D.
Department of Pharmacology and Physiology
UMDNJ - New Jersey Medical School
Medical Sciences Building, I619
185 S. Orange Avenue
Newark, NJ 07103
Labs: I628, I675 & I671
Office Phone (973)972-1489
Lab Phone (973) 972-0312
Postdoctoral Fellow: Zhentao Song, Ph.D; Xiaohong Liu, M.D.
Technician: Lauren Avenia
Graduate Student: Ruokun Wang; Debra Cinco
routhvh@umdnj.edu
Neuronal Glucose Sensing in Health, Obesity and Diabetes
The focus of my research is the dysfunctional coupling between energy balance and
neuronal activity that occurs in diet-induced obesity (DIO) and type 2 diabetes mellitus.
Central dysfunction is well documented in obesity and diabetes. However, little is known
about the way that the brain actually senses glucose. There are neurons in the brain which
change their firing rate in response to changes in extracellular glucose levels. It is
hypothesized that these neurons may be involved in the regulation of food intake, body weight
and glucose homeostasis. However, the majority of studies on these glucose sensing neurons
have been performed using extracellular glucose levels which are well outside the physiologic
range. This raises considerable concern about the physiologic relevance of these neurons.
Thus, a major thrust in my laboratory is to characterize hypothalamic glucose sensing
neurons using levels of extracellular glucose within the physiologic range. In addition, I am
using a rodent model of DIO and type 2 diabetes mellitus to determine whether alterations in
glucose sensing neurons may be involved in their dysfunctional central glucose sensing.
Patch clamp techniques in both intact brain slices and freshly dissociated neurons are being
used to address these issues. Recent studies in my laboratory indicate that these neurons do
sense changes in extracellular glucose levels which span the physiologic range. Moreover,
these studies revealed the presence of novel subtypes of glucose sensing neurons that are
sensitive to specific changes in extracellular glucose within the physiologic range. These
subtypes of glucose sensing neurons may allow the brain to differentially regulate the
response to hypo- and hyperglycemia, and well as monitoring small variations in extracellular
glucose associated with meal patterns. Another aspect of my research involves the
mechanism(s) by which these neurons themselves sense glucose. Certain subtypes of
glucose sensing neurons possess an ATP sensitive K+ (K-ATP) channel similar to that on the
pancreatic beta cell. This K-ATP channel enables the beta cell to secrete insulin in response
to increasing plasma glucose. In the brain, the K-ATP channel is found on both cell bodies
and nerve terminals. Closure of the K-ATP channel on cell bodies by ATP increases action
potential frequency. In contrast, closure of the K-ATP channel on nerve terminals increases
neurotransmitter release. Thus, the K-ATP channel may serve as neuronal glucose sensor
which links metabolic state with neuronal activity. Interestingly, our recent work suggests that
central glucose sensing involves a complex interaction between K-ATP channels on cell
bodies and nerve terminals. Moreover, we have found that the ATP sensitivity of the K-ATP
channel is reduced by 50% in rats that are prone to develop DIO and diabetes. Finally, the
phenotype of these neurons is completely unknown. Thus, single cell PCR analysis will be
used in conjunction with these electrophysiologic studies of glucosensing neurons in order to
phenotype them with regard to channel subtypes and neurotransmitter systems.
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Routh, V.H., McArdle, J.J., and Levin, B.E. Phosphorylation modulates the activity of
the ATP-sensitive K+ channel in the ventromedial hypothalamic nucleus. Brain Res.
778: 107-119, 1997.
Levin, B.E., and Routh, V.H. The role of the brain in energy balance. Am. J. Physiol.
271(40): R491-R500, 1996.
Spanswick, D., Smith, M.A., Mirshamsi, S., Routh, V.H. and M.L.J. Ashford. Insulin
activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese
rats. Nature Neuroscience 3(8): 757-758, 2000.