Vanessa H. Routh, PhD

Clinical Investigations and Precision Therapeutics Program

Academic Appointment

Professor
Department of Pharmacology, Physiology, and Neuroscience
New Jersey Medical School
Rutgers, The State University of New Jersey

Links

• Department of Pharmacology, Physiology & Neuroscience Profile

Research Interests

• Central Mechanisms in the Regulation of Energy Balance
• Disease Applications: Type 1 and 2 Diabetes Mellitus, Insulin-Induced Hypoglycemia, Hypoglycemia-Associated-Autonomic-Failure, Obesity, Disease-related Anorexia and/or Cachexia
• At the present time, there are 3 major areas of research in our laboratory which investigates dysfunctional glucose sensing by GE and GI neurons during the following disease-related abnormalities in whole body energy and/or glucose homeostasis:
• 1. Hypoglycemia-associated autonomic failure (HAAF). Insulin therapy in patients with Type 1 or advanced Type 2 Diabetes Mellitus is required to prevent complications of hyperglycemia. However, intensive insulin therapy has a severe side effect: hypoglycemia. Unfortunately, even one episode of hypoglycemia can impair the ability of the brain to sense hypoglycemia and initiate corrective mechanisms to restore blood glucose levels, a condition known as HAAF. We have found that the ability of glucose sensing neurons to sense glucose deficit is also impaired in an animal model of HAAF. This may be due, in part, to nitric oxide resistance in GI neurons as a result of increased oxidative stress during hypoglycemia.
• 2. Type 2 Diabetes Mellitus (T2DM) and Obesity . The satiety hormones, insulin and leptin, prevent GE and GI neurons, respectively, from responding to small glucose decreases. We believe that this prevents the activation of strong compensatory metabolic circuits in response to decreases in glucose seen between meals. However, glucose sensing neurons become sensitized to decreased glucose under conditions where insulin and leptin levels are low (e.g., fasting) or as a result of insulin resistance during T2DM. We hypothesize that increased sensitivity of glucose sensing to small daily decreases in glucose may lead to signals of energy and/or glucose deficit in the presence of energy sufficiency or even excess. Such changes in glucose sensitivity may lead to activation of mechanisms which favor energy storage over expenditure and exacerbate obesity and diabetes.
• 3. Disease-related anorexia cachexia . This new project in our laboratory tests the hypothesis that the sensitivity of glucose sensing neurons to glucose deficit becomes impaired in diseases associated with anorexia and cachexia (e.g., inflammation, cancer). Such a change in glucose sensitivity would lead to the opposite effect as that described above. Under these conditions, glucose decreases would not be detected and compensatory mechanisms would not be initiated even under conditions of severe energy deficit. Our data using models of sepsis and cancer anorexia are consistent with this hypothesis.
• In order to address these issues we use a variety of in vivo and in vitro techniques including electrophysiology (patch clamp) in brain slices and isolated neurons, microscopy/imaging in primary hypothalamic cultures, hypothalamic peptide release, stereotaxic surgery and hyperinsulinemic/hypoglycemic clamps in vivo , as well as standard immunohistochemical, biochemical and molecular techniques.