Submitted on November 18, 2008
Revised on February 13, 2009
Accepted on February 13, 2009
Insulin blunts the response of glucose-excited (GE) neurons in the ventrolateral-ventromedial hypothalamic nucleus (VL-VMN) to decreased glucose
Victoria Eugenia Cotero1 and Vanessa H. Routh2*
1 University of Medicine and Dentistry of NJ
2 New Jersey Medical School
* To whom correspondence should be addressed. E-mail: routhvh{at}umdnj.edu.
Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose sensing neurons. Glucose sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis such as the ventromedial hypothalamus (VMH). Our results indicate that insulin inhibited glucose excited (GE) neurons by opening the KATP channel in 5, 2.5, and 0.1mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1mM. This increase in glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol-3-kinase (PI3K) inhibitor wortmannin (wort; 10nM), but not by the mitogen activated kinase (MAPK) inhibitor PD98059 (PD; 50µM). Finally, neither the AMPK inhibitor Compound C, nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.
