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Victoria Cotero
Pharmacology and Physiology

BS, 2003 Fairleigh Dickerson University

Thesis Advisor: Vanessa Routh, Ph.D.
Associate Professor
Pharmacology and Physiology

MSB H 609
Conference Room

Wednesday, April 29, 2009
3:30 p.m.


Obesity and type 2 diabetes mellitus (T2DM) are associated with dysfunctional insulin signaling. Moreover, central glucose sensing mechanisms are impaired in these diseases. Glucose sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Since the central effect of insulin is to promote satiety and increase energy expenditure we hypothesized that insulin would attenuate the ability of glucose-excited (GE) neurons to sense energy deficit (e.g. decreased glucose). Furthermore, we predict that the effect of insulin on GE neurons will be impaired in mice with T2DM.
Whole-cell patch clamp recordings were made in brain slices containing the VMH from 14-21 day old male Sprague-Dawley rats, 14-21 and 35-45 day old C57BLK/6J (wild-type) mice, and 35-45 day old C57BLKs-m-Leprdb (db/db) mice. GE neurons were concentrated in the ventrolateral region of the ventromedial nucleus (VL-VMN) within the VMH. That is, 3.2% of neurons in the lateral arcuate nucleus within the VMH were GE neurons compared to 19.6% of neurons in the VL-VMN. The glucose sensitivity of these neurons was greatest as glucose decreased below 2.0mM. Insulin directly inhibited 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 levels from 2.5 to 0.1mM in wild-type Sprague-Dawley rats and wild-type mice via activation of the phosphotidylinositol-3-kinase (PI3K) pathway. However, insulin administration had no significant effect on the glucose sensitivity of VL-VMN GE neurons from adult diabetic db/db mice. The Merck small molecule insulin sensitizer, compound 2, restored the effect of insulin on VL-VMN GE neurons from db/db mice. 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. However, in T2DM, central insulin resistance increases the response of VL-VMN GE neurons to decreased glucose. We hypothesize that in T2DM, GE neurons signal for energy deficit in the presence of energy sufficiency leading to activation of compensatory mechanisms. This compensation may contribute to the development of obesity and T2DM.

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