Glucose-Sensing by Neurons: its Importance and the Role of UCP2 Glucose-sensing by the brain is a well documented phenomenon with potentially important implications for the pathogenesis of type 2 diabetes. Prior electrophysiological studies have determined that subpopulations of neurons are regulated by glucose. As glucose rises, """"""""glucose-excited"""""""" neurons depolarize and increase their firing rate. Examples of glucose-excited neurons include POMC neurons in the arcuate nucleus, MCH neurons in the lateral hypothalamus and a subgroup of neurons in the ventromedial hypothalamus (VMH). The molecular apparatus responsible for excitation by glucose is thought to have similarities to that found in pancreatic (3-cells. Specifically, neuronal oxidation of glucose and/or lactate (thelatter generated by glucose metabolism in glial cells), increases the ATP/ADP ratio. This then closes neuronal KATP channels, depolarizing the neuron which then increases its firing rate. While the phenomenon of """"""""P-cell-like"""""""" glucose- sensing in the brain is robust, its physiologic relevance and its contribution to disease states such as type 2 diabetes, is unknown. The overall goal of these studies is to assess the role of """"""""p-cell-like"""""""" glucose-sensing by neurons in normal physiology and in the development of type 2 diabetes. This will be accomplished through the use of genetically engineered mice. First, we will disrupt """"""""P-cell-like"""""""" glucose-sensing in a neuron-specific fashion, through transgenic expression of a mutant KATP channel, and then determine if this adversely affects insulin / glucose homeostasis (Aim 1). Second, we will determine if uncoupling protein-2 (UCP2) negatively regulates """"""""P-cell-like"""""""" glucose-sensing in neurons and whether this could be a cause of defective glucose-sensing in type 2 diabetes (Aim 2). Third, we will determine if absence of UCP2 in neurons, which we predict will prevent loss of glucose-sensing, improves obesity-induced impairments in insulin / glucose homeostasis (Aim 3). Studies proposed in this application could provide novel insight into the role of the brain in the pathogenesis of type 2 diabetes. Such insight could result in novel treatments for this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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Beth Israel Deaconess Medical Center
United States
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