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Abstract

Type 2 Diabetes Mellitus (TD2M), characterized by fasting and post-prandial glucose intolerance and β-cell dysfunction, is an epidemic in the United States that continues to worsen. Despite the various therapeutics that successfully treats T2DM, the rate of this disease continues to rise. The Central Nervous System (CNS) has been implicated in controlling metabolic homeostasis; however, much is still unknown about the various ways the CNS, more specifically the hypothalamus, regulate whole body metabolic homeostasis. Our research investigated the role of insulin signaling in the hypothalamus on pancreatic islet cell function. From previous work, we established a circuit that connects the hypothalamus to the pancreatic islet, and utilized this map to investigate the activation of the circuit in the presence of insulin signaling in the different areas of the hypothalamus. We came upon the discovery that insulin significantly activates the CNS-Islet circuit in the Ventromedial Nucleus (VMN) compared to the other areas of the hypothalamus. ,With this information, we decided to investigate the role of insulin signaling in the VMN on pancreatic islet function by knocking out the insulin receptor in the VMN of Insulin Receptor floxed mice. Using the stereotaxic apparatus, we delivered an Adenovirus carrying Cre-Recombinase or β-galactosidase into the VMN of these mice (VMN-Cre or VMN-LacZ) and conducted metabolic tests, which showed mild glucose intolerance with a robust counter-regulatory response, but no change in insulin or glucagon levels. These mice also seemed to conserve glucose reserves and utilize fat, based on the Respiratory Exchange Ratio (RER). However, in a pilot study, we showed that if we extended the study on these mice, they eventually became glucose intolerant with severe hyperinsulinemia. Further study needs to be done to investigate long term insulin resistance in the VMN on pancreatic islet cell function.

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