Project Summary/Abstract Endogenous glucose production (EGP) is a crucial process that maintains blood glucose levels under fasting conditions and is normally inhibited by both glucose and insulin. Inappropriately high EGP is the major source of hyperglycemia in individuals with type 2 diabetes (T2D) and contributes significantly to diabetes complications. Our groups’ ongoing work suggests that central nervous system (CNS) signals play an important role in regulating EGP. ATP-sensitive potassium (KATP) channels in the ventromedial hypothalamus (VMH) appear to mediate some of the suppressive effects of circulating insulin and glucose on EGP, but this regulation is impaired in T2D and diabetic rodents. We have observed that lowering free fatty acid (FFA) levels completely restored the regulation of EGP by central KATP channel activation. Therefore, we hypothesize that chronic lipid overload may contribute to the central signaling defects in T2D. Thus, through complementary human and rodent studies we propose to expand our understanding of how specific CNS signaling pathways regulate EGP through the following specific aims: 1) To establish whether central regulation of EGP can be restored by lowering FFA levels in patients with T2D, 2) To determine whether intact hepatic innervation is required for restoration of central regulation of EGP upon lowering FFA in individuals with T2D, and 3) To establish whether the impaired central regulation of EGP in T2D is mediated by neuron-specific defects in KATP channel activation within the VMH. Furthermore, we will determine whether lowering FFA levels contributes to restoring central regulation of glucose production by reducing endoplasmic reticulum (ER) stress in specific glucose-sensing neurons. Collectively, these studies should provide mechanistic explanation(s) for the impaired central regulation of EGP in T2D and help point toward novel therapeutic targets.