Endogenous glucose production (EGP) is a critical process that maintains blood glucose levels under fasting conditions. While EGP is suppressed by both glucose and insulin, it is inappropriately elevated in type 2 diabetes mellitus (T2DM) and is the major source of hyperglycemia in these individuals. Although rises in plasma glucose and insulin rapidly inhibit EGP in nondiabetic individuals, T2DM is associated with loss of these suppressive effects of glucose and insulin on EGP. Of note, recent rodent studies suggest that hepatic glucose fluxes are centrally regulated, since activation of hypothalamic KATP channels by insulin and glucose suppresses EGP and gluconeogenesis, apparently via vagal efferent signals. Given considerable controversy about potential species differences, it will be important to establish how important this is to normal regulation of glucose homeostasis in humans, and whether this central nervous system (CNS) regulation is impaired in individuals with T2DM. We will address these questions in human subjects using state-of-the-art 'pancreatic clamp' studies, with quantification of hepatic glucose fluxes by tracer methodologies. We will first determine whether and how activation of KATP channels impacts hepatic glucose fluxes in nondiabetic subjects under fixed hormonal conditions, and whether this effect can be abolished by inhibiting KATP channels. Additionally, we will determine the extent to which CNS pathways of glucose regulation could contribute to the suppressive effects of glucose and insulin on EGP. We will then examine whether this regulation is impaired in individuals with T2DM. Since our preliminary data suggest that CNS inputs play a key role in the regulation of hepatic glucose fluxes in humans, restoring this regulation could be an important target for intervention in individuals with T2DM.
The rapidly increasing prevalence and serious complications of type 2 diabetes mellitus (T2DM) underscore its importance as a public health issue. Despite recent advances in therapeutic options for T2DM, optimizing glycemic control still remains an elusive goal. Since excessive glucose production is the main source of increased glucose levels in T2DM, understanding mechanisms that regulate glucose production would have important therapeutic implications. Following up on some exciting findings in animals, the proposed studies will be the first to examine whether and how the brain regulates glucose production in humans and whether this regulation is lost in T2DM. These studies could therefore lead to a new therapeutic target for the treatment of T2DM.
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