Pilot & Feasibility Program Application Abstract
Circadian Control of Glucose Metabolism and Insulin Action
Carl Johnson (Nashville, TN)
Many physiological processes display day-night rhythms, including feeding behavior, lipid and carbohydrate metabolism, sleep, and blood pressure control. This circadian clock system regulates downstream target genes involved in metabolism of glucose and lipids, synthesis of cholesterol and bile acids. Recent exciting reports indicate an interplay between circadian clock-regulated sleep and insulin resistance/Type II diabetes in humans that support an association between clock properties and the risk for obesity and diabetes, as well as the so-called “dawn phenomenon.” Dysregulation of the pathways involved in glucose, cholesterol/fatty acids and oxidative phosphorylation (that are potentially a result of a sedentary lifestyle and high caloric intake) results in the development of cholesterol abnormalities, insulin resistance, obesity and hypertension, resulting in “metabolic syndrome.” Recent studies show that deletion of the key clock gene Bmal1 results not only in circadian disturbances, but also in metabolic abnormalities of lipid and glucose homeostasis—a phenotype resembling metabolic syndrome. The goal of this proposal is to carefully study insulin/glucose responsiveness in wild-type and Bmal1-/- mice by superior methods to ascertain the relationship of insulin/glucose metabolism to the circadian cycle in wild-type animals and to define a potential role for the Bmal1 gene in regulating insulin/glucose metabolism. The project will use state-of-the-art measurements of blood glucose, metabolism, and response to insulin at different times of day and night (and in constant conditions) in wild-type, Bmal1-/-, and diabetic mice. These studies will additionally define the optimal timeof- day conditions for hyperinsulinemic-euglycemic clamping. Public Health Significance: The finding that circadian clock genes, including Bmal1, regulate metabolism provides a potential molecular basis for these conditions and may therefore suggest possibilities for new therapeutic approaches for the treatment of diabetes and obesity. In addition, this study will provide important time-of-day information about the optimization of MMPC protocols for monitoring metabolism.
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