During feeding and in the post-prandial state, elevated blood glucose levels promptly increase the secretion of insulin and decrease the secretion of glucagon, leading to the suppression of glucose release and storage of glucose as glycogen in the liver. In the post-absorptive state and during early fasting, hepatic glycogenolysis is activated to maintain euglycemia. In contrast, gluconeogenesis plays a dominant role in maintaining blood glucose levels during prolonged fasting after glycogen stores are depleted. Contrary to this model, studies in humans have shown that gluconeogenesis is not completely suppressed even in the presence of excess insulin. These data suggest that a component of hepatic gluconeogenesis may be normally unregulated, and it is estimated that as much as 40-70% of newly synthesized glycogen is formed via the gluconeogenic pathway. We suggest that p300 normally drives basal gluconeogenesis and glycogen synthesis because depletion of hepatic p300 leads to reduced glycogen content and relative hypoglycemia. In contrast, high-fat diet (HFD) feeding markedly and promptly increases p300 protein levels. Given that inappropriate hepatic gluconeogenesis is a major cause of hyperglycemia in obese and diabetic patients, the early induction of p300 by HFD feeding may be responsible for elevated hepatic gluconeogenesis. Understanding the mechanism of early p300 induction by HFD feeding will prove invaluable for understanding basic mechanisms underlying unregulated hepatic glucose production in T2DM. We therefore propose three specific aim to address these questions: 1) To define the interaction between FOXO1 and p300 in regulation of hepatic glucose production (HGP); 2) To determine the effect of p300 on hepatic glycogen synthesis through gluconeogenesis and glycogenesis; and 3) To define the mechanism of early induction of p300 protein in the liver of mice fed a HFD and compare to p300 expression in a chronic obesity mouse model (ob/ob).
Elevated hepatic glucose production is a major cause of hyperglycemia in obese and diabetic patients. This proposal seeks to define the mechanism(s) underlying the cause of elevated hepatic glucose production leading to hyperglycemia.
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