Grant: Operating Grant

BACKGROUND The liver plays a unique role in controlling blood sugar levels by maintaining glucose concentrations within a normal range during periods of fasting and feeding. Under fasting conditions, the hormone glucagon instructs the liver to manufacture glucose through a process refered to as gluconeogenesis. Insulin, released by the pancreas during feeding, shuts down the liver's ability to produce glucose. Regulation of this process is complex and involves many gene networks. Some major players in these networks are the transcriptional co-activators TORC2, Pgc1a and CREB. These proteins converge on a number of liver genes whose expression is influenced by nutritional status. Our lab has discovered a novel gene we refer to as PHIP1, that suppresses the function of this network of proteins. HYPOTHESIS: We hypothesize that PHIP plays a prominent role in the regulation of blood glucose by the liver. In this grant proposal we will use both in vitro and in vivo approaches to decipher the molecular mechanisms by which PHIP1 fine tunes nutritional signals to the liver under normal and diseased states. SIGNIFICANCE: The control of diabetic hyperglycemia is of significant clinical interest in obesity-related disorders. The suppression of hepatic glucose output remains a very attractive therapeutic target in diabetes. Enhancing PHIP function in the liver could yield medically significant anti-diabetic effects.