In the United States, diabetes is the leading cause of blindness, end-stage renal disease, and nontraumatic loss of limb, with associated health care costs estimated to exceed $130 billion per year. Although the primary cause of this disease is unknown, it is clear that insulin resistance plays an early role in its pathogenesis and that increased glucose production is instrumental in the progression to hyperglycemia.

In normal individuals plasma glucose levels remain relatively constant in periods of feeding, fasting, or prolonged exercise. High stress and physical conditions such as fatigue, combined with food deprivation, make soldiers very vulnerable to changes in blood glucose levels. Moreover, among soldiers, as in the general population, there is a risk group that is more susceptible to diabetes, largely compromising the control of plasma glucose levels, particularly in situations of stress. Therefore, a precise and tight regulation of plasma glucose levels is critical for preventing states of life-threatening conditions such as lactic or ketone acidosis due to hypoglycemia. On the other hand, chronic hyperglycemia is a major predisposing factor for long-term damage, dysfunction, and failure of various organs, including kidney, heart, eye, nerve, and blood vessels, which are collectively termed diabetic complications. Taken together, it is critical for an optimal performance of a soldier, operating under extreme environments of stress, intense exercise, or food restriction conditions, to be able to control blood glucose levels relatively constant. Therefore, studies to identify molecular mechanisms and targets that control glucose homeostasis are very important for development of new therapies and drugs to prevent both hypoglycemia and hyperglycemia in diabetes.

Effective drug therapies for diabetes include insulin replacement as well as other oral drugs such as sulfonylureas, PPARg agonists such as thiazolidinediones and metformin. It is important to mention that metformin preferentially targets glucose production in the liver; however, it is a relatively impotent drug and has to be used at high concentrations.

We have identified that a chemical modification called acetylation is a key regulatory step that controls glucose production in the liver by "turning-off" an important protein called PGC-1a. Genetic and clinical evidence in humans indicates that PGC-1a is dysregulated in both type 1 and type 2 diabetes and it is locked in an "on" active position in fasting and diabetic states resulting in an increase in blood glucose levels. Importantly, recently, we have identified the molecule responsible for PGC1a acetylation as GCN5. In this research proposal, we will perform biochemical and physiological experiments in cells and mice to understand how GCN5 and PGC-1a are controlling glucose production in the liver.

The understanding of the molecular mechanisms and regulation of hepatic glucose production constitutes a key step toward finding specific novel molecular targets for small molecules or drugs to use in the clinics and treat diabetic patients. Efficient drugs able to reduce hepatic glucose production will certainly represent an enormous advance in the clinical treatment of diabetes. Finally, understanding the function of these two proteins could also provide the molecular basis for drugs to treat life-threatening conditions such as hyperglycemia, hypoglycemia, and lactic and ketone acidosis. As these are conditions that personnel from the army could develop with high frequency, especially in highly stressful conditions such as combat, the military could certainly benefit from these studies.