Metabolic Characterization of a Putative Novel Antidiabetic Drug, GTI-421
Abstract
Topic Area: Diabetes Area of Encouragement: Research on interventions to prevent complications of diabetes including diabetic retinopathy and diabetic neuropathy. Diabetes is a disorder of sugar metabolism that afflicts nearly one in four Veterans. This is a dangerous disease that predisposes patients to a greater risk of retinal, kidney, neurologic, and heart diseases, as well as overall mortality. The fact that diabetes remains a progressive disease despite a number of treatments available suggests that a new approach to diabetic therapy is warranted. One particularly attractive and novel area to interrogate in generating new diabetes therapy is the liver s adaptive response to fasting. During nutrient deprivation, the liver coordinates the body s response by activating a network of genes that together increase fat and overall caloric utilization and improve sugar metabolism. This normal physiological response can be harnessed to improve the diabetic patient s physiology, which is characterized by impaired sugar metabolism. A search for compounds that activate the liver s adaptive fasting response identified GTI-421, which activated several genes known to be active in the fasting liver. Preliminary studies also indicated that this compound may mimic starvation by blocking sugar transport into the liver, which itself is a novel means by which to activate the liver s fasting response. Moreover, animals treated with this compound burned more calories than animals that were untreated. In all, these metabolically favorable effects of GTI-421 suggest it is a reasonable candidate anti-diabetic therapy. With regard to the Peer Reviewed Medical Research Program Area of Encouragement, understanding how to prevent or treat diabetes with this novel therapeutic will advance the care and prevention of diabetic complications, including diabetic retinopathy and neuropathy. The goal of this proposal is to define and characterize a potentially novel anti-diabetic compound, GTI-421. The hypothesis is that GTI-421 exerts its anti-diabetic effects via specific pathways involved in the adaptive hepatic response. First, the effectiveness of GTI-421 in improving calorie-burning and sugar metabolism in diabetic mouse models will be explored. Then, the exact means by which GTI-421 exerts its putative anti-diabetic effects is examined. The anticipated benefit for these studies is at least four-fold. First, a novel compound and its role in treating diabetes will be defined. Second, new insights into exactly how the adaptive fasting response is activated -- and thus how that response s effects can be harnessed therapeutically -- will be gleaned from these studies. Third, insights learned from these studies can be used to build better, higher potency drugs in future studies. Fourth, these studies will inform the rationale and optimal uses for GTI-421 in human clinical trials to treat diabetes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710133
Entities
People
- Brian J DeBosch
Organizations
- United States Army
- Washington University in St. Louis