Our studies focus on the regulation of hepatic and muscle glucose disposal during infection and inflammation. We examine its interaction with obesity and nutritional support. Our approach is to assess metabolism using a combination of tracer and arterio-venous difference techniques in conscious chronically catheterized conscious dogs and mice. We use a combination of pharmacological and surgical approaches to dissect the role that individual hormones and other mediators might play in the response. In addition we take advantage of genetically modified mouse models to determine the role inflammatory mediators play in controlling the metabolic response to infection and obesity. In our canine model, we observed that the liver is a major site of glucose disposal in a normal animal receiving nutritional support. We have also observed that the presence of an infection impairs hepatic glucose uptake in animals receiving nutritional support. Our studies address the mechanism for the impairment in liver glucose uptake and the role that elevations in glucagon, substrate supply, route of nutrient delivery and nitric oxide might play in contributing to or correcting the alteration. In our mouse model, we are developing strategies to examine the interaction of inflammation and obesity in a high fat fed mouse model. We are examining the role that NFkappaB plays in contributing to observed impairment in insulin action. In addition we are assessing the mechanism whereby interleukin-6 (a cytokine that is increased in metabolic disease) augments glucagon secretion.
Possible rotation projects: 1. Glucagon plays an important role in determining the ability of the liver to adapt to nutritional support. The project will focus on the interaction of glucagon with other factors that may play an important role in the adaptive response of the liver. 2. What is unclear is the molecular mechanism for the adaptation of the liver to total parenteral nutrition. The goal of this project is to determine which glucoregulatory enzymes are responsible for the adaptation of the liver to total parenteral nutrition. 3. Recent work suggests that accompanying inflammatory events may contribute to the insulin resistance seen in high fat fed states. Studies are ongoing to determine how obesity and inflammation interact to limit insulin action in muscle and liver. 4. Defects in hepatic lipid handling in insulin resistant states can lead to the accumulation of fat in the liver studies will develop methods to assess the metabolic source of the lipid that accumulates in the liver using state of the art stable isotopic methodology.
