A common side effect of an illness such as an infection is appetite suppression, which can quickly lead to malnutrition. Because malnutrition extends hospital stay, increases costs and exacerbates mortality, nutritional support (NS) is instituted. Unfortunately hyperglycemia is common in infected individuals and hyperglycemia negatively impacts on morbidity and mortality. We discovered that in healthy subjects the liver and muscle adapt to sustained NS by increasing their capacity to take up and oxidize glucose. As glucose is a major caloric source in NS, this adaptation is essential to minimize hyperglycemia. Infection impairs this adaptive response to NS and the current therapy administration of exogenous insulin cannot reverse this impairment. We also discovered in response to NS plasma glucagon decreases and liver derived and plasma FGF-21 increase. In addition if glucagon is increased as occurs with an infection, hepatic FGF-21 and plasma FGF-21 decrease and both hepatic and muscle carbohydrate oxidation are decreased. As FGF-21 is known to augment tissue glucose uptake our hypothesis is that, during NS, infection induced hyperglucagonemia limits FGF-21 availability and that together these changes attenuate tissue glucose uptake. We will use state of the art tracer and controlled metabolic studies to assess glucose and lipid flux in healthy and infected animals.
In Aim 1 we will determine if glucagon mediated suppression of hepatic FGF-21 secretion is responsible for the decrease in muscle glucose uptake and determine whether Gs and/or Gq dependent signaling (using designer receptor technology) in the liver can explain the glucagon-mediated decrease in muscle glucose uptake.
In Aim 2 we will determine if antagonizing glucagon can reverse the infection-induced impairment in tissue glucose uptake during NS. We will also determine if liver derived FGF-21 serves a protective role during infection and whether replacement of FGF-21 can sustain tissue glucose uptake during infection.
Hyperglycemia negatively impact outcomes in infected patients receiving nutritional support. A major cause of the hyperglycemia during an infection is a failure of the liver and muscle to adapt to nutritional support and take up glucose more efficiently. This proposal will determine the role glucagon and FGF-21 have in this response.
Showing the most recent 10 out of 24 publications
