Alcoholics appear to be immunocompromised and have an increased tendency to become infected and to tolerate infection poorly. Although the nutritional status of the alcoholic is related to the outcome of the septic insult, malnutrition alone cannot fully explain the predisposition to infection. Altered glucose utilization and production are observed after infection and carbohydrate dyshomeostasis also occurs in chronic alcoholism. Yet, systematic studies examining the alterations in glucose homeostasis in alcoholics with systemic infection are lacking. The long-term goal of the proposed project is to define the mechanisms that are responsible for the alterations in glucose balance in vivo following chronic alcohol ingestion in the presence and absence of sepsis, and to elucidate the importance of these changes in causing the increased susceptibility to infection. Three working hypotheses will be considered: (1) chronic alcohol ingestion produces alterations in carbohydrate homeostasis in vivo; (2) gram-negative infection interferes with glucose production, utilization and storage in alcoholic rats thereby increasing their susceptibility to infection, and (3) alcohol withdrawal following chronic ethanol ingestion further impairs glucose homeostasis, leading to an increased risk of infection. Alcoholism will be induced by including ethanol as part of a nutritionally adequate liquid diet; time-matched non-alcoholic rats will be pairfed an isocaloric liquid diet. Hypermetabolic sepsis will be induced by subcutaneous injections of live E. coli. All 3 hypotheses will be addressed in chronically catheterized conscious rates by determining (a) glucose kinetics using the primed-constant infusion of (6-3H) and (U-14C)-glucose, (b) hepatic and skeletal muscle glycogen content, and the activity of the rate-controlling enzymes of glycogen metabolism, (c) the rates of glycogen repletion in liver and muscle, as well as the contribution of the direct and indirect pathways of hepatic glycogenesis, (d) insulin sensitivity by quantitating the rate of glucose disposal using euglycemic and hyperglycemic insulin clamps and (e) the specific tissues which remove exogenous glucose in vivo using 3H-2-deoxyglucose. These studies will provide novel information on the mechanisms of changes in whole body carbohydrate kinetics and insulin sensitivity following chronic alcohol ingestion and infection. The data concerning the interaction of these two conditions will aid in understanding the factors that predispose alcoholics to gram-negative infections.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007287-03
Application #
3111036
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Type
School of Medicine & Dentistry
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112