Early in the course of HIV infection, a cytokine mediated metabolic- endocrine imbalance likely occurs and appears to be responsible for the progressive elevation in resting energy expenditure (REE) observed in advancing disease. Our preliminary data reveal elevations in serum T3/T4 values in asymptomatic HIV infected patients which are neither altered by fasting noradministration of insulin-like growth factor-I (IGFI). Further, basal serum IGF-I and BP-3 values may be reduced producing an apparent anabolic-endocrine imbalance which would foster loss of lean body mass (LBM). Recent reports indicate that progressive primary gonadal failure may occur in the early phases of HIV infection which would further exaggerate this imbalance. Therefore, we hypothesize that a metabolic-endocrine dysregulation is present in HIV infection which serves as a pathogenetic prerequisite for the development of the wasting commonly found with advancing disease and/or intercurrent infection. To test this hypothesis, the following multidisciplined study is proposed: 1) to determine in cross- sectional studies of asymptomatic HIV infected patients if the progressive increase in REE observed with advancing disease can be correlated with alterations in LBM and various anabolic-endocrine parameters, including thyroid, IGF-I and sex hormones, 2) to determine if the response of REE and anabolic-endocrine indices to provocative testing, including acute meal response, fasting and carbohydrate hyperalimentation, IGF-I and dexamethasone administration, are progressively distorted with advancing HIV infection, 3) to determine the response of REE, LBM and anabolic- endocrine indices to spontaneously occurring intercurrent infections, 4) to determine whether there are gender-related differences in the above parameters, and 5) determine if a relationship exists between serum interleukin-6 (lL-6) values and these metabolic-endocrine alterations. We anticipate that the increases in REE associated with advancing HIV infection will be paralleled by a progressive dysregulation in the anabolic-endocrine system and that these parameters will fail to appropriately respond to provocative challenges or to catabolic stresses associated with naturally occurring secondary infections. Measurements of serum lL-6 values associated with these aberrancies may support or refute the role that this cytokine may play in orchestrating these multiple metabolic-endocrine alterations. On the basis of this multidisciplined approach, we hope to develop specific and precise methods for assessing the presence and magnitude of the metabolic-endocrine derangements associated with HIV infection and to propose more insightful approaches for the study and treatment wasting.
