Effects of recombinant human insulin-like growth factor-1 and recombinant human growth hormone on anabolism and immunity in calorie-restricted alcoholic rats.
Patients with severe alcoholic liver injury exhibit very low serum insulin-like growth factor-1 (IGF-1) concentrations, along with many of the symptoms that might occur with an IGF-1 deficiency state (including severe protein calorie malnutrition and immunosuppression). This study was performed to assess the effects of recombinant human (rh) IGF-1 and/or rh growth hormone (rhGH) on anabolism and immunity in the calorie-restricted, immunosuppressed alcoholic rat.


METHODS
Undernutrition was induced by calorie restriction such that each animal consumed 40% of ad libitum-fed controls. Alcohol was administered orally in the diet such that the mean daily intake was 9.4 g/kg/day. rhIGF-1 was administered by continuous subcutaneous infusion (380 micrograms/day) using a 14-day miniosmotic pump; rhGH was given by subcutaneous injections (400 micrograms/day). Matching placebo groups were also studied.


RESULTS
On this regimen, ad libitum-fed controls were well nourished and increased body weight 34%, whereas Restricted controls lost 7.7% and Restricted alcohol-fed rats lost 15.2%. Significant but incomplete reversal of undernutrition was achieved with hormone therapy. Best improvement was obtained with combined therapy: rhIGF-1 + rhGH (p < 0.005; placebo versus active treatments). Immunologic impairment was observed to be severe in both thymus and spleen. The most severe changes were seen in thymi of the calorie-restricted, alcohol-fed rats, wherein 98% of the T lymphocytes were lost. rhIGF-1 treatment, but not rhGH, produced significant improvements in thymus. This was most pronounced in control rats (p < 0.005). Splenic T lymphocytes were less impaired and were more responsive to rhIGF-1 treatment; there was a maximum loss of 71% of T cells in Restricted, alcohol-fed rats. rhIGF-1 treatment completely restored splenic cellularity, as well as each of the T lymphocytes studied: CD5, CD4, and CD8. Functional status of splenic T lymphocytes was assessed by blast transformation after concanavalin A stimulation. Calorie restriction did not impair significantly this function in controls [Lieber-DeCarli control diet (LCD)]. However, it was significantly impaired in the Restricted, alcohol-fed rats (p = 0.003). In the presence of continued calorie restriction and alcohol, this function was not restored with either hormone (rhIGF-1 and/or rhGH). Their role in facilitating functional recovery after calories is restored, and alcohol is discontinued is under investigation.
Mendenhall
C L
CL
Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Roselle
G A
GA
Gartside
P
P
Grossman
C J
CJ
D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D013006:Growth Hormone / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D011502:Protein-Energy Malnutrition / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone