Effects of Recombinant Human Insulin‐like Growth Factor‐1 and Recombinant Human Growth Hormone on Anabolism and Immunity in Calorie‐Restricted Alcoholic Rats

Abstract

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. 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. 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.