Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness.
Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.
Weekers
Frank
F
Department of Intensive Care Medicine, Burn Unit and Center for Experimental Surgery and Anesthesiology, Catholic University of Leuven, Leuven, Belgium. frank.weekers@uz.kuleuven.ac.be
Michalaki
Marina
M
Coopmans
Willy
W
Van Herck
Eric
E
Veldhuis
Johannes D
JD
Darras
Veerle M
VM
Van den Berghe
Greet
G
D000208:Acute Disease; D000818:Animals; D001786:Blood Glucose; D002056:Burns / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D016638:Critical Illness / Q000401:mortality; D004195:Disease Models, Animal; D004734:Energy Metabolism; D013006:Growth Hormone / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D007668:Kidney / Q000033:anatomy & histology / Q000502:physiology; D008099:Liver / Q000033:anatomy & histology / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D009929:Organ Size; D011817:Rabbits; D013961:Thyroid Gland / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009842:Oligopeptides; D013973:Thyrotropin-Releasing Hormone; D013006:Growth Hormone; C091874:growth hormone-releasing peptide-2