Rationale: GH and IGF-1 are vital to growth and metabolism across the human lifespan. In disorders of GH/IGF-1 excess and deficiency and the many other disease processes that perturb these hormones, significant growth and metabolic abnormalities can develop. GH is known to act on peripheral tissues, but recent data suggest that central effects of GH on the orexigenic hypothalamic neuropeptide AgRP (agouti-related peptide) is another important mechanism by which GH exerts its nutritional and metabolic effects. AgRP neurons express GH receptors and, in mice, GH was shown to activate AgRP neurons to produce orexigenic responses. GH may signal nutrient status via AgRP neurons. Our data in patients with acromegaly suggests that GH increases AgRP, but whether GH stimulates AgRP has not been tested. Therefore, this project directly tests that GH administration stimulates AgRP in humans. To further investigate the GH-AgRP axis, this project also tests the effect of the GLP-1R agonist liraglutide on plasma AgRP levels and explores the potential link of GH-stimulated changes in AgRP to GH-induced insulin resistance.~Study population and Design: The study population will include 40 healthy and 24 GH deficient adults. Each group will be half female and all will be between the ages of 18-45 years. The study is a randomized, participant-blind, placebo-controlled cross-over study of four arms: GH, GH+liraglutide, liraglutide and placebo, that are each 3 weeks and separated by an 8-week washout period. Each phase of the study will consist of a 7-day baseline period including 2 days of testing and 21 days on therapy with visits on days 2, 7, 14 and 21. We will apply a Williams cross-over design and randomization procedure(1) to ensure balance within and across groups. Subjects will take nightly subcutaneous injections of study medications or placebo during each arm. Participants will undergo anthropometric measurements and fasting blood sampling at every visit, an oral glucose tolerance test before and at the day 14 visit and assessments of body composition by quantitative magnetic resonance (QMR), energy expenditure and insulin sensitivity before and at the end of each arm. They will complete food and activity recording daily throughout the study except on study visit days.
This is a randomized, placebo-controlled, cross-over study with 4 arms. Healthy and GH deficient adults ages 18-45 years will be studied. Arms will consist of 21-day treatment periods and be separated by 8-week washout periods. Subjects will receive, in random order: i) GH alone, ii) GH with liraglutide, iii) liraglutide alone and iv) placebo. Each phase of the study will consist of a 7-day baseline period including 2 days of testing and 21 days on therapy with visits on days 2, 7, 14 and 21. Testing before, during and at the completion of each arm will include blood sampling and assessments of insulin resistance, energy expenditure and body composition.