Effects of GH and Lirglutide on AgRP

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.

Inclusion criteria

HEALTHY SUBJECTS

• 40 healthy subjects, 20 male, 20 female, ages 18-45 yr.: (i) 20 (10 male, 10 female) who are overweight/Class 1 Obese (BMI 25-34.9) with abdominal fat accumulation (central adiposity) defined by waist circumference (WC) ≥ 102 cm in men, ≥ 88 cm in women, except in East/South Asians for whom the criteria will be WC ≥ 90 men and ≥ 80 women; (ii) 20 (10 male,10 female) who are lean (BMI 19-24.9) and not meeting these WC criteria.
• No medical conditions except being overweight/obese in half of subjects
• No prescription medication or other drug use
• On screening testing: BP<140/<90 mmHg, HbA1c<5.7%, FPG<100 mg/dL, normal IGF-1 and TSH levels.
• Premenopausal women: use of nonhormonal method of contraception
• Current non-smoker

GH DEFICIENT SUBJECTS

• 24 patients with isolated GH deficiency:12 males, 12 females.
• Ages 18-45 years
• Diagnosis of isolated GH deficiency based on accepted, BMI-appropriate GH stimulation test cut offs within 12 months of enrollment
• No prior GH therapy within 12 months of study enrollment
• Normal thyroid, adrenal and gonadal function documented by accepted stimulation test and clinical criteria
• Premenopausal women: use of nonhormonal method of contraception

Exclusion criteria

HEALTHY SUBJECTS

• History of malignancy, diabetes, thyroid cancer or pancreatitis
• Recent dieting, weight change >5%, pregnancy or lactation or heavy exercise
• Use of glucocorticoids, hormonal supplements or medications that could affect GH or IGF-1 or for weight loss within 6 months of enrollment

GH DEFICIENT SUBJECTS

• DM requiring medication
• HbA1C > 7.5
• Malignancy, pancreatitis or thyroid cancer history.
• Deficiency of other pituitary hormones, liver or renal disease
• Use of glucocorticoids, hormonal supplements or medications that could affect GH or IGF-1 or for weight loss within 6 months of enrollment

• Recent dieting, weight change > 5%, pregnancy, lactation or heavy exercise 6. Current smoking