Effects of Administration of Growth Hormone, Without and With Liraglutide, on AgRP, Energy and Glucose Metabolism in Healthy and GH Deficient Humans
概览
- 阶段
- 4 期
- 干预措施
- growth hormone
- 疾病 / 适应症
- Healthy
- 发起方
- Columbia University
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- AgRP change in GH vs. placebo arms
- 状态
- 招募中
- 最后更新
- 上个月
概览
简要总结
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.
详细描述
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.
研究者
Pamela U. Freda
Professor of Medicine at CUIMC
Columbia University
入排标准
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Growth hormone
GH will be administered as one nightly subcutaneous self-injection at 11pm at a dose of 0.03 mg/kg/day in healthy and 0.5 mg in male and 0.6 mg in female GHD subjects. Injections will be performed from the night of day 0 to the night of day 20.
干预措施: growth hormone
Liraglutide
Liraglutide will be administered by subcutaneous injection taken by subjects beginning at a dose at 0.6 mg nightly from 9-11 pm and escalated in 0.6 mg increments weekly as tolerated to a final dose of 1.8 mg nightly. Injections will be performed from the night of day 0 to the night of day 20.
干预措施: liraglutide
Growth hormone and liraglutide
GH will be administered as one nightly subcutaneous self-injection at 11pm at a dose of 0.03 mg/kg/day in healthy and 0.5 mg in male and 0.6 mg in female GHD subjects. Liraglutide will be administered by subcutaneous injection taken by subjects beginning at a dose at 0.6 mg nightly from 9-11 pm and escalated in 0.6 mg increments weekly as tolerated to a final dose of 1.8 mg nightly. Injections will be performed from the night of day 0 to the night of day 20.
干预措施: growth hormone and lirglutide
Placebo
Placebo will be administered as one nightly subcutaneous self-injection at 9-11pm from the night of day 0 to the night of day 20.
干预措施: Placebo
结局指标
主要结局
AgRP change in GH vs. placebo arms
时间窗: Baseline to weeks 1, 2, 3 of each study arm.
Difference in percent change in morning fasting level of AgRP (agouti-related peptide) in plasma in GH vs. placebo arms.
AgRP change in GH vs. GH + liraglutide arms
时间窗: Baseline to weeks 1, 2, 3 of each study arm.
Difference in percent change in morning fasting level of AgRP in plasma in GH vs. GH+liraglutide arms.
次要结局
- AgRP change in liraglutide vs. placebo arms(Baseline to weeks 1,2, 3 of each study arm)
- AgRP change in GH arm(Baseline to week 1,2, 3 of study arm.)