GLP-2 和 GIP 对骨转换有独立作用：一项健康年轻男性中随机、安慰剂对照、交叉研究。
GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men.
机构信息
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark.
出版信息
Bone. 2019 Aug;125:178-185. doi: 10.1016/j.bone.2019.05.014. Epub 2019 May 15.
BACKGROUND
Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR).
OBJECTIVE
Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH.
METHODS
The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP).
RESULTS
CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH + GLP-2 (to 63.2 ± 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC (-6801 ± 879%*min vs -6027 ± 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 ± 2.2% of baseline compared with 103.1 ± 1.5% after placebo. Both GLP-2 and GIP(3-30)NH + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 ± 1.1% and 88.1 ± 3.0% of baseline, respectively (at t = 45 min) compared with placebo.
CONCLUSIONS
GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans.
CLINICAL TRIALS INFORMATION
ClinicalTrials.gov (NCT03159741).
背景
胰高血糖素样肽-2 (GLP-2) 和葡萄糖依赖性胰岛素释放肽 (GIP) 均可抑制人体的骨吸收，但作用机制尚不清楚。体外研究表明，GLP-2 可激活 GIP 受体 (GIPR)。
目的
基于体外研究，我们假设 GLP-2 的抗吸收作用是通过 GIPR 介导的。本研究采用选择性 GIPR 拮抗剂 GIP(3-30)NH 进行了测试。
方法
该研究是在丹麦 Hvidovre 大学医院进行的一项随机、单盲、安慰剂对照、交叉研究。共纳入 8 名健康年轻男性，并在 4 个研究日进行研究：GIP（200μg）、GLP-2（800μg）、GIP(3-30)NH（800pmol/kg/min）+GLP-2（800μg）和安慰剂。主要结局指标为胶原 1 C 端末端肽（CTX）测量的骨吸收和原胶原 1 N 端前肽（P1NP）测量的骨形成。
结果
GIP（至 t=90min 时为基础值的 55.3±6.3%）和 GLP-2（至 t=180min 时为基础值的 60.5±5.0%）均可显著降低 CTX。GIP(3-30)NH+GLP-2（至 t=30min 时为基础值的 63.2±3.1%）的最大 CTX 降低值与 GLP-2 单独给药无差异（p=0.95），净 AUC（-6801±879%*min 与 -6027±648%*min，p=0.56）也无差异。在 t=30min 时，GIP 显著（p<0.0001）增加 P1NP 至基础值的 115.1±2.2%，而安慰剂组为 103.1±1.5%。GLP-2 和 GIP(3-30)NH+GLP-2 均显著（p<0.0001）降低 P1NP 至基础值的 91.3±1.1%和 88.1±3.0%，与安慰剂组相比（t=45min）。
结论
在健康年轻男性中，GIPR 拮抗剂并未抑制 GLP-2 诱导的骨吸收（CTX）减少。与 GLP-2 相反，尽管 GIP 降低了 CTX，但 GIP 增加了 P1NP，表明骨吸收与形成脱偶联。因此，GLP-2 和 GIP 似乎在人类的骨转换中发挥了单独的作用。
临床试验信息
ClinicalTrials.gov（NCT03159741）。
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