Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Endocrinol Metab. 2019 Dec 1;317(6):E1081-E1093. doi: 10.1152/ajpendo.00239.2019. Epub 2019 Sep 10.
DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS. We show that ) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, ) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and ) the secretion of S was GLP-1 receptor dependent. We conclude that SS is a tonic inhibitor of GLP-1 secretion, and interventions in the somatostain-GLP-1 paracrine loop lead to increased GLP-1 secretion.
DPP-4 抑制剂，用于治疗 2 型糖尿病，通过增加完整胰高血糖素样肽-1 (GLP-1) 的浓度起作用，但同时，它们抑制 GLP-1 的分泌，可能通过负反馈机制。我们假设 GLP-1 的分泌受到来自相邻 D 细胞的生长抑素 (SS) 的反馈调节，阻断这个反馈回路会导致 GLP-1 分泌增加。我们使用了广泛的实验技术，包括基因表达分析、免疫组织化学方法和灌注的小鼠肠道，以描述控制 GLP-1 和 SS 的旁分泌回路。我们表明，) 拮抗 SS 受体 (SSTR) 2 和 SSTR5 导致小鼠中 GLP-1 和 SS 的分泌增加，) SS 通过 SSTR5 对 GLP-1 分泌表现出强烈的紧张性抑制，并且) S 的分泌是 GLP-1 受体依赖性的。我们的结论是，SS 是 GLP-1 分泌的紧张性抑制剂，而生长抑素-GLP-1 旁分泌环的干预会导致 GLP-1 分泌增加。
