Novel Biological Action of the Dipeptidylpeptidase-IV Inhibitor, Sitagliptin, as a Glucagon-Like Peptide-1 Secretagogue
Novel Biological Action of the Dipeptidylpeptidase-IV Inhibitor, Sitagliptin, as a Glucagon-Like Peptide-1 Secretagogue
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DOI：
10.1210/en.2011-1732
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Brubaker, Patricia L.
中科院分区：
文献类型：
--
作者：
Sangle, Ganesh V.;Lauffer, Lina M.;Brubaker, Patricia L.
胰高血糖素样肽-1（GLP-1）是由肠道L细胞分泌到循环中的肠促胰岛素激素。二肽基肽酶-IV（DPP-IV）抑制剂西格列汀可防止GLP-1降解，并在临床上用于治疗2型糖尿病患者，从而改善糖化血红蛋白水平。当在新生链脲佐菌素大鼠（2型糖尿病模型）中检查西格列汀对GLP-1水平的影响时，观察到活性GLP-1的基础血浆水平增加4.9 ± 0.9倍，口服葡萄糖刺激血浆水平增加3.6 ± 0.4倍（P < 0.001），与肠L细胞总数的1.5 +/-0.1倍增加相关（P < 0.01）。因此，在体外小鼠GLUTag（mGLUTag）和人hNCI-H716肠L细胞中检查了西格列汀对GLP-1分泌和L细胞信号传导的直接影响。西格列汀（0.1-2 μ M）增加mGLUTag和hNCI-H716细胞的总GLP-1分泌（P < 0.01-0.001）。然而，MK 0626（1-50 μ M），一种结构上不相关的DPP-IV抑制剂，在两种模型中均不影响GLP-1分泌。用GLP-1受体激动剂毒蜥外泌肽-4处理mGLUTag细胞未调节GLP-1释放，表明GLP-1对L细胞不存在反馈效应。西格列汀增加mGLUTag和hNCI-H716细胞中cAMP水平（P < 0.01）和ERK 1/2磷酸化（P < 0.05），但不改变细胞内钙或磷酸化Akt水平。用蛋白激酶A（H89和蛋白激酶抑制剂）或MAPK激酶-ERK 1/2（PD 98059和U 0126）抑制剂预处理mGLUTag细胞可抑制西格列汀诱导的GLP-1分泌（P < 0.05-0.01）。这些研究首次证明，西格列汀对肠道L细胞产生直接的、不依赖于DPP-IV的作用，激活cAMP和ERK 1/2信号传导并刺激总GLP-1分泌。（内分泌学153：564-573，2012）
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted into the circulation by the intestinal L cell. The dipeptidylpeptidase-IV (DPP-IV) inhibitor, sitagliptin, prevents GLP-1 degradation and is used in the clinic to treat patients with type 2 diabetes mellitus, leading to improved glycated hemoglobin levels. When the effect of sitagliptin on GLP-1 levels was examined in neonatal streptozotocin rats, a model of type 2 diabetes mellitus, a 4.9 +/- 0.9-fold increase in basal and 3.6 +/- 0.4-fold increase in oral glucose-stimulated plasma levels of active GLP-1 was observed (P < 0.001), in association with a 1.5 +/- 0.1-fold increase in the total number of intestinal L cells (P < 0.01). The direct effects of sitagliptin on GLP-1 secretion and L cell signaling were therefore examined in murine GLUTag (mGLUTag) and human hNCI-H716 intestinal L cells in vitro. Sitagliptin (0.1-2 mu M) increased total GLP-1 secretion by mGLUTag and hNCI-H716 cells (P < 0.01-0.001). However, MK0626 (1-50 mu M), a structurally unrelated inhibitor of DPP-IV, did not affect GLP-1 secretion in either model. Treatment of mGLUTag cells with the GLP-1 receptor agonist, exendin-4, did not modulate GLP-1 release, indicating the absence of feedback effects of GLP-1 on the L cell. Sitagliptin increased cAMP levels (P < 0.01) and ERK1/2 phosphorylation (P < 0.05) in both mGLUTag and hNCI-H716 cells but did not alter either intracellular calcium or phospho-Akt levels. Pretreatment of mGLUTag cells with protein kinase A (H89 and protein kinase inhibitor) or MAPK kinase-ERK1/2 (PD98059 and U0126) inhibitors prevented sitagliptin-induced GLP-1 secretion (P < 0.05-0.01). These studies demonstrate, for the first time, that sitagliptin exerts direct, DPP-IV-independent effects on intestinal L cells, activating cAMP and ERK1/2 signaling and stimulating total GLP-1 secretion. (Endocrinology 153: 564-573, 2012)