Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell
Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell
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DOI：
10.1210/en.2008-0726
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发表时间：
2009-02-01
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：
Lim, Gareth E.;Huang, Guan J.;Brubaker, Patricia L.
胰岛素抵抗和2型糖尿病与餐后胰高血糖素样肽-1(GLP-1)分泌受损有关，GLP-1是一种有效的促胰岛素激素。胰岛素和胰岛素抵抗对L细胞的直接影响尚不清楚。因此，我们假设L细胞对胰岛素有反应，胰岛素抵抗会损害GLP-1的分泌。在具有良好特性的L细胞模型：小鼠GLUTag、人NCL-H716和胎鼠肠道细胞中检测了胰岛素和胰岛素抵抗的影响。采用MKR小鼠慢性高胰岛素血症模型，对L细胞的体内功能进行了评价。在所有细胞中，胰岛素激活磷脂酰肌醇3激酶-Akt和MAPK-ERK1/2通路，并刺激GLP-1分泌高达275+/-58%。10(-7)M胰岛素可诱导胰岛素抵抗，使Akt和ERK1/2的活性显著降低。此外，胰岛素诱导的GLP-1的释放和分泌对葡萄糖依赖型胰岛素依赖型多肽和佛波醇-12-肉豆蔻酸酯13-醋酸酯的反应均显著减弱。而用LY294002抑制磷脂酰肌醇3激酶可增强胰岛素诱导的GLP-1的释放，而用PD98059抑制MEK-ERK1/2通路或过表达死于激酶的MEK1-ERK2融合蛋白可抑制GLP-1的分泌。与对照组相比，MKR小鼠表现出胰岛素抵抗，并表现出显著的空腹血浆胰岛素水平。此外，他们有显著更高的基础GLP-1水平，但在口服葡萄糖挑战后表现出GLP-1分泌受损。这些发现表明，肠道L细胞对胰岛素有反应，体内和体外的胰岛素抵抗与GLP-1分泌受损有关。(内分泌学150：580-591,2009)
Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCl-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 +/- 58%. Insulin resistance was induced by 24 h pretreatment with 10(-7) M insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion. (Endocrinology 150: 580-591, 2009)