Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic β-cells
Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic β-cells
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DOI：
10.2337/diabetes.49.10.1681
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发表时间：
2000-10-01
期刊：
影响因子：
7.7
通讯作者：
Habener, JF
中科院分区：
文献类型：
--
作者：
Hussain, MA;Daniel, PB;Habener, JF
胰高血糖素是由内分泌胰腺（胰岛）的α细胞在禁食期间分泌的，并且对于通过刺激肝葡萄糖输出来维持血糖水平至关重要。胰岛α细胞过度产生和分泌胰高血糖素是糖尿病的常见伴随物。由此产生的高胰高血糖素血症刺激肝葡萄糖产生，从而促成糖尿病的高血糖症。据信，糖尿病中胰岛素分泌减少以及由此导致的不能通过胰岛内旁分泌机制抑制胰高血糖素分泌导致胰高血糖素分泌过多。在这里，我们报告了胰高血糖素抑制胰岛素分泌的新机制的发现。我们表明，胰高血糖素，但不是胰高血糖素样肽1（GLP-1），或垂体腺苷酸环化酶激活肽（PACAP）特异性诱导的转录抑制因子诱导型cAMP早期阻遏物（ICER）在胰腺β细胞的表达，导致抑制胰岛素基因的转录表达。值得注意的是，胰高血糖素、GLP-1和PACAP都在大鼠胰岛中刺激cAMP形成的程度相当，但只有胰高血糖素激活ICER的表达并抑制β细胞中的胰岛素基因转录。这些发现使我们提出，高胰高血糖素血症可能通过抑制转录抑制因子ICER介导的胰岛素基因表达而加重糖尿病表型。
The hormone glucagon is secreted by the alpha-cells of the endocrine pancreas (islets of Langerhans) during fasting and is essential for the maintenance of blood glucose levels by stimulation of hepatic glucose output. Excessive production and secretion of glucagon by the alpha-cells of the islets is a common accompaniment to diabetes. The resulting hyperglucagonemia stimulates hepatic glucose production, thereby contributing to hyperglycemia of diabetes. The reduced insulin secretion in diabetes and resultant failure to suppress glucagon secretion by intra-islet paracrine mechanisms is believed to cause the hypersecretion of glucagon. Here, we report the discovery of a new mechanism by which glucagon suppresses insulin secretion. We show that glucagon, but not glucagon-like peptide 1 (GLP-1), or pituitary adenylyl cyclase-activating peptide (PACAP) specifically induces the expression of the transcriptional repressor inducible cAMP early repressor (ICER) in pancreatic beta-cells, resulting in a repression of the transcriptional expression of the insulin gene. Remarkably, glucagon, GLP-1, and PACAP all stimulate the formation of cAMP to a comparable extent in rat pancreatic islets, but only glucagon activates the expression of ICER and represses insulin gene transcription in beta-cells. These findings lead us to propose that hyperglucagonemia may additionally aggravate the diabetic phenotype via a suppression of insulin gene expression mediated by the transcriptional repressor ICER.