Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic β-cells and inhibiting insulin secretion
Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic β-cells and inhibiting insulin secretion
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DOI：
10.1074/jbc.m804372200
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发表时间：
2008-09-19
影响因子：
4.8
通讯作者：
Stoffers, Doris A.
中科院分区：
文献类型：
--
作者：
De Leon, Diva D.;Li, Changhong;Stoffers, Doris A.
先天性高胰岛素血症是一种胰腺β细胞功能障碍，其特征在于在低血糖情况下无法抑制胰岛素分泌，如果不治疗，会导致脑损伤或死亡。K-ATP通道（由两个亚基组成：Kir6.2和SUR-1）的功能丧失突变是最常见和最严重的先天性高胰岛素血症的原因。大多数患者对现有的药物治疗无反应，需要姑息性胰腺切除术。与人类状况相似，SUR-1（-/）-小鼠在禁食时血糖降低，在葡萄糖负荷时血糖升高。我们以前曾报道胰高血糖素样肽-1受体拮抗剂exendin-（9-39）在正常小鼠中升高空腹血糖。在这里，我们检查了毒蜥外泌肽-（9-39）对SUR-1（-/）-小鼠空腹血糖的影响。将小鼠随机接受毒蜥外泌肽-（9-39）或媒介物。用毒蜥外泌肽-（9-39）处理的SUR-1（-/）-小鼠的空腹血糖水平显著高于溶剂处理的小鼠，并且与野生型同窝小鼠没有差异。Exendin-（9-39）没有进一步恶化葡萄糖耐量，对体重和胰岛素敏感性没有影响。孤立的胰岛灌注研究表明，exendin-（9-39）阻断氨基酸刺激的胰岛素分泌，这是异常增加的SUR-1（-/）-胰岛。此外，在SUR-1（-/）-胰岛cAMP含量减少exendin-（9-39）的基础上，当刺激氨基酸，而胞浆钙水平不受影响。这些结果表明，cAMP在K-ATP非依赖性胰岛素分泌中起关键作用，GLP-1受体在SUR-1（-/）-β细胞中具有组成性活性。我们的研究结果表明，毒蜥外泌肽-（9-39）通过对胰岛素分泌的直接作用使SUR-1（-/）-小鼠的空腹低血糖正常化，从而提高毒蜥外泌肽-（9-39）作为K-ATP高胰岛素血症的潜在治疗剂的可能性。
Congenital hyperinsulinism is a disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K-ATP channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1(-/)-mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9-39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9-39) on fasting blood glucose in SUR-1(-/)-mice. Mice were randomized to receive exendin-(9-39) or vehicle. Fasting blood glucose levels in SUR-1(-/)-mice treated with exendin-(9-39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9-39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9-39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1(-/)-islets. Furthermore, cAMP content in SUR-1(-/)-islets was reduced by exendin-(9-39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K-ATP-independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1(-/)-beta-cells. Our findings indicate that exendin-(9-39) normalizes fasting hypoglycemia in SUR-1(-/)-mice via a direct effect on insulin secretion, thereby raising exendin-(9-39) as a potential therapeutic agent for K-ATP hyperinsulinism.