Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.
Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.
复制标题
胰腺β细胞在啮齿动物和人糖尿病中表达胎儿胰岛激素胃癌。
作者：
Dahan T;Ziv O;Horwitz E;Zemmour H;Lavi J;Swisa A;Leibowitz G;Ashcroft FM;In't Veld P;Glaser B;Dor Y
2型糖尿病的β细胞衰竭(T2D)最近被认为涉及β细胞的去分化和其他胰岛激素的异位表达，包括生长抑素和胰高血糖素。在这里，我们展示了胃泌素，一种通常只在胚胎发育期间在胰腺表达的胃激素，在糖尿病啮齿动物和患有T2D的人类的胰岛中表达。虽然小鼠的胃泌素在胰岛素+细胞中表达，但患有T2D的人类胃泌素在胰岛素+细胞和生长抑素+细胞中都有表达。小鼠的遗传谱系追踪表明，在暴露于严重高血糖后，分化的β细胞亚群中胃泌素的表达是开启的。成人β细胞中胃泌素的表达不涉及内分泌前体细胞调节因子3，但需要膜去极化、钙内流和钙调神经磷酸酶信号。体内和体外实验表明，当β细胞暴露在正常的葡萄糖水平时，胃泌素的表达迅速被消除。这些结果揭示了胎儿激素胃泌素作为糖尿病患者可逆性人类β细胞重编程的新标记物。
β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin+ cells, gastrin expression in humans with T2D occurs in both insulin+ and somatostatin+ cells. Genetic lineage tracing in mice indicates that gastrin expression is turned on in a subset of differentiated β-cells after exposure to severe hyperglycemia. Gastrin expression in adult β-cells does not involve the endocrine progenitor cell regulator neurogenin3 but requires membrane depolarization, calcium influx, and calcineurin signaling. In vivo and in vitro experiments show that gastrin expression is rapidly eliminated upon exposure of β-cells to normal glucose levels. These results reveal the fetal hormone gastrin as a novel marker for reversible human β-cell reprogramming in diabetes.