The expression and function of glucose-dependent insulinotropic polypeptide in the embryonic mouse pancreas.
The expression and function of glucose-dependent insulinotropic polypeptide in the embryonic mouse pancreas.
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作者：
Prasadan K;Koizumi M;Tulachan S;Shiota C;Lath N;Paredes J;Guo P;El-Gohary Y;Malek M;Shah S;Gittes GK
葡萄糖依赖性胰岛素性多肽（GIP）是与胰高血糖素、胰高血糖素样肽和分泌素结构相关的激素群中的一员。GIP是一种肠促胰岛素，已知可调节葡萄糖诱导的胰岛素分泌。最近的研究表明，胰高血糖素是早期胰岛素阳性分化所必需的，而肠促胰岛素在调节胚胎胰岛素阳性分化方面的类似作用似乎很可能。我们研究了GIP信号在小鼠胚胎胰腺胰岛素阳性分化中的作用。采用免疫组织化学和RT-PCR方法研究胚胎胰腺中GIP配体和GIP受体的发生机制。在体外培养的胚胎胰脏中，利用针对GIP配体和受体的morpholine-ring反义或针对GIP配体和受体的小干扰RNA （small interfering RNA, siRNA）抑制GIP信号传导。采用免疫组织化学和RT-PCR方法研究内分泌细胞及其祖细胞的标志物。胚胎胰腺在胚胎第9.5天检测到GIP和GIP受体mRNA，并持续整个妊娠期。免疫染色显示GIP与胰高血糖素共表达。GIP受体通常与胰岛素共表达。针对GIP配体或GIP受体的Morpholine-ring反义rna或siRNA均能抑制胰岛素阳性细胞的分化。抑制GIP或其受体也导致培养的胚胎胰腺中pdx -1阳性和sox9阳性细胞的数量减少。Pax6-阳性细胞和nkx2.2阳性细胞（分别代表发育中的胰腺内分泌细胞和β-细胞）数量也减少。GIP信号可能在早期胚胎胰腺分化形成胰岛素阳性细胞或β细胞的过程中发挥作用。
Glucose-dependent insulinotropic polypeptide (GIP) is a member of a structurally related group of hormones that also includes glucagon, glucagon-like peptides, and secretin. GIP is an incretin, known to modulate glucose-induced insulin secretion. Recent studies have shown that glucagon is necessary for early insulin-positive differentiation, and a similar role for incretins in regulating embryonic insulin-positive differentiation seems probable. Here we studied the role of GIP signaling in insulin-positive differentiation in the embryonic mouse pancreas. The ontogeny of the GIP ligand and GIP receptor in the embryonic pancreas was investigated by immunohistochemistry and RT-PCR. GIP signaling was inhibited in cultured embryonic pancreata using morpholine-ring antisense against GIP ligand and receptor, or small interfering RNA (siRNA) for GIP ligand and receptor. Markers of endocrine cells and their progenitors were studied by immunohistochemistry and RT-PCR. GIP and GIP receptor mRNA were both detected in the embryonic pancreas by embryonic day 9.5 and then persisted throughout gestation. GIP was generally coexpressed with glucagon by immunostaining. The GIP receptor was typically coexpressed with insulin. Morpholine-ring antisense or siRNA against either GIP ligand or GIP receptor both inhibited the differentiation of insulin-positive cells. Inhibition of GIP or its receptor also led to a decrease in the number of Pdx-1–positive and sox9-positive cells in the cultured embryonic pancreas. The number of Pax6- and Nkx2.2-positive cells, representative of developing pancreatic endocrine cells and β-cells, respectively, was also decreased. GIP signaling may play a role in early embryonic pancreas differentiation to form insulin-positive cells or β-cells.