Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Gastroenterology. 2010 May;138(5):1966-75. doi: 10.1053/j.gastro.2010.01.049. Epub 2010 Feb 4.
BACKGROUND & AIMS: Glucose-dependent insulinotropic polypeptide (GIP) and the proglucagon product glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones that are released in response to nutrient intake and promote insulin secretion. Interestingly, a subset of enteroendocrine cells express both GIP and GLP-1. We sought to determine whether GIP also might be co-expressed with proglucagon in pancreatic alpha-cells.
We assessed GIP expression via reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. We developed a novel bioassay to measure GIP release from isolated islets, compared the biological activities of full-length and truncated GIP, and assessed the impact of immunoneutralization of islet GIP on glucose-stimulated insulin secretion in isolated islets.
GIP messenger RNA was present in mouse islets; GIP protein localized to islet alpha-cells of mouse, human, and snake pancreas, based on immunohistochemical analyses. However, using a C-terminal GIP antibody, immunoreactivity was detected in islets from prohormone convertase (PC) 2 knockout but not wild-type mice. Bioactive GIP was secreted from mouse and human islets after arginine stimulation. In the perfused mouse pancreas, GIP(1-42) and amidated GIP(1-30) had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion.
GIP is expressed in and secreted from pancreatic islets; in alpha-cells, PC2 processes proGIP to yield a truncated but bioactive form of GIP that differs from the PC1/3-derived form from K-cells. Islet-derived GIP promotes islet glucose competence and also could support islet development and/or survival.
葡萄糖依赖性胰岛素释放多肽（GIP）和前胰高血糖素产物胰高血糖素样肽-1（GLP-1）是响应营养摄入而释放的胃肠道激素，可促进胰岛素分泌。有趣的是，一部分肠内分泌细胞同时表达 GIP 和 GLP-1。我们试图确定胰岛中的α细胞是否也能共表达 GIP 和前胰高血糖素。
我们通过逆转录聚合酶链反应、原位杂交和免疫组织化学评估 GIP 的表达。我们开发了一种新的生物测定法来测量分离胰岛中 GIP 的释放，比较全长和截短 GIP 的生物学活性，并评估胰岛 GIP 的免疫中和对分离胰岛中葡萄糖刺激的胰岛素分泌的影响。
GIP 信使 RNA 存在于小鼠胰岛中；基于免疫组织化学分析，GIP 蛋白定位于小鼠、人及蛇胰腺的胰岛α细胞。然而，使用 C 端 GIP 抗体，在原激素转化酶（PC）2 敲除而非野生型小鼠的胰岛中检测到免疫反应性。Arg 刺激后，来自小鼠和人胰岛的生物活性 GIP 被分泌。在灌注的小鼠胰腺中，GIP(1-42)和酰胺化 GIP(1-30)具有等效的胰岛素促分泌作用。最后，分离胰岛分泌的 GIP 免疫中和降低了葡萄糖刺激的胰岛素分泌。
GIP 在胰岛中表达和分泌；在胰岛α细胞中，PC2 处理前胰高血糖素生成短肽但具有生物活性的 GIP，与 K 细胞中 PC1/3 衍生的形式不同。胰岛衍生的 GIP 促进胰岛葡萄糖能力，也可能支持胰岛发育和/或存活。
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