Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides.
Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides.
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作者：
Fukami A;Seino Y;Ozaki N;Yamamoto M;Sugiyama C;Sakamoto-Miura E;Himeno T;Takagishi Y;Tsunekawa S;Ali S;Drucker DJ;Murata Y;Seino Y;Oiso Y;Hayashi Y
胰高血糖素和胰高血糖素样肽-1分别在胰腺α细胞和肠内分泌细胞中以组织特异性的方式由相同的前体产生，该前体由胰高血糖素基因编码，在血糖稳态中起关键作用。在这里，我们研究了GCG-GFP敲入等位基因(Gcggfp/Gfp)纯合的GCG缺陷小鼠的葡萄糖稳态和β细胞功能。通过口服葡萄糖耐量试验(OGTT)和腹腔葡萄糖耐量试验(IPGTT)，Gcggfp/GFP小鼠表现出糖耐量改善和胰岛素分泌增加。Gcggfp/gfp小鼠体内葡萄糖依赖的促胰岛素多肽对口服和腹腔葡萄糖负荷的反应性显著增强，免疫组织化学显示GIP定位于胰腺β细胞。此外，在Gcggfp/GFP小鼠的分离胰岛中检测到对葡萄糖的反应而分泌GIP。分别通过cAMP拮抗和GIP受体基因缺失阻断GIP在体外和体内的作用，几乎完全阻断Gcggfp/GFP小鼠胰岛素分泌的增强。这些结果表明，在β细胞中异位表达GIP可维持胰岛素的分泌，而不存在胰升糖素原衍生多肽(PGDP)，从而揭示了维持胰岛胰岛素作用的一种新的代偿机制。
Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcggfp/gfp). The Gcggfp/gfp mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcggfp/gfp mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcggfp/gfp mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcggfp/gfp mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcggfp/gfp mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
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影响因子：
7.7
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
通讯作者：
Gittes GK
影响因子：
7.7
作者：
Hansotia, T;Baggio, LL;Drucker, DJ
通讯作者：
Drucker, DJ
DOI：
10.1073/pnas.96.26.14843
发表时间：
1999-12-21
影响因子：
11.1
作者：
Miyawaki, K;Yamada, Y;Seino, Y
通讯作者：
Seino, Y
影响因子：
3.2
作者：
Seino Y;Fukushima M;Yabe D
通讯作者：
Yabe D
影响因子：
5
作者：
Dallas-Yang, Q;Shen, XL;Jiang, GQ
通讯作者：
Jiang, GQ