A novel GIP receptor splice variant influences GIP sensitivity of pancreatic β-cells in obese mice
A novel GIP receptor splice variant influences GIP sensitivity of pancreatic β-cells in obese mice
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DOI：
10.1152/ajpendo.00358.2007
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发表时间：
2008-01-01
影响因子：
5.1
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Harada, Norio;Yamada, Yuichiro;Inagaki, Nobuya
胃抑制多肽（GIP）是一种肠促胰岛素，通过与GIP受体（GIPR）结合并随后增加细胞内腺苷3 '，5'-环一磷酸（cAMP）的水平来增强胰腺β细胞的胰岛素分泌。我们已经在小鼠β细胞中鉴定了一种新的GIPR剪接变体，其保留内含子8，导致COOH末端截短形式（截短的GIPR）。该同种型与全长GIPR（野生型GIPR）在正常GIPR表达组织中共表达。在使用两种GIPR转染的细胞的实验中，截短的GIPR不导致GIP诱导的cAMP产生，但通过野生型GIPR抑制GIP诱导的cAMP产生（n = 3-4，P < 0.05）。野生型GIPR通常位于细胞表面，但在存在截短GIPR的情况下其表达降低，表明截短GIPR对野生型GIPR的显性负效应。研究了截短的GIPR在体内的功能相关性。在高脂饮食喂养的肥胖小鼠（HFD小鼠）中，血糖水平通过代偿性增加胰岛素分泌来维持（n = 8，P < 0.05），并且在离体胰岛中，GIP诱导的cAMP产生（n = 6，P < 0.01）和胰岛素分泌（n = 10，P < 0.05）显著增加，提示GIPR的超敏性。HFD小鼠胰岛中总GIPR mRNA的表达量没有增加，但截短型GIPR占总GIPR的表达量比对照组降低了32%（n = 6，P < 0.05）。这些结果表明，截短的GIPR表达的相对减少可能参与饮食诱导的肥胖小鼠中GIPR的超敏反应和高胰岛素血症。
Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic beta-cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3', 5'-cyclic monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse beta-cells that retains intron 8, resulting in a COOH-terminal truncated form (truncated GIPR). This isoform was coexpressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR did not lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR (n = 3-4, P < 0.05). Wild-type GIPR was normally located on the cell surface, but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high-fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion (n = 8, P < 0.05), and cAMP production (n = 6, P < 0.01) and insulin secretion (n = 10, P < 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared with that of control mice (n = 6, P < 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.