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【Diabetes】GLP-1通过增加IGF受体自分泌环路来保护

Glucagon-Like Peptide-1 Protects β-Cells Against Apoptosis by Increasing the Activity of an Igf-2/Igf-1 Receptor Autocrine Loop

OBJECTIVE The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect β-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect.

RESEARCH DESIGN AND METHODS We performed comparative transcriptomic analysis of islets from control and GipR−/−;Glp-1-R−/− mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis.

RESULTS We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1–induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary β-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1–induced protection against apoptosis.

CONCLUSIONS An IGF-2/IGF-1 receptor autocrine loop operates in β-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1–induced protection against apoptosis. These findings may lead to novel ways of preventing β-cell loss in the pathogenesis of diabetes. 本人已认领该文编译,48小时后若未提交译文,请其他战友自由认领。 Glucagon-Like Peptide-1 Protects β-Cells Against Apoptosis by Increasing the Activity of an Igf-2/Igf-1 Receptor Autocrine Loop
胰高血糖素样肽-1(GLP-1)通过增加Igf-2/Igf-1受体自分泌环的活性保护β细胞免遭凋亡

OBJECTIVE The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect β-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect.
研究目的:糖-肠激素胰高血糖素样肽(GLP)-1和胃抑肽(GIP)能保护β细胞免遭细胞因子诱导的凋亡。他们通过与活化cAMP信号通路的特异受体结合来启动该效应,但该下调机制并未完全明了。我们对该保护性效应可能的机制做一研究。

ESEARCH DESIGN AND METHODS We performed comparative transcriptomic analysis of islets from control and GipR−/−;Glp-1-R−/− mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis.
研究设计与方法:我们使用比较转录组学分析对来自对照组及GipR−/−;Glp-1-R−/−小鼠的胰岛进行研究。后者对细胞因子诱导的凋亡敏感性增加。我们发现IGF-1受体表达在突变胰岛上显著减少。由于IGF-1受体信号传导通路在抗凋亡效应中的已知作用,故我们研究糖-肠作用、IGF-1受体表达与信号传导及凋亡之间的关系。

RESULTS We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1–induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary β-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1–induced protection against apoptosis.
研究结果:我们发现GLP-1能强力刺激IGF-1受体表达及Akt磷酸化。而后者的磷酸化是依靠IGF-1而并非胰岛素受体的表达。我们的研究表明GLP-1诱导的Akt磷酸化需要活化分泌,这证明了自分泌活化机制的存在。我们还发现IGF-1受体信号传导的活化依靠IGF-2的分泌。综上我们认为在MIN6细胞系和胰岛β细胞中IGF-1受体或IGF-2表达减少或已分泌IGF-2被中和都会对GLP-1诱导的抗凋亡保护产生抑制。

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作者:admin@医学,生命科学    2010-12-19 05:11
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