Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance.
Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance.
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DOI：
10.1016/j.celrep.2015.01.046
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发表时间：
2015-02-24
期刊：
影响因子：
8.8
通讯作者：
Montminy M
中科院分区：
文献类型：
--
作者：
Blanchet E;Van de Velde S;Matsumura S;Hao E;LeLay J;Kaestner K;Montminy M
尽管循环葡萄糖浓度的持续升高促进胰岛质量的代偿性增加，但持续的胰岛素抵抗引起β细胞功能的恶化，从而导致糖尿病的进展。在这里，我们表明，敲除β细胞中CREB辅激活因子CRTC2的小鼠由于循环胰岛素浓度降低而导致口服葡萄糖耐量受损。发现CRTC2部分通过刺激转录因子MafA的表达来促进β细胞功能。慢性高血糖通过激活低氧诱导因子（HIF 1）依赖性诱导蛋白激酶A抑制剂β（PKIB）（PKA催化活性的强效抑制剂）破坏胰岛中的cAMP信号传导。事实上，PKIB基因的破坏改善了肥胖症患者的胰岛功能。这些结果表明，营养和激素途径之间的相互作用如何导致胰岛功能丧失。
Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes a deterioration in beta cell function that leads to the progression to diabetes. Here we show that mice with a knockout of the CREB coactivator CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia disrupted cAMP signaling in pancreatic islets by activating the hypoxia inducible factor (HIF1)-dependent induction of the Protein Kinase A Inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity. Indeed, disruption of the PKIB gene improved islet function in the setting of obesity. These results demonstrate how cross-talk between nutrient and hormonal pathways contributes to loss of pancreatic islet function.