Inhibition of beta cell growth and function by bone morphogenetic proteins
Inhibition of beta cell growth and function by bone morphogenetic proteins
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DOI：
10.1007/s00125-014-3384-8
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发表时间：
2014-12-01
期刊：
影响因子：
8.2
通讯作者：
Billestrup, Nils
中科院分区：
文献类型：
--
作者：
Bruun, Christine;Christensen, Gitte L.;Billestrup, Nils
在1型和2型糖尿病中，β细胞质量和功能的损害都很明显。在健康的生理条件下，胰腺β细胞通过增殖和改善功能来适应身体对胰岛素的需求。我们假设，在糖尿病的发展过程中，抑制因子的表达增加，阻止β细胞适应对胰岛素的需求增加。我们评估了骨形态发生蛋白（BMP） 2和-4对β细胞的影响。研究了BMP2和-4对大鼠、小鼠和人离体朗格汉斯胰岛β细胞增殖、凋亡、基因表达和胰岛素释放的影响。采用免疫细胞化学和实时荧光定量PCR分析bmp的表达。使用可溶性和中和形式的BMP受体1A研究了内源性BMP的作用。发现BMP2和-4抑制大鼠和小鼠的基础细胞和生长因子刺激的原代β细胞增殖。Bmp2和Bmp4 mRNA和蛋白在胰岛中表达，受炎症因子的调控。内源性BMP活性的中和导致啮齿动物β细胞的增殖增强。BMP4在大鼠和人胰岛中诱导了Id mrna的表达。最后，经BMP4预处理的啮齿动物和人胰岛中，葡萄糖诱导的胰岛素分泌明显受损，抑制BMP活性导致胰岛素释放增强。这些数据表明BMP2和-4在体外对β细胞有抑制作用，表明BMPs对β细胞的生长和功能有调节作用。
Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the development of diabetes, there is an increase in the expression of inhibitory factors that prevent the beta cells from adapting to the increased need for insulin. We evaluated the effects of bone morphogenetic protein (BMP) 2 and -4 on beta cells.The effects of BMP2 and -4 on beta cell proliferation, apoptosis, gene expression and insulin release were studied in isolated islets of Langerhans from rats, mice and humans. The expression of BMPs was analysed by immunocytochemistry and real-time PCR. The role of endogenous BMP was investigated using a soluble and neutralising form of the BMP receptor 1A.BMP2 and -4 were found to inhibit basal as well as growth factor-stimulated proliferation of primary beta cells from rats and mice. Bmp2 and Bmp4 mRNA and protein were expressed in islets and regulated by inflammatory cytokines. Neutralisation of endogenous BMP activity resulted in enhanced proliferation of rodent beta cells. The expression of Id mRNAs was induced by BMP4 in rat and human islets. Finally, glucose-induced insulin secretion was significantly impaired in rodent and human islets pre-treated with BMP4, and inhibition of BMP activity resulted in enhanced insulin release.These data show that BMP2 and -4 exert inhibitory actions on beta cells in vitro and suggest that BMPs exert regulatory roles of beta cell growth and function.