Glucose promotes survival of rat pancreatic beta cells by activating synthesis of proteins which suppress a constitutive apoptotic program
Glucose promotes survival of rat pancreatic beta cells by activating synthesis of proteins which suppress a constitutive apoptotic program
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DOI：
10.1172/jci118950
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发表时间：
1996-10-01
影响因子：
15.9
通讯作者：
Pipeleers, D
中科院分区：
文献类型：
--
作者：
Hoorens, A;VandeCasteele, M;Pipeleers, D
这项研究表明，大鼠胰岛β细胞组成性表达的凋亡程序时，被激活的mRNA或蛋白质合成被阻断。用放线菌素D或放线菌酮处理后，通过电子显微镜可检测到凋亡的β细胞。通过荧光显微镜测定，发现这两种药物都能以剂量和时间依赖性方式增加凋亡β细胞的数量，培养1周后高达70%;在对照制剂或导致原发性坏死的条件下，几乎没有发生凋亡β细胞。因此，β细胞的存活似乎依赖于抑制内源性自杀程序的蛋白质的合成。这一机制解释了早期观察到的葡萄糖对培养的β细胞存活的影响。已知葡萄糖剂量依赖性地增加活跃生物合成中的β细胞的百分比和在培养期间存活的百分比。现在证明，培养1周的β细胞的葡萄糖诱导的存活是由于在细胞凋亡中死亡的β细胞百分比的剂量依赖性降低（3 mM葡萄糖为49%，6 mM为40%，10 mM为9%）。因此，葡萄糖敏感性的细胞间差异似乎是β细胞对凋亡条件敏感性异质性的原因。这些数据表明，葡萄糖通过激活抑制细胞凋亡的蛋白质的合成来促进β细胞的存活。本模型允许进一步研究β细胞中细胞凋亡的调节和诱导或预防β细胞死亡的试剂的鉴定。
This study demonstrates that rat islet beta cells constitutively express an apoptotic program which is activated when mRNA or protein synthesis is blocked. Apoptotic beta cells were detectable by electron microscopy after treatment with actinomycin D or cycloheximide. With a fluorescence microscopic assay both agents were found to increase the number of apoptotic beta cells dose- and time-dependently, up to 70% after 1 wk of culture; virtually no apoptotic beta cells occurred in control preparations or in conditions leading to primary necrosis. Thus, survival of beta cells seems dependent on synthesis of proteins which suppress an endogenous suicide program. This mechanism explains earlier observed effects of glucose on survival of cultured beta cells. Glucose is known to dose-dependently increase the percentage of beta cells in active biosynthesis and the percentage that survives during culture. It is now demonstrated that the glucose-induced survival of beta cells cultured for 1 wk results from a dose-dependent reduction in the percentage of beta cells dying in apoptosis (49% at 3 mM glucose, 40% at 6 mM, 9% at 10 mM). Thus, intercellular differences in glucose sensitivity appear responsible for the heterogeneity in beta cell sensitivity to apoptotic conditions. These data indicate that glucose promotes survival of beta cells by activating synthesis of proteins which suppress apoptosis. The present model allows for further investigation of the regulation of apoptosis in beta cells and the identification of agents which induce or prevent beta cell death.