Wang Rong, Munoz Elyse E, Zhu Siying, McGrath Barbara C, Cavener Douglas R
The Pennsylvania State University, Department of Biology, Center of Cellular Dynamics, University Park, Pennsylvania, United States of America.
PLoS One. 2014 Jun 10;9(6):e99684. doi: 10.1371/journal.pone.0099684. eCollection 2014.
Insulin synthesis and cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient β-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels.
Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in β-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the β-cells.
We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice.
In addition to the essential functions of PERK in β-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on β-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of β-cell function and growth in order to achieve normoglycemia.
胰腺β细胞中的胰岛素合成和细胞增殖受到严格调控，以维持葡萄糖稳态。这两个方面的功能障碍都会导致糖尿病的发生。人类和小鼠中PERK（EIF2AK3）功能丧失突变表现为永久性新生儿糖尿病，其特征是β细胞量不足、胰岛素原转运减少和胰岛素分泌减少。出乎意料的是，我们发现Perk杂合小鼠的血糖水平较低。
进行纵向研究以评估Perk杂合小鼠的血清葡萄糖和胰岛素、细胞内胰岛素合成和储存、胰岛素分泌以及β细胞增殖。此外，特异性调节β细胞中Perk的剂量表明，Perk杂合小鼠的葡萄糖稳态表型是由β细胞中PERK表达降低所决定的。
我们发现Perk杂合小鼠在新生儿期和幼年期发育期间首先表现出胰岛素合成和分泌增强，随后在成年期β细胞增殖增强且β细胞量大幅增加。这些差异不太可能涉及PERK在培养细胞中调节内质网应激反应的众所周知的功能，因为内质网应激的几个标志物在Perk杂合小鼠中没有差异表达。
除了人类和完全缺乏PERK的小鼠中严重糖尿病表型所揭示的PERK在β细胞中的基本功能外，将Perk基因表达降低一半表明PERK的中等水平对β细胞功能和葡萄糖稳态有深远影响。这些结果表明，为了实现正常血糖水平，需要PERK表达的最佳水平来平衡β细胞功能和生长的几个参数。
