Raiter A, Tenenbaum A, Yackobovitch-Gavan M, Battler A, Hardy B
Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel.
The Jesse Z and Sara Lea Shafer, Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
Exp Clin Endocrinol Diabetes. 2016 Apr;124(4):239-45. doi: 10.1055/s-0035-1569356. Epub 2016 Apr 28.
Diabetes Type 1 is characterized by hyperglycemia due to reduced insulin secretion that results from the death of pancreatic β cells. It was suggested that endoplasmic reticulum (ER) stress is associated with the autoimmune-mediated β cell destruction. Glucose regulated protein 78 (GRP78) functions as a key regulator to maintain the ER function. Under stress conditions GRP78 is up-regulated and expressed on the cell surface serving as a signaling receptor. Our first objective was to examine the effects of peptide binding cell surface GRP78 to reduce the deleterious effects of diabetes induced by streptozotocin. The second objective was to demonstrate the ability of the peptide to protect the pancreatic β cells from apoptosis.
The effect of ADoPep on weight loss, HbA1c levels and anti GRP78 antibody titers was evaluated in a diabetes mouse model. The effect of ADoPep on the pancreatic β Ins1E cell apoptosis was determined by FACS analysis.
The administration of ADoPep to diabetic mice retained the weight loss and reduced HbA1c significantly in 60% of mice. Titers of anti GRP78 antibodies increased in 70% of the treated mice. Apoptosis was significantly inhibited in stressed pancreatic β Ins 1E cells.
We demonstrate that administration of the peptide ADoPep to diabetic mice improved type 1 diabetes by preventing pancreatic β cell apoptosis.
1型糖尿病的特征是由于胰腺β细胞死亡导致胰岛素分泌减少而引起的高血糖。有人提出内质网（ER）应激与自身免疫介导的β细胞破坏有关。葡萄糖调节蛋白78（GRP78）作为维持内质网功能的关键调节因子发挥作用。在应激条件下，GRP78上调并在细胞表面表达，作为信号受体。我们的首要目标是研究肽结合细胞表面GRP78以减轻链脲佐菌素诱导的糖尿病有害影响的作用。第二个目标是证明该肽保护胰腺β细胞免于凋亡的能力。
在糖尿病小鼠模型中评估ADoPep对体重减轻、糖化血红蛋白（HbA1c）水平和抗GRP78抗体滴度的影响。通过流式细胞术分析确定ADoPep对胰腺β Ins1E细胞凋亡的影响。
给糖尿病小鼠施用ADoPep可抑制体重减轻，并使60%的小鼠糖化血红蛋白水平显著降低。70%的受试小鼠抗GRP78抗体滴度升高。应激的胰腺β Ins 1E细胞凋亡受到显著抑制。
我们证明给糖尿病小鼠施用肽ADoPep可通过防止胰腺β细胞凋亡改善1型糖尿病。
