Skak Kresten, Gotfredsen Carsten F, Lundsgaard Dorthe, Hansen John Bondo, Sturis Jeppe, Markholst Helle
Department of Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
Diabetes. 2004 Apr;53(4):1089-95. doi: 10.2337/diabetes.53.4.1089.
Treatment with ATP-sensitive K(+) channel openers (KCOs) leads to inhibition of insulin secretion and metabolic "rest" in beta-cells. It is hypothesized that in type 1 diabetes this may reduce beta-cell death resulting from metabolic stress as well as reduce the immunogenicity of the beta-cells during autoimmune beta-cell destruction. We have investigated whether the beta-cell-selective KCO compound, NN414, can be used to improve beta-cell survival in DR-BB rats rendered diabetic by modulation of their immune system. The rats were treated three times daily on days 1-19 with NN414, diazoxide, or vehicle. On day 21, an intravenous glucose tolerance test was conducted to assess beta-cell function. Postmortem histological analysis of rats' pancreata assessed the degree of insulitis and beta-cell volume. Among NN414-treated rats, 46% (16 of 35) were found to have a beta-cell mass similar to that of nondiabetic controls and significant glucose-stimulated C-peptide values, whereas only 11% (4 of 36) of vehicle-treated rats possessed a normal beta-cell mass and function (P < 0.002, by chi(2) test). Furthermore, responsive NN414-treated rats were almost free of insulitis. Thus, this study demonstrated that treatment with KCO compounds can indeed lead to preservation of beta-cell function and reduction of insulitis in a rat diabetes model.
用ATP敏感性钾（K(+)）通道开放剂（KCOs）进行治疗会导致胰岛素分泌受到抑制以及β细胞出现代谢“静止”状态。据推测，在1型糖尿病中，这可能会减少因代谢应激导致的β细胞死亡，同时在自身免疫性β细胞破坏过程中降低β细胞的免疫原性。我们研究了β细胞选择性KCO化合物NN414是否可用于通过调节免疫系统使糖尿病化的DR - BB大鼠改善β细胞存活情况。在第1 - 19天，每天给大鼠三次NN414、二氮嗪或赋形剂进行治疗。在第21天，进行静脉葡萄糖耐量试验以评估β细胞功能。对大鼠胰腺进行死后组织学分析以评估胰岛炎程度和β细胞体积。在接受NN414治疗的大鼠中，发现46%（35只中的16只）的β细胞量与非糖尿病对照组相似，且有显著的葡萄糖刺激C肽值，而接受赋形剂治疗的大鼠中只有11%（36只中的4只）具有正常的β细胞量和功能（通过卡方检验，P < 0.002）。此外，对NN414有反应的治疗大鼠几乎没有胰岛炎。因此，本研究表明用KCO化合物进行治疗确实可以在大鼠糖尿病模型中使β细胞功能得以保留并减少胰岛炎。
