Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice
Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice
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DOI：
10.1530/eje.0.1460717
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发表时间：
2002-05-01
影响因子：
5.8
通讯作者：
Ahrén, B
中科院分区：
文献类型：
--
作者：
Reimer, MK;Holst, JJ;Ahrén, B
目的：胰高血糖素样肽-1（GLP-1）降解酶二肽基肽酶IV（DPPIV）的抑制剂正在糖尿病的治疗中进行探索。我们研究了一种选择性口服DPPIV抑制剂的长期影响，在正常雌性C57 BL/6 J小鼠中，NVP DPP 728，通过喂食高脂饮食，这些小鼠呈现葡萄糖不耐受和胰岛素抵抗。在喂食标准饮食（11%脂肪）或高脂肪饮食（58%脂肪）的小鼠中，NVP DPP728（0.12 μ mol/g体重）在饮用水中给药8周。DPPIV抑制使血浆DPPIV活性降低至0.01 +/- 0.03 mU/ml，而对照组为3.26 +/- 0.19 mU/ml（P < 0.001）。通过120分钟研究期间血浆葡萄糖水平曲线下面积判断，胃饲葡萄糖后的葡萄糖耐量在喂食正常饮食的小鼠（P = 0.029）和喂食高脂饮食的小鼠（P = 0.036）中通过NVP DPP 728增加8周。这伴随着胰岛素和完整GLP-1的血浆水平升高。与对照动物的胰岛相比，在5.6、8.3和11.1 mmol/l葡萄糖下，在喂食正常饮食的小鼠和喂食高脂饮食的小鼠中，在处理8周后，从NVP DPP 728处理动物分离的胰岛的葡萄糖刺激的胰岛素分泌增加（均P < 0.05）。胰岛胰岛素和胰高血糖素免疫细胞化学显示NVP DPP 728不影响胰岛结构。然而，免疫反应性葡萄糖转运蛋白亚型2（GLUT-2）的表达因DPPIV抑制而增加，在喂食高脂饮食的小鼠中，NVP DPP 728处理后胰岛大小从对照组的16.7 +/- 2.6 × 10（3）mum（2）降至7.6 +/- 1.0 × 10（3）mum（2）。结论：长期DPPIV抑制通过改善胰岛功能改善正常和葡萄糖不耐受小鼠的葡萄糖耐受性，如通过增加GLUT-2表达、增加胰岛素分泌和保护胰岛素抵抗中胰岛大小的增加所判断的。
Objectives: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet.Design: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 mumol/g body weight) was administered in the drinking water for an 8 week period.Results: DPPIV inhibition reduced plasma DPPIV activity to 0.01 +/- 0.03 mU/ml vs 3.26 +/- 0.19 mU/ml in controls (P < 0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P = 0.029) and in mice fed a high-fat diet (P = 0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P < 0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7 +/- 2.6 x 10(3) mum(2) in controls to 7.6 +/- 1.0 X 10(3) mum(2) (p = 0.0019).Conclusion: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.