Progressive erosion of β-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes.
Progressive erosion of β-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes.
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DOI：
10.2337/db11-0373
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发表时间：
2011-08
期刊：
影响因子：
7.7
通讯作者：
Mathews CE
中科院分区：
文献类型：
--
作者：
Ize-Ludlow D;Lightfoot YL;Parker M;Xue S;Wasserfall C;Haller MJ;Schatz D;Becker DJ;Atkinson MA;Mathews CE
在1型糖尿病发病前，胰岛素对葡萄糖的反应进行性下降。我们确定这种异常是否发生在糖尿病前期NOD小鼠-人类1型糖尿病的原型模型。在NOD女性队列中每隔一天测量一次早晨血糖。在6至14周龄的NOD/ShiLtJ和BALB/cJ小鼠中通过腹膜内葡萄糖耐量试验纵向测量葡萄糖耐量和胰岛素分泌。精氨酸刺激的胰岛素分泌和胰岛素敏感性进行了评估，在腹腔内精氨酸或腹腔内胰岛素耐量试验。在糖尿病前期，NOD女性表现出葡萄糖水平的逐步增加，随后出现急性高血糖症。在NOD中，腹膜内葡萄糖耐量试验（IPGTT）期间的第一时相胰岛素反应（FPIR）在葡萄糖耐量丧失之前下降。可检测到FPIR失败，IPGTT期间胰岛素分泌峰值下降。精氨酸刺激的胰岛素分泌在研究期间保持不变。NOD小鼠胰岛素分泌的下降不能用胰岛素敏感性的变化来解释。在葡萄糖耐量变化之前，FPIR显著下降，表明FPIR受损是NOD小鼠和人1型糖尿病中进行性β细胞衰竭的早期体内标志物。我们预示NOD小鼠的这些表型与1型糖尿病患者的表型相似，并以一种新的方式验证了这种动物模型对研究这种疾病的重要性。
A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes. Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests. During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity. There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.
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