Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets
Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets
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DOI：
10.1172/jci60610
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发表时间：
2012-10-01
影响因子：
15.9
通讯作者：
Engelhardt, John F.
中科院分区：
文献类型：
--
作者：
Olivier, Alicia K.;Yi, Yaling;Engelhardt, John F.
糖尿病是囊性纤维化（CF）的常见合并症，影响预后。由于缺乏CF相关糖尿病（CFRD）的动物模型，因此很难分析胰腺病变的发生如何影响CFRD的发生。我们使用一种新的CFTR基因敲除雪貂模型评估新生CF内分泌胰腺的结构和功能。虽然CF试剂盒出生时仅患有轻度外分泌胰腺疾病，但在出生后最初几个月内进行性外分泌和内分泌胰腺损失与胰腺炎症、自发性高血糖症和葡萄糖耐受不良相关。有趣的是，在发生主要外分泌胰腺疾病之前，CF试剂盒显示血糖和胰岛素调节的显著异常，包括响应于葡萄糖的第一时相胰岛素分泌减少和峰值胰岛素分泌增加，葡萄糖激发后峰值葡萄糖水平升高，以及非禁食状态下胰岛素和C肽水平显著升高。虽然出生时基因型之间的小叶胰岛素和胰高血糖素表达没有差异，但观察到小胰岛和大胰岛的频率发生了显着变化。与对照组相比，新生儿培养的CF胰岛表现出葡萄糖依赖性胰岛素分泌失调，表明CF胰岛存在内在异常。这些发现表明CF内分泌胰腺对胰岛素分泌的调节存在早期异常。
Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas.