Uc Aliye, Olivier Alicia K, Griffin Michelle A, Meyerholz David K, Yao Jianrong, Abu-El-Haija Maisam, Buchanan Katherine M, Vanegas Calderón Oriana G, Abu-El-Haija Marwa, Pezzulo Alejandro A, Reznikov Leah R, Hoegger Mark J, Rector Michael V, Ostedgaard Lynda S, Taft Peter J, Gansemer Nick D, Ludwig Paula S, Hornick Emma E, Stoltz David A, Ode Katie L, Welsh Michael J, Engelhardt John F, Norris Andrew W
*Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
†Department of Pathology, University of Iowa, Iowa City, IA, U.S.A.
Clin Sci (Lond). 2015 Jan;128(2):131-42. doi: 10.1042/CS20140059.
Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF. In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.
糖尿病是囊性纤维化（CF）常见且重要的合并症。囊性纤维化相关糖尿病（CFRD）的发病机制尚未完全阐明。由于人类和患有CF的猪的外分泌胰腺疾病相似，CF猪模型有可能为理解CFRD发病机制做出重大贡献。我们确定了胎儿期、新生期及大龄CF猪和非CF猪内分泌胰腺的结构，并通过静脉葡萄糖耐量试验（IV-GTT）评估内分泌胰腺功能。在胎儿期猪中，CF猪和非CF猪的胰腺胰岛素和胰高血糖素密度相似。在新生期和大龄猪中，CF猪和非CF猪每单位胰腺总面积的胰岛素和胰高血糖素密度没有变化，但CF猪每单位残余小叶组织中的密度增加，反映出外分泌胰腺的损失。虽然CF新生猪和非CF新生猪的空腹血糖水平没有差异，但CF新生猪在IV-GTT期间表现出葡萄糖耐量受损和曲线下葡萄糖面积增加。CF新生猪的二期胰岛素分泌反应受损，且明显低于非CF新生猪。与非CF猪相比，大龄CF猪的随机血糖水平升高。总之，CF新生猪存在血糖异常和胰岛素分泌缺陷，且随着时间推移会出现自发性高血糖。CF猪胰腺的功能变化与胰岛细胞数量减少无关。我们的结果表明，独立于胰岛结构损失的功能性胰岛异常促成了CFRD的早期发病机制。
