JCI：囊性纤维化引发病人患糖尿病的机制

近日，来自爱荷华大学研究者的一项研究揭示了，和囊性纤维化相关的一种糖尿病的两个根本原因。这项研究发现后续为临床开发出抑制囊性纤维化病人患糖尿病提供新的思路，相关研究成果刊登在了9月17日的国际杂志Journal of Clinical Investigation上。

近乎一半的囊性纤维化（CF）病人在其30岁的时候都会患上糖尿病，然而有四分之一的患者在其青少年时期都已经换上了糖尿病。目前对于囊性纤维化病人患糖尿病的原因并不清楚。因此本文研究作者试图揭开这个谜题，研究者使用新型的CF动物模型，通过深入研究发现了产生胰岛素器官-胰腺的两种异常现象，研究揭示了囊性纤维化可以损伤胰腺，破坏胰岛素产生。更有意思的是，研究者也发现了，早在物理损伤之前，囊性纤维化就可以破坏胰腺的胰岛素产生。

在人类中，CF可以损伤胰腺，进而降低胰岛素产量，研究者发现患CF的雪貂在其1-2月大的时候就可以患上糖尿病。这项研究首次揭示了来源于胰腺物理损伤的CF相关的糖尿病可以限制胰腺产生胰岛素。

通过进一步研究，研究者发现，在雪貂出生时，囊性纤维化就可以破坏其胰岛素的产生。在囊性纤维化病人中氯离子通道的缺失直接或者间接地可以控制胰岛素的产生。这或许揭示了CF相关糖尿病的主要根源，也可以帮助科学家开发出新型的疾病疗法。

研究者Norris总接道，尽管这些研究重点关注了囊性纤维化相关的糖尿病，但是未来研究中研究，囊性纤维化氯离子通道功能如何调节胰岛素的分泌或许可以帮助研究者开发出治疗II型糖尿病或者其它类型糖尿病的潜在疗法。

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Alicia K. Olivier1, Yaling Yi2, Xingshen Sun2, Hongshu Sui2, Bo Liang2, Shanming Hu3, Weiliang Xie2, John T. Fisher2, Nicholas W. Keiser2, Diana Lei2, Weihong Zhou2, Ziying Yan2, Guiying Li4, Turan I.A. Evans2, David K. Meyerholz1, Kai Wang5, Zoe A. Stewart4, Andrew W. Norris3,6 and John F. Engelhardt2,6

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.