Early Pathogenesis of Cystic Fibrosis Related Diabetes

描述(申请人提供)：囊性纤维化(CF)是高加索人群中最常见的致死性遗传病，由囊性纤维化传导调节因子(CFTR)氯通道缺陷引起。慢性阻塞性肺疾病是一种影响肺、胰腺、肝、肠、胆的多脏器疾病。囊性纤维化相关糖尿病(CFRD)是CF最常见的重要并发症，与发病率和死亡率增加有关。CFRD在病理生理学上有别于1型和2型糖尿病，它显著恶化了CF患者的营养和肺健康。血糖异常在CF儿童中很常见，在6-10岁的CF儿童中，有13%的儿童血糖水平异常，在未来几年内患糖尿病的风险极高。 我们对3个月至5岁的CFRD雪貂和儿童的研究表明，CFRD的基础发生在生命的早期。在12名年龄在1-5岁且至少有一个ΔF508等位基因的儿童中，42%的人存在糖耐量异常。与年龄稍大的儿童(6-10岁时为13%)相比，幼龄CF儿童糖耐量异常的发生率较高，这与我们的发现一致，即在CF雪貂中，葡萄糖耐量异常的发展是分阶段的(中间有暂时的恢复期)，这与胰岛轴激素调节和胰腺纤维化重塑的变化有关。R24的一个主要目标是确定与CF胰腺重塑和CFRD发展有关的早期病理生理事件。在幼年CF儿童中观察到的岛轴和肠岛轴激素的紊乱与积极和消极的适应性变化都影响胰岛素调节和潜在的胰岛素作用的假设是一致的。类似的与年龄相关的变化也发生在CF雪貂中，这将使我们能够剖析这些过程背后的机制。在分离的人、雪貂和猪胰岛上的研究表明，CFTR通过其在内分泌细胞或胰岛相关导管细胞中的活性影响胰岛对葡萄糖刺激的胰岛素分泌。这项拟议的研究将确定改变CF中胰岛素分泌和血糖状态的胰腺内源性和外源性事件，重点在于确定(I)在体外和体内控制CFTR依赖的胰岛素分泌的胰岛内源性机制，(Ii)导致CF胰岛素分泌异常和葡萄糖生理改变的胰腺外源性机制，以及(Iii)内分泌重建在多大程度上促进随后的胰岛素分泌异常，以及在CF中改善胰腺炎症的初级波是否可以防止不良适应性胰岛重建。这些研究有望确定CFRD风险的早期血液生物标记物，以及早期干预的方法。

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is the most common significant complication of CF and is associated with increased morbidity and mortality. CFRD, which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly worsens the nutritional and pulmonary health of CF patients. Glycemic abnormalities are common in children with CF, and the 13% of CF children 6-10 years of age that have abnormal glycemic status are at extraordinarily high risk for developing diabetes within the next few years. Our studies in CF ferrets and children 3 months to 5 years of age suggest that the underpinnings of CFRD occur very early in life. Of 12 CF subjects who were 1-5 years of age and have at least one ΔF508 allele, 42% demonstrated abnormal glucose tolerance. This high incidence of abnormal glucose tolerance in young CF children as compared to slightly older children (13% at 6-10 years of age) is consistent with our discovery that in CF ferrets glucose intolerance develops in phases (with intervening periods of temporary recovery) that are associated with changes in the regulation of insular axis hormones and fibrotic remodeling of the pancreas. A major goal of this R24 is to identify the early pathophysiologic events involved in CF pancreas remodeling and the development of CFRD. The observed disturbances in insular and entero-insular axis hormones in young CF children are consistent with the hypothesis that both positive and negative adaptive changes influence insulin regulation, and potentially insulin action. Similar age-dependent alterations occur in CF ferrets and will enable us to dissect the mechanisms that underlie these processes. Studies in isolated human, ferret, and pig islets have demonstrated that CFTR impacts glucose-stimulated insulin secretion by islets through its activity in either endocrine cells or islet-associated ductal cells. The propose research will identify pancreas-intrinsic and -extrinsic events that alter insulin secretion and glycemic status in CF, with a focus on defining (i) the islet-intrinsic mechanisms that control CFTR-dependent insulin secretion in vitro and in vivo, (ii) the pancreas-extrinsic mechanisms that lead to abnormal insulin secretion and altered glucose physiology in CF, and (iii) the extent to which endocrine pancreas remodeling contributes to subsequent abnormalities in insulin secretion, and whether amelioration of the primary wave of pancreas inflammation in CF can prevent maladaptive islet remodeling. These studies are expected to identify early blood biomarkers of CFRD risk, as well as methods for early intervention.