Early Pathogenesis of Cystic Fibrosis Related Diabetes

描述（由申请人提供）：囊性纤维化（CF）是高加索人群中最常见的致死性遗传疾病，由囊性纤维化传导调节因子（CFTR）氯离子通道缺陷引起。CF是一种影响肺、胰腺、肝、肠和胆囊的多器官疾病。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在病理生理学上与1型和2型糖尿病不同，显著影响CF患者的营养和肺部健康。糖基化异常在患有CF的儿童中很常见，并且具有异常血糖状态的6-10岁CF儿童的13%在未来几年内发展为糖尿病的风险非常高。 我们对CF雪貂和3个月至5岁儿童的研究表明，CFRD的基础发生在生命的早期。在12名1-5岁且至少有一个ΔF508等位基因的CF受试者中，42%表现出糖耐量异常。与稍大的儿童相比，年幼CF儿童中葡萄糖耐量异常的发生率较高（6-10岁时为13%），这与我们的发现一致，即CF雪貂葡萄糖耐量不耐症的发展是分阶段的（有暂时恢复的干预期），与胰岛轴激素调节和胰腺纤维化重塑的变化有关。R24的主要目标是确定CF胰腺重塑和CFRD发展中涉及的早期病理生理事件。在幼年CF儿童中观察到的胰岛和肠-胰岛轴激素紊乱与以下假设一致，即积极和消极的适应性变化都影响胰岛素调节，并可能影响胰岛素作用。类似的年龄依赖性改变发生在CF雪貂，将使我们能够剖析这些过程的机制。在分离的人、雪貂和猪胰岛中的研究已经证明，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的葡萄糖刺激的胰岛素分泌。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，重点是定义（i）体外和体内控制CFTR依赖性胰岛素分泌的胰岛内源性机制，（ii）导致CF中胰岛素分泌异常和葡萄糖生理学改变的胰腺外源性机制，以及（iii）内分泌胰腺重塑导致随后的胰岛素分泌异常的程度，以及CF中胰腺炎症的初级波的改善是否可以防止适应不良的胰岛重塑。预计这些研究将确定CFRD风险的早期血液生物标志物以及早期干预方法。

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.