Prevention of Cystic Fibrosis Diabetes

描述（由申请人提供）： 急性全身性高血糖引起氧化应激和促炎反应。由高血糖诱导的促炎细胞因子对胰岛细胞具有毒性，从而加重葡萄糖耐受不良。囊性纤维化（CF）患者的CF相关糖尿病（CFRD）患病率较高，高达40%的CF成人发生CFRD。 在CF的糖尿病前期，存在以餐后和呼吸恶化期间急性高血糖发作为特征的糖耐量受损（IGT）。 预计这种高血糖会诱导炎症和氧化应激，反复发作可能导致CFRD的发展。 这一过程可能在CF中加速，因为CF肺病和由此产生的呼吸恶化与氧化应激和炎症相关，这将进一步导致β细胞损伤。西格列汀是最近批准的2型糖尿病药物，可显著增强高血糖依赖性胰岛素分泌。 申请方假设IGT CF患者接受西格列汀给药可预防CF糖尿病的发生。申请人进一步假设，由于急性高血糖症在CF中引起全身和肺部的氧化应激和促炎反应，西格列汀给药还将降低高血糖症和气道高糖血症、氧化应激和炎症。西格列汀的这些作用将转化为改善肺部健康和细胞功能。为了检验这些假设，提出了以下具体目标： 具体目标1： 在16岁或16岁以上的糖耐量受损CF受试者中，开展一项随机、双盲、安慰剂对照、24个月纵向、多中心研究，证明长期西格列汀给药可显著降低发生CF糖尿病的受试者比例。 具体目标#2： 在这些糖耐量受损的CF受试者中，证明长期西格列汀给药：在基础条件下和急性葡萄糖挑战下降低气道和全身氧化应激和炎症指标;减缓肺部疾病的进展速度;并导致细胞质量和功能的保留。

DESCRIPTION (provided by applicant): Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The pro-inflammatory cytokines induced by hyperglycemia are toxic to islet cells and thus worsen glucose intolerance. Patients with cystic fibrosis (CF) have a high prevalence of CF related diabetes (CFRD) and up to 40% of CF adults develop CFRD. During the prediabetic phase in CF, there is impaired glucose tolerance (IGT) characterized by episodes of acute hyperglycemia after meals and during respiratory exacerbations. This hyperglycemia would be expected to induce inflammation and oxidant stress, which, with repeated episodes could lead to the development of CFRD. This process may be accelerated in CF because CF lung disease and resultant respiratory exacerbations are associated with oxidative stress and inflammation and this will further contribute to beta cell damage. Sitagliptin is a recently approved agent for type 2 diabetes that markedly enhances hyperglycemia-dependent insulin secretion. The applicant hypothesized that administration of sitagliptin in CF patients with IGT will prevent the development of CF diabetes. The applicant further hypothesized that because acute hyperglycemia causes oxidative stress and a pro-inflammatory response both systemically and in the lung in CF, administration of sitagliptin will also reduce hyperglycemia and airway hyperglycosis, oxidative stress, and inflammation. These actions of sitagliptin will translate to improved lung health and ¿ cell function. To test these hypotheses, the following specific aims are proposed: Specific Aim #1: In CF subjects aged 16 years of age or older who have impaired glucose tolerance, conduct a randomized, double-blind, placebo-controlled, 24-month longitudinal, multi-center study and demonstrate that chronic sitagliptin administration significantly decreases the fraction of subjects that develops CF diabetes. Specific Aim #2: In these CF subjects with impaired glucose tolerance, demonstrate that chronic sitagliptin administration: reduces airway and systemic measures of oxidative stress and inflammation both under basal conditions and with an acute glucose challenge; slows the rate of progression of lung disease; and results in preservation of ¿ cell mass and function.