Prevention of Cystic Fibrosis Diabetes

描述(由申请人提供)： 急性全身性高血糖会引起氧化应激和促炎反应。高血糖诱导的促炎细胞因子对胰岛细胞有毒性作用，从而加重糖耐量异常。囊性纤维化(CF)患者有高发病率的囊性纤维化相关糖尿病(CFRD)，高达40%的成人囊性纤维化发展为CFRD。在CF的糖尿病前期，存在糖耐量受损(IGT)，其特征是餐后和呼吸加重期间出现急性高血糖。这种高血糖可能会导致炎症和氧化应激，反复发作可能会导致CFRD的发展。这一过程在慢性肺病中可能会加速，因为慢性肺病肺部疾病和由此导致的呼吸恶化与氧化应激和炎症有关，这将进一步促进β细胞损伤。西格列汀是最近批准的一种治疗2型糖尿病的药物，可显著增强高血糖依赖的胰岛素分泌。申请人假设西格列汀对合并IGT的CF患者给予西格列汀可以预防CF糖尿病的发展。申请人进一步假设，由于急性高血糖会引起全身和肺内的氧化应激和促炎反应，服用西格列汀也会降低高血糖和呼吸道高糖、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，我们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的CF受试者中，进行一项随机、双盲、安慰剂对照、为期24个月的多中心纵向研究，并证明长期服用西格列汀显著降低了患CF型糖尿病的受试者的比例。 具体目标2：在这些糖耐量受损的CF受试者中，证明长期服用西格列汀：在基础条件和急性葡萄糖挑战下减少呼吸道和全身氧化应激和炎症的测量；减缓肺部疾病的进展速度；并导致细胞质量和功能的保存。

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.