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.
CF is the most common fatal inherited disease of Caucasians and affects about 30,000 people in the US. Over 90% of the morbidity and mortality is due to progressive pulmonary disease. Patients with CFRD have a significantly higher mortality, up to 6-fold higher, than CF patients without diabetes. Death in CFRD is due to accelerated progression of lung disease and respiratory failure, not diabetes-induced vascular disease. Thus, preventing the development of CFRD would improve survival of CF patients as well as quality of life.
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