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Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The pro-inflammatory cytokines induced by hyperglycemia are toxic to islet cells, the insulin producing 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 progression from normal glucose homeostasis to impaired glucose tolerance (IGT) characterized by episodes of acute hyperglycemia after meals and during respiratory exacerbations. The mild hyperglycemia seen in CF patients with IGT following a meal would be expected to induce a degree of systemic inflammation and oxidant stress. These repetitive episodes of acute postprandial hyperglycemia in CF patients, if left unchecked, could lead to progression of glucose impairment, worsening severity of postprandial hyperglycemia, worsening severity of oxidant stress and inflammation, and ultimately the development of CFRD, all via hyperglycemia-induced toxicity to beta cells. Furthermore, 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 and markedly enhances insulin secretion in the presence of hyperglycemia and has been shown to be effective in preventing postprandial hyperglycemia. The hypothesis to be tested in this project is that sitagliptin will prevent the development of CF diabetes in CF subjects with IGT by blocking postprandial hyperglycemia. The investigators propose a randomized, double-blind, placebo-controlled, multicenter, 24-month longitudinal study in 186 CF subjects with IGT to test this hypothesis.
Specifically, the investigators aim to show that chronic treatment with sitagliptin: prevents the conversion to diabetes; results in preservation of beta cell mass and function; reduces airway and systemic measures of oxidative stress and inflammation; and slows the rate of progression of lung disease. The investigators further hypothesize that treatment with sitagliptin of CFRD early in the course of the disease will result in normalization of glucose levels without requiring insulin treatment. Specifically, in those subjects that convert to diabetes, the investigators will show that sitagliptin improves glucose control, nutrition, and degree of lung dysfunction.