This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cystic fibrosis (CF) is the most common, lethal autosomal recessive disorder in Caucasians. Pulmonary disease, marked by dysregulated inflammation and chronic infection is the major cause of morbidity and mortality in CF. Although, there has been considerable progress in the therapy of CF in recent decades, the median survival of patients with CF remains around 35 years. Novel therapeutic approaches are clearly needed. There is an direct correlation between nutritional status and the severity of lung disease in patients with CF. Malabsorption due to pancreatic exocrine insufficiency is the norm in CF. Even with reversal of malabsorption via pancreatic enzyme therapy, negative nitrogen balance is common. In fact, patients with CF have abnormally high rates of protein catabolism of unknown etiology. Correction of protein hyper-catabolism should provide significant clinical benefits for patients with CF. Recent reports raise the possibility that pancreatic endocrine insufficiency underlies negative nitrogen balance in patients with CF. Of note, most CF patientseven those with normal glucose tolerance testsexhibit functionally key defects in insulin secretion. Among the many important roles ascribed to insulin, its anabolic effects (e.g., promotion of protein and triglyceride storage) is of likely relevance in CF. Consistent with this, two small case series suggest that therapeutic administration of low dose insulin appears to improve nutritional status and pulmonary function in non-diabetic CF patients. Taken together, these data suggest both an underlying mechanism for this critical nutritional problem in CF, as well as a practical therapeutic strategy. If true, insulin therapy has the potential for having a major impact on clinical care and outcomes in CF. A pilot study to determine the maximal dose of long acting insulin needed to reduce catabolism without inducing hypoglycemia is necessary to further explore the potential of insulin therapy in CF. It should also be noted that, in addition to direct effects on nitrogen balance, insulin may well have another important salutary effect on CF-related pulmonary disease. Dysregulated inflammatory responses are thought to be central to the pathogenesis of airway disease in CF. Indeed, both steroids and non-steroidal anti-inflammatory drugs appear to preserve lung function in patients with CF, without increasing the pulmonary infectious burden. It has recently become apparent that insulin has important anti-inflammatory effects. These findings suggest that: (a) the aberrant proinflammatory diathesis of the CF airway may further be augmented by insulin deficiency; and (b) provision of exogenous insulin may reverse this, acting to suppress maladaptive pulmonary inflammation. The long-term goal of this research program is to generate and validate novel therapeutic approaches to compromised nutritional status and lung disease in patients with CF. The specific goals of this project are to determine the dose of exogenous insulin therapy necessary to reduce protein catabolism and inflammation without inducing hypoglycemia. Our central hypothesis is that daily administration of low dose, long-acting insulin to non-diabetic CF patients with defects in insulin secretion can be safely titrated up without inducing hypoglycemia. Our inter-related secondary hypotheses are that such treatment will lead to measurable improved catabolism and decreased pulmonary inflammation. Our exploratory hypotheses are that such treatment will impact nutritional and pulmonary clinical outcomes. To test these hypotheses, we will address to following Specific Aims: 1) Primary Specific Aim: To determine a safe, maximum dose of exogenous insulin administration in non-diabetic patients with CF. Working Hypothesis: Daily administration of low-dose, long acting insulin can be safely titrated without inducing hypoglycemia. 2) Secondary Specific Aims: A) To determine the measurability of effect on protein catabolism of exogenous insulin in patients with CF. Working Hypothesis: The effect of daily administration of low dose, long acting insulin on protein catabolism is measurable in patients with CF. B) To determine the measurability of effect on pulmonary inflammation of exogenous insulin administration in patients with CF. Working Hypothesis: The effect of daily administration of low dose, long acting insulin on pulmonary inflammation is measurable in patients with CF.
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