DIABETES THER TO IMPROVE BMI & PULM FUNCT IN CF SUBJ WITH ABNORMAL GLUC TOL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary objective of this research is to determine whether treatment with either insulin or an oral diabetes agent that increases endogenous insulin secretion will improve body mass index (BMI) and pulmonary function in cystic fibrosis patients who have diabetes without fasting hyperglycemia. The majority of cystic fibrosis (CF) patients now survive beyond childhood, and CF related diabetes (CFRD), due to insulin deficiency, is common. CFRD without fasting hyperglycemia (FH) is found in 25% of CF adults and is associated with increased morbidity and mortality. BMI and pulmonary function deteriorate much more rapidly in these patients than in CF patients with normal glucose tolerance. Insulin deficiency alters protein and fat metabolism resulting in loss of weight and lean body mass and contributing to pulmonary disease and clinical decline. These patients are not routinely treated with exogenous insulin despite the detrimental effects of insulin deficiency on protein and fat metabolism, weight, and lean body mass. Preliminary isotopic data have shown that insulin and, to a lesser extent, the oral diabetes agent repaglinide acutely improve protein synthesis in patients with CFRD without FH. If it can be shown that insulin or repaglinide also improves body mass and pulmonary function, it would have a major impact on the current therapy and prognosis for adult CF patients. The question of whether these patients should receive diabetes therapy was given the highest priority for future research funding at a national consensus conference on CFRD. SPECIFIC AIM #1 To recruit 150 adult patients with CFRD without fasting hyperglycemia for a multi-center, twelve month, placebo-controlled intervention trial testing the ability of insulin or repaglinide to improve BMI and stabilize pulmonary function in CF. SPECIFIC AIM #2 To examine participants at three-month intervals to obtain weight and height measurements and diet assessment, and at six-month intervals for MRI measurement of thigh muscle volume and DEXA estimation of lean body mass (LBM). Hypothesis #1 Participants receiving either insulin or repaglinide will increase their BMI compared to control participants. Hypothesis #2 Insulin will be more effective than repaglinide at increasing BMI. Hypothesis #3 The increase in BMI will be primarily due to increased muscle mass. Hypothesis #4 The increase in BMI will be accomplished without significant changes in dietary macronutrient or calorie composition. SPECIFIC AIM #3 To examine participants at three-month intervals for clinical assessment of pulmonary function and hand grip strength, and at baseline and twelve months for assessment of the NIH clinical score. Hypothesis #5 Insulin or repaglinide therapy will prevent pulmonary function decline compared to both control subjects and to their own baseline as measured the previous year. This will be associated with improvement in NIH clinical score and will be directly related to weight gain and increase in thigh muscle volume. Hypothesis #6 Participants receiving insulin or repaglinide will improve hand grip strength, and this will be directly related to weight gain and increase in thigh muscle volume.