DIABETES THER TO IMPROVE BMI & PULMONARY FUNCTION IN CF WITH ABN GLUCOSE TOL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项研究的主要目的是确定胰岛素或一种增加内源性胰岛素分泌的口服糖尿病药物治疗是否会改善患有糖尿病但没有空腹高血糖的囊性纤维化患者的体重指数(BMI)和肺功能。 大多数囊性纤维化(CF)患者现在可以存活到童年以后，由于胰岛素缺乏而导致的囊性纤维化相关糖尿病(CFRD)很常见。无空腹高血糖(FH)的CFRD在25%的CF成人中被发现，并与增加的发病率和死亡率有关。与糖耐量正常的CF患者相比，这些患者的体重指数和肺功能恶化得更快。胰岛素缺乏会改变蛋白质和脂肪代谢，导致体重减轻和瘦体重，并导致肺部疾病和临床下降。尽管胰岛素缺乏对蛋白质和脂肪代谢、体重和瘦体重有不利影响，但这些患者并未常规接受外源性胰岛素治疗。初步的同位素数据表明，胰岛素和口服糖尿病药物瑞格列奈(在较小程度上)显著改善了无FH的CFRD患者的蛋白质合成。如果能证明胰岛素或瑞格列奈也能改善体重和肺功能，这将对目前成人CF患者的治疗和预后产生重大影响。在关于CFRD的全国共识会议上，这些患者是否应该接受糖尿病治疗的问题被列为未来研究资金的最高优先事项。 特定目标#1 招募150名无空腹高血糖的成人CFRD患者，进行多中心、12个月的安慰剂对照干预试验，测试胰岛素或瑞格列奈改善CFRD患者体重指数和稳定肺功能的能力。 特定目标#2 每隔三个月对参与者进行一次检查，以获得体重和身高测量以及饮食评估，并每六个月检查一次，以进行大腿肌肉体积的MRI测量和瘦体重(LBM)的DEXA估计。 假设1 与对照组相比，接受胰岛素或瑞格列奈的参与者会增加他们的BMI。 假设2 在增加BMI方面，胰岛素比瑞格列奈更有效。 假设3 体重指数的增加将主要是由于肌肉质量的增加。 假设4 体重指数的增加将在饮食中大量营养素或卡路里组成没有明显变化的情况下实现。 特定目标#3 每隔3个月对参与者进行一次肺功能和握力的临床评估，并在基线和12个月对NIH临床评分进行评估。 假设5 胰岛素或瑞格列奈治疗将防止肺功能下降，与对照组和他们自己在前一年测量的基线相比。这将与NIH临床评分的改善有关，并将与体重增加和大腿肌肉体积的增加直接相关。 假设6 接受胰岛素或瑞格列奈的参与者将改善手握力，这将与体重增加和大腿肌肉体积增加直接相关。

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.