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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的主要目的是确定胰岛素或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无空腹高血糖症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）患者现在存活超过儿童期，由于胰岛素缺乏，CF相关糖尿病（CFRD）很常见。在25%的CF成人中发现了无空腹高血糖（FH）的CFRD，并与发病率和死亡率增加相关。 与糖耐量正常的CF患者相比，这些患者的BMI和肺功能恶化更快。 胰岛素缺乏会改变蛋白质和脂肪代谢，导致体重和瘦体重减轻，并导致肺部疾病和临床衰退。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，但这些患者不常规使用外源性胰岛素治疗。 初步的同位素数据表明，胰岛素和口服降糖药瑞格列奈（程度较轻）可显著改善无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，这将对成人CF患者的当前治疗和预后产生重大影响。 这些患者是否应该接受糖尿病治疗的问题在CFRD全国共识会议上被赋予了未来研究资金的最高优先权。 具体目标#1 招募150例无空腹高血糖症的成人CFRD患者，进行一项多中心、12个月、安慰剂对照干预试验，检测胰岛素或瑞格列奈改善CF患者BMI和稳定肺功能的能力。 具体目标#2 每三个月检查一次参与者，以获得体重和身高测量值以及饮食评估，每六个月检查一次参与者，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 接受胰岛素或瑞格列奈治疗的受试者与对照受试者相比，其BMI会增加。 假设#2 在BMI增加时，胰岛素比瑞格列奈更有效。 假设#3 BMI的增加主要是由于肌肉质量的增加。 假设#4 BMI的增加将在膳食常量营养素或卡路里组成没有显著变化的情况下完成。 具体目标#3 每隔三个月检查参与者的肺功能和握力的临床评估，并在基线和12个月评估NIH临床评分。 假设#5 胰岛素或瑞格列奈治疗将防止肺功能下降相比，对照组和他们自己的基线测量前一年。 这将与NIH临床评分的改善相关，并与体重增加和大腿肌肉体积增加直接相关。 假设#6 接受胰岛素或瑞格列奈治疗的受试者将改善握力，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.