The Impact of Insulin Therapy on Protein Turnover in Pre-Diabetic CF Patients

 描述(由申请人提供)：几乎所有囊性纤维化(CF)患者都存在与胰腺纤维化和胰岛细胞功能障碍相关的胰岛素不足。胰岛素分泌的渐进性异常始于儿童时期，在成人中，超过一半的CF人群最终出现CF相关糖尿病(CFRD)。CFRD与体重减轻、蛋白质分解代谢、瘦体重减少(LBM)以及因肺部疾病和营养不良而过早死亡有关。糖尿病的负面后果只是“冰山一角”，因为有证据表明，临床恶化始于糖尿病前期。非糖尿病糖耐量异常与蛋白质分解代谢、体重减轻和肺功能下降有关，所有这些都与胰岛素分泌缺陷的严重程度相关，提示胰岛素不足的关键病理作用。胰岛素是一种有效的合成代谢激素，对保持体重和肌肉质量至关重要。在一项安慰剂对照的临床试验中，胰岛素治疗改善了极早期CFRD(无空腹高血糖的CFRD)患者的体重指数(BMI)和LBM，这现在是这些患者的标准护理。越来越多的初步证据表明，胰岛素治疗在更早的时候对因胰岛素不足而患有糖尿病前期的CF患者是有益的。鉴于胰岛素缺乏在CF中的普遍存在，糖尿病的高终生风险，胰岛素缺乏和蛋白质分解代谢的临床影响以及在这一人群中保持体重和LBM的关键重要性，迫切需要确定是否应该在糖尿病实际发病之前为合成代谢目的而实施胰岛素替代治疗，如果是的话，确定最佳的方案。目前的方案描述了一项双盲、安慰剂对照试验，以确定胰岛素治疗是否改善患有CF和糖耐量异常的青年患者的蛋白质分解代谢，并探索每日多次餐前胰岛素剂量(如目前用于早期CFRD的标准剂量)与更方便的每日一次基础胰岛素剂量(如在小型非对照试点研究中使用的剂量)之间的疗效差异。这项研究的结果将为在患有CF和糖尿病前期的青年患者中使用胰岛素提供一个机制基础，并将为研究和临床实践提供信息，以确定在这一人群中使用胰岛素的最佳方案。

 DESCRIPTION (provided by applicant): Insulin insufficiency related to pancreatic fibrosis and ß-cell dysfunction is present in almost every cystic fibrosis (CF) patient. Progressive abnormalities in insulin secretion begin in childhood, and, in adults, CF related diabetes (CFRD) is eventually present in more than half of the CF population. CFRD is associated with weight loss, protein catabolism, loss of lean body mass (LBM), and early death from lung disease and malnutrition. The negative consequences of diabetes are just the "tip of the iceberg", since clinical deterioration has been documented to begin in the pre-diabetic period. Non-diabetic glucose tolerance abnormalities in CF are associated with protein catabolism, weight loss and lung function decline, all of which correlate with the severity of insulin secretory defects, suggesting a key pathologic role for insulin insufficiency. Insulin is a potent anabolic hormone, critical for maintenance of body weight and muscle mass. In a placebo-controlled clinical trial, insulin therapy improved body mass index (BMI) and LBM in patients with very early CFRD (CFRD without fasting hyperglycemia), and this is now standard care for these patients. There is growing preliminary evidence that insulin therapy is beneficial even earlier, in CF patients with pre-diabetes due to insulin insufficiency. Given the universal prevalence of insulin insufficiency in CF, the high lifetime risk of developing diabetes, the clinical impact of insulin insufficiency n protein catabolism and survival in CF, and the critical importance of maintaining body weight and LBM in this population, there is an urgent need to determine whether insulin replacement therapy should be instituted for anabolic purposes prior to the actual onset of diabetes and, if so, to ascertain the optimal regimen. The current protocol describes a double-blind, placebo-controlled trial to determine whether insulin therapy improves protein catabolism in youth with CF and abnormal glucose tolerance, and to explore differences in efficacy between multiple daily pre-meal insulin dosing (as is currently standard for early CFRD) versus a more convenient once daily basal insulin dose (as has been used in small uncontrolled pilot studies). The findings of this study will provide a mechanistic rationale for instituting insulin in youth wih CF and pre-diabetes, and will inform both research studies and clinical practice as to the best regimen for insulin delivery in this population.