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

胰岛素治疗对糖尿病前期 CF 患者蛋白质周转的影响

• 批准号: 9115576
• 负责人: Antoinette M. Moran
• 金额: $ 69.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115576
• 关键词: Address; Adult; Affect; Age; Albumins; American; Beta Cell; Body Weight; Body Weight decreased; Body mass index; Catabolism; Cells; Cessation of life; Childhood; Clinical; Consensus; Controlled Clinical Trials; Cystic Fibrosis; Defect; Deterioration; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Educational workshop; Endocrine; Fasting; Fibrosis; Foundations; Functional disorder; Health; Hormones; Hyperglycemia; Individual; Institutes; Insulin; Lung diseases; Maintenance; Malnutrition; Methods; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Oxidative Stress; Pancreas; Pathologic; Pathology; Patients; Pilot Projects; Placebo Control; Placebos; Population; Prediabetes syndrome; Prevalence; Proteins; Protocols documentation; Regimen; Replacement Therapy; Research Priority; Respiratory physiology; Role; Severities; Societies; Therapeutic; Transferrin; Youth; basal insulin; clinical practice; cystic fibrosis patients; diabetic; double-blind placebo controlled trial; early cystic fibrosis; glucose tolerance; improved; insulin secretion; lean body mass; lifetime risk; loss of function; mortality; muscle form; non-diabetic; novel; oxidative damage; placebo controlled study; protein degradation; research study; standard care; sulfated glycoprotein 2; symposium

 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.

 描述（由申请方提供）：几乎所有囊性纤维化（CF）患者均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。胰岛素分泌的进行性异常开始于儿童期，在成人中，CF相关的糖尿病（CFRD）最终存在于超过一半的CF人群中。CFRD与体重减轻、蛋白质分解、瘦体重（LBM）减少以及肺病和营养不良导致的早期死亡有关。糖尿病的负面后果只是“冰山一角”，因为临床恶化已被记录为在糖尿病前期开始。CF中的非糖尿病葡萄糖耐量异常与蛋白质分解、体重减轻和肺功能下降相关，所有这些都与胰岛素分泌缺陷的严重程度相关，表明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，对维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，现在这是这些患者的标准治疗。有越来越多的初步证据表明，胰岛素治疗是有益的，甚至更早，在CF患者与糖尿病前期由于胰岛素不足。考虑到CF中胰岛素不足的普遍患病率、发生糖尿病的高终生风险、胰岛素不足对CF中蛋白质代谢和存活率的临床影响以及在该人群中维持体重和LBM的至关重要性，迫切需要确定是否应在糖尿病实际发作之前开始胰岛素替代疗法以用于合成代谢目的，如果是，来确定最佳的治疗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能改善患有CF和糖耐量异常的青年的蛋白质代谢，并探索每日多次餐前胰岛素给药（目前是早期CFRD的标准）与更方便的每日一次基础胰岛素剂量（已用于小型非对照初探性研究）之间的疗效差异。本研究的结果将为在患有CF和糖尿病前期的年轻人中建立胰岛素提供机械原理，并将为研究和临床实践提供关于该人群中胰岛素输送的最佳方案的信息。