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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：几乎每个囊性纤维化 (CF) 患者都存在与胰腺纤维化和 β 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始于儿童期，而在成人中，囊性纤维化相关糖尿病 (CFRD) 也开始出现。最终存在于超过一半的 CF 人群中，CFRD 与体重减轻、蛋白质分解代谢、去脂体重 (LBM) 减少和早逝有关。肺部疾病和营养不良只是“冰山一角”，因为临床恶化已被证明是在糖尿病前期开始的，CF 的非糖尿病葡萄糖耐量异常与蛋白质分解代谢、体重有关。损失和肺功能下降，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，对于维持体重和肌肉至关重要。在一项安慰剂对照临床试验中，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，目前有初步证据表明，这是这些患者的标准护理。考虑到 CF 患者普遍存在胰岛素不足、终生患糖尿病的风险较高、胰岛素不足的临床影响，对于因胰岛素不足而患有糖尿病前期的 CF 患者来说，治疗甚至更早也是有益的。由于 CF 中的蛋白质分解代谢和生存，以及体重和 LBM 在该人群中的至关重要性，迫切需要确定是否应在糖尿病实际发病前出于合成代谢目的而开始胰岛素替代治疗，如果是，则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可以改善患有 CF 和糖耐量异常的青少年的蛋白质分解代谢，并探讨每日多次餐前胰岛素的疗效差异。剂量（如目前早期 CFRD 的标准）与更方便的每日一次胰岛素基础剂量（如在小型非对照试点研究中使用的）相比，本研究的结果将为患有 CF 和 pre 的青少年提供胰岛素的机制原理。 -糖尿病，并将为研究和临床实践提供有关该人群胰岛素输送最佳方案的信息。