Circulating miRNA Signatures of Beta-Cell Response to Metformin or Insulin in Youth with Dysglycemia

患有血糖异常的青少年β细胞对二甲双胍或胰岛素反应的循环miRNA特征

• 批准号: 9975159
• 负责人: Pandora Luke Januszewski
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975159
• 关键词: 19 year old; Acute; Address; Adipose tissue; Adult; Age; Arginine; Beta Cell; Biological Assay; Blood Circulation; C-Peptide; Cell physiology; Chemosensitization; Childhood; Data; Development; Diabetes prevention; Disease; Disease remission; Epigenetic Process; Failure; Gene Expression; Genes; Glucose; Goals; Infusion procedures; Insulin; Insulin Resistance; Intervention; Linear Models; Liver; Logistic Regressions; Logistics; Measures; Mediating; Mediation; Medical; Metabolic; Metabolism; Metformin; MicroRNAs; Minority; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Participant; Pathologic; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Prediabetes syndrome; Prevalence; Preventive; Randomized; Randomized Controlled Trials; Role; Sampling; Skeletal Muscle; Specificity; Testing; Tissues; Untranslated RNA; Work; Youth; blood glucose regulation; circulating microRNA; design; diabetes mellitus therapy; epigenetic marker; epigenetic regulation; experience; glargine; glucose metabolism; impaired glucose tolerance; insulin secretion; insulin sensitivity; lifestyle intervention; novel; prevent; primary outcome; response; secondary analysis; transcriptome sequencing

ABSTRACT Youth with prediabetes (impaired glucose tolerance) or type 2 diabetes (T2D) experience relatively rapid beta-cell failure that is not prevented or delayed by metformin or insulin. Mechanisms underlying the fulminant course of T2D and the lack of preventive benefit from metformin and insulin in youth are unknown. Epigenetic biomarkers such as microRNAs (miRNAs) regulate genes important in glucose and insulin metabolism and may play a role in mediating responsiveness to metformin or insulin. miRNAs are short non-coding RNAs that regulate expression of genes important to glucose homeostasis, but their role in systemic responses to metformin and insulin is poorly understood, especially in youth. Our objective is to identify circulating miRNAs related to insulin resistance and beta-cell failure despite pharmacotherapy in youth. To achieve this goal, we propose a secondary analysis of the Restoring Insulin Secretion (RISE) Pediatric Mediation Study, a randomized controlled trial of glargine insulin followed by metformin or metformin alone in youth ages 10–19 with dysglycemia. We will assay circulating miRNAs using RNA sequencing (at baseline and at the end of the 12-month intervention) and fit regression (logistic and generalized linear) models to identify miRNAs related to metformin and insulin response. The overarching hypothesis of this application is that circulating miRNA profiles (reflecting tissue-specific miRNA changes) contribute to progression of beta-cell failure and insulin resistance during treatment with metformin and/or insulin in youth with dysglycemia. We will test the following aims: (1) To identify baseline circulating miRNAs associated with improvement or worsening in beta-cell function (insulin sensitivity- adjusted steady-state C-peptide and acute C-peptide response to arginine at maximal glycemic potentiation [ACPRmax]) and insulin sensitivity (mean glucose infusion rate divided by mean steady-state plasma insulin concentration [M/I]) at 12 months in youth with prediabetes or early T2D after a 12-month intervention with glargine + metformin or metformin alone (n=32) and (2) to identify changes in circulating miRNAs (between baseline and month 12) associated with improvement or worsening in beta-cell function and insulin sensitivity at 12 months in youth with prediabetes or early T2D after a 12-month intervention with glargine + metformin or metformin alone (n=32). Successful completion of the proposed work will identify circulating miRNAs related to progression of beta- cell failure and insulin resistance in youth. In addition, it will provide necessary pilot data that will inform design of larger studies to determine the epigenetic mechanisms contributing to progression of beta-cell failure and insulin resistance despite treatment with insulin and/or metformin in youth with prediabetes and early T2D. Identifying epigenetic mechanisms of metformin and insulin failure is a critical next step in the development of novel treatments to prevent pediatric T2D or induce remission of prediabetes.

抽象的 患有前驱糖尿病（糖耐量受损）或 2 型糖尿病 (T2D) 的青少年发病速度相对较快 二甲双胍或胰岛素无法预防或延迟的β细胞衰竭。其背后的机制 T2D 的暴发性病程以及二甲双胍和胰岛素在青少年中缺乏预防作用是 未知。表观遗传生物标志物，例如 microRNA (miRNA)，调节葡萄糖和葡萄糖中重要的基因。 胰岛素代谢并可能在介导二甲双胍或胰岛素的反应中发挥作用。 miRNA 是 短非编码 RNA 调节对葡萄糖稳态重要的基因表达，但它们在 人们对二甲双胍和胰岛素的全身反应知之甚少，尤其是在年轻人中。我们的目标是 尽管进行了药物治疗，但仍鉴定出与胰岛素抵抗和 β 细胞衰竭相关的循环 miRNA 青年。为了实现这一目标，我们建议对恢复胰岛素分泌 (RISE) 进行二次分析 儿科中介研究，一项随机对照试验，先使用甘精胰岛素，然后使用二甲双胍或 对于患有血糖异常的 10-19 岁青少年，单独使用二甲双胍治疗。我们将使用 RNA 检测循环 miRNA 测序（在基线和 12 个月干预结束时）和拟合回归（逻辑和 广义线性）模型来识别与二甲双胍和胰岛素反应相关的 miRNA。首要的 该应用的假设是循环 miRNA 谱（反映组织特异性 miRNA 变化） 在二甲双胍和/或治疗期间导致β细胞衰竭和胰岛素抵抗的进展 患有血糖异常的年轻人使用胰岛素。我们将测试以下目标：（1）确定循环基线 与 β 细胞功能改善或恶化相关的 miRNA（胰岛素敏感性 - 调整最大血糖时对精氨酸的稳态 C 肽和急性 C 肽反应 增强[ACPRmax]）和胰岛素敏感性（平均葡萄糖输注率除以平均值 糖尿病前期或早期 T2D 青少年 12 个月时的稳态血浆胰岛素浓度 [M/I]） 经过 12 个月的甘精+二甲双胍或单独二甲双胍干预后 (n=32) 和 (2) 来确定 循环 miRNA 的变化（基线和第 12 个月之间）与改善或 患有前驱糖尿病或糖尿病的青少年在 12 个月时 β 细胞功能和胰岛素敏感性恶化 使用甘精胰岛素+二甲双胍或单独使用二甲双胍进行 12 个月干预后的早期 T2D (n=32)。 成功完成拟议的工作将鉴定与β-进展相关的循环miRNA 青年细胞衰竭和胰岛素抵抗。此外，它将提供必要的试点数据，以告知 设计更大规模的研究以确定有助于β细胞进展的表观遗传机制 尽管患有糖尿病前期和/或糖尿病的青少年接受胰岛素和/或二甲双胍治疗，但仍出现衰竭和胰岛素抵抗 早期 T2D。确定二甲双胍和胰岛素衰竭的表观遗传机制是下一步的关键 开发预防儿童 T2D 或诱导糖尿病前期缓解的新疗法。