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: 9806708
• 负责人: Pandora Luke Januszewski
• 金额: $ 11.66万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806708
• 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; polypeptide C; 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.

摘要 患有前驱糖尿病（葡萄糖耐量受损）或2型糖尿病（T2 D）的青少年经历相对快速的 二甲双胍或胰岛素不能预防或延迟β细胞衰竭。机制研究 T2 D的暴发性病程以及二甲双胍和胰岛素在青年中缺乏预防益处， 未知表观遗传生物标志物如microRNA（miRNAs）调节在葡萄糖和葡萄糖代谢中重要的基因。 胰岛素代谢，并可能在介导对二甲双胍或胰岛素的反应性中起作用。mirna是 调节对葡萄糖稳态重要的基因表达的短的非编码RNA，但它们在 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 鉴定与胰岛素抵抗和β细胞衰竭相关的循环miRNA，尽管药物治疗 青年为了实现这一目标，我们提出了恢复胰岛素分泌（RISE）的二次分析。 儿科调解研究，一项甘精胰岛素后续二甲双胍或 二甲双胍单药治疗10-19岁患有精神障碍的青少年。我们将使用RNA检测循环中的miRNA， 排序（基线和12个月干预结束时）和拟合回归（logistic和 广义线性）模型来鉴定与二甲双胍和胰岛素反应相关的miRNA。总体 本申请的假设是循环miRNA谱（反映组织特异性miRNA变化） 在二甲双胍治疗期间导致β细胞衰竭和胰岛素抵抗进展，和/或 胰岛素在青年精神障碍患者中的应用我们将测试以下目标：（1）确定基线循环 与β细胞功能改善或恶化相关的miRNA（胰岛素敏感性- 调整稳态C肽和急性C肽反应精氨酸在最大血糖 增强[ACPRmax]）和胰岛素敏感性（平均葡萄糖输注速率除以平均 糖尿病前期或早期T2 D青年患者12个月时的稳态血浆胰岛素浓度[M/I] 甘精胰岛素+二甲双胍或二甲双胍单药干预12个月后（n=32）和（2）确定 与改善相关的循环miRNA的变化（基线和第12个月之间），或 糖尿病前期青年患者12个月时β细胞功能和胰岛素敏感性恶化，或 甘精胰岛素+二甲双胍或二甲双胍单药干预12个月后的早期T2 D（n=32）。 这项工作的成功完成将鉴定出与β-半乳糖苷酶进展相关的循环miRNA。 细胞衰竭和胰岛素抵抗。此外，它还将提供必要的试点数据， 设计更大规模的研究，以确定促进β细胞增殖的表观遗传机制。 糖尿病前期青年患者尽管接受胰岛素和/或二甲双胍治疗， 早期T2 D确定二甲双胍和胰岛素治疗失败的表观遗传机制是研究二甲双胍和胰岛素治疗失败的关键下一步。 开发新的治疗方法，以预防儿童T2 D或诱导前驱糖尿病的缓解。