Circulating miRNAs and prediction of beta-cell treatment response: The Restoring Insulin Secretion Study

循环 miRNA 和 β 细胞治疗反应的预测：恢复胰岛素分泌研究

• 批准号: 10611488
• 负责人: Pandora Luke Januszewski
• 金额: $ 48.11万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611488
• 关键词: Address; Adult; Aftercare; Age; Apoptosis; BCL2 gene; Beta Cell; Bioinformatics; Biological Assay; Biological Markers; Body mass index; Categories; Cell Proliferation; Cell Survival; Cell physiology; Cells; Childhood; Circulation; Clinical; Closure by clamp; Data; Data Analyses; Development; Diabetes Mellitus; Exposure to; Fasting; Gene Expression Regulation; Genes; Glucose; Goals; Heterogeneity; Human; Hyperglycemia; In Vitro; Insulin; Intervention; Islets of Langerhans; Knowledge; Measurement; Measures; Mediating; Medical; Metabolism; Metformin; MicroRNAs; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Organ; Participant; Pathway Analysis; Patients; Pattern; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Plasma; Prediabetes syndrome; Prediction of Response to Therapy; Randomized; Randomized, Controlled Trials; Role; Sampling; Subgroup; Testing; Tissues; Untranslated RNA; Youth; age related; aged; bariatric surgery; biomarker panel; candidate marker; case control; circulating biomarkers; circulating microRNA; design; epigenetic regulation; exosome; experimental study; gain of function; glargine; improved; in vitro Model; indexing; insulin secretion; insulin sensitivity; islet; islet amyloid polypeptide; liraglutide; locked nucleic acid; malignant stomach neoplasm; member; next generation; next generation sequencing; novel; precision medicine; predictive marker; predictive panel; preservation; prevent; prospective; responders and non-responders; response; sex; standard measure; tool; transcriptome sequencing; transcriptomics; treatment responders; treatment response

Abstract Despite treatment, a significant proportion of patients with type 2 diabetes (T2D) do not experience clinical improvement (i.e., lack treatment response). In analyses of data from the Restoring Insulin Secretion (RISE) Study, a randomized controlled trial testing the potential of medical and surgical therapies to improve and maintain β-cell function, members of our team have demonstrated substantial heterogeneity in treatment response at the level of the β cell using gold standard measures from hyperglycemic clamps. We know little, however, about contributing factors to heterogeneity of T2D treatment response and lack tools to prospectively identify treatment responders and non-responders. A major reason for this is lack of circulating biomarkers that predict or reflect treatment response at the level of the β cell. Epigenetic regulation of genes important in glucose and insulin metabolism by short non-coding RNAs such as microRNAs (miRNAs) may mediate improvement or preservation of β-cell function with treatment, and circulating miRNAs may be predictive biomarkers of treatment response. In the β cell, regulation of gene expression by miRNAs is crucial to both insulin secretion and cell turnover. In addition, miRNAs secreted into the circulation may reflect tissue-level differences in expression and/or participate actively in inter-organ crosstalk. While miRNAs in a variety of tissues and in the circulation have been shown to be altered by exposure to the RISE interventions in humans or in vitro models, effects of most of these miRNAs in the β cell are not yet described. Using data and samples from the RISE Pediatric Medication Study (n=49; R03DK122100; PI Wander), we identified 9 plasma miRNAs that are prospectively related to treatment response in youth aged 10–19 years including two novel miRNAs, miR-4468 and miR-6727, which are predicted to regulate islet apoptosis via Bcl-2 like 1 and islet amyloid polypeptide. Our objective is to characterize miRNAs that are related to preservation or improvement in β-cell function among adult RISE participants, defined by clamp-derived measures of β-cell response paired with insulin sensitivity, after treatment with medications or gastric banding. To achieve this goal, we propose a two-part study. In Aim 1, we will assay circulating miRNAs using next-generation sequencing at baseline and after treatment in a nested case-control sample of treatment responders vs. non-responders in RISE. In Aim 2, we will examine effects of miR-4468, miR- 6727, and miRNAs identified in Aim 1 on β-cell function, survival, and de-differentiation in gain-of-function in vitro experiments using locked nucleic acid-based miRNA mimics in human islets. Our overarching hypothesis is that circulating miRNAs contribute to treatment heterogeneity via effects on insulin secretion and β-cell survival. To our knowledge, this project will be the first to directly test the role of treatment-related miRNAs in mediating or reflecting treatment response. Better understanding of miRNAs as biomarkers of treatment heterogeneity will facilitate T2D precision medicine by prospectively identifying subgroups likely to benefit from specific treatments and promote development of targeted interventions to prevent or delay the progression of T2D.

抽象的 尽管接受了治疗，仍有相当一部分 2 型糖尿病 (T2D) 患者没有经历临床症状 改善（即缺乏治疗反应）。恢复胰岛素分泌 (RISE) 数据分析 研究是一项随机对照试验，测试药物和手术疗法改善和改善的潜力。 维持β细胞功能，我们团队的成员在治疗中表现出很大的异质性 使用高血糖钳测量的金标准测量 β 细胞水平的反应。我们所知甚少， 然而，关于 T2D 治疗反应异质性的影响因素，缺乏前瞻性工具 识别治疗有反应者和无反应者。造成这种情况的一个主要原因是缺乏循环生物标志物 预测或反映 β 细胞水平的治疗反应。葡萄糖重要基因的表观遗传调控 短非编码 RNA（例如 microRNA (miRNA)）的胰岛素代谢可能会介导改善或 通过治疗保留 β 细胞功能，循环 miRNA 可能是治疗的预测生物标志物 回复。在 β 细胞中，miRNA 对基因表达的调节对于胰岛素分泌和细胞至关重要 周转。此外，分泌到循环中的 miRNA 可能反映组织水平表达差异 和/或积极参与器官间串扰。而多种组织和循环中的 miRNA 已被证明会因人类或体外模型中暴露于 RISE 干预措施而改变， β细胞中的大多数 miRNA 尚未被描述。使用 RISE Pediatric 的数据和样本 药物研究（n=49；R03DK122100；PI Wander），我们鉴定了 9 种血浆 miRNA，这些 miRNA 具有前瞻性 与 10-19 岁青少年的治疗反应相关，包括两种新的 miRNA，miR-4468 和 miR-6727， 预计它们可通过 Bcl-2 like 1 和胰岛淀粉样多肽调节胰岛细胞凋亡。我们的目标是 表征与成人 RISE 中 β 细胞功能的保存或改善相关的 miRNA 参与者，通过治疗后β细胞反应的钳夹衍生测量与胰岛素敏感性相结合来定义 使用药物或胃束带。为了实现这一目标，我们提出了一项分为两部分的研究。在目标 1 中，我们将分析 在巢式病例对照中，在基线和治疗后使用下一代测序来检测循环 miRNA RISE 中治疗反应者与无反应者的样本。在目标 2 中，我们将检查 miR-4468、miR- 6727，目标 1 中鉴定的 miRNA 对 β 细胞功能、存活和功能获得中去分化的影响 在人类胰岛中使用基于锁定核酸的 miRNA 模拟物进行体外实验。我们的总体假设是 循环 miRNA 通过影响胰岛素分泌和 β 细胞存活而导致治疗异质性。 据我们所知，该项目将是第一个直接测试治疗相关 miRNA 在介导或调节中的作用的项目。 反映治疗反应。更好地理解 miRNA 作为治疗异质性的生物标志物将 通过前瞻性地识别可能受益于特定治疗的亚组，促进 T2D 精准医疗 促进制定有针对性的干预措施，以预防或延缓 T2D 的进展。