Mechanism-Based Biomarkers for Glucose-Lowering in TINSAL-T2D

TINSAL-T2D 中基于机制的降血糖生物标志物

• 批准号: 8045219
• 负责人: STEVEN E SHOELSON
• 金额: $ 39.91万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045219
• 关键词: Adverse effects; Affect; Aftercare; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Biological Markers; Blood Cells; Blood Glucose; Blood specimen; Clinical Research; Clinical Trials Design; Collaborations; Complex; Computational Biology; Computing Methodologies; Cultured Cells; Daphne plant; Data Analyses; Data Set; Diabetes Mellitus; Dose; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Funding; Gene Expression; Genetic; Genetic Transcription; Glucose; Glycosylated hemoglobin A; Human; Immunogenetics; Immunologist; Immunology; Inflammation; Institutes; Letters; Leukocytes; Lipids; Messenger RNA; Methods; Molecular; Molecular Profiling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Placebo Control; Placebos; Population; Proteins; Published Comment; RNA; Randomized; Research; Reverse Transcriptase Polymerase Chain Reaction; Rodent Model; Running; Safety; Salicylic Acids; Sampling; Sorting - Cell Movement; Staging; Staining method; Stains; Subgroup; Time; Tissue-Specific Gene Expression; Toxic effect; Triglycerides; Validation; Variant; Western Blotting; Whole Blood; Work; abstracting; adiponectin; base; biological adaptation to stress; clinical efficacy; data mining; genome-wide; glycemic control; healthy volunteer; mRNA Expression; member; response; salicylate; salicylsalicylic acid; tissue/cell culture; transcription factor; treatment duration; validation studies

DESCRIPTION (provided by applicant): TINSAL-T2D is a multicenter, randomized, placebo-controlled, dose-ranging clinical trial designed to determine glycemic efficacy, safety and tolerability of salsalate in patients with T2D. The trial was divided into two stages. Stage 1, having a 14-week treatment period comparing 3 doses of salsalate vs. placebo, has been completed; stage 2, which is ongoing, compares a single dose of salsalate to placebo for 48 weeks of exposure. The results of stage 1 demonstrated HbA1c lowering as well as improvements in other parameters of glycemic control. Triglyceride levels were also reduced and adiponectin levels increased, suggesting potential cardioprotection. The results from stage 1 of TINSAL-T2D thus support the potential use of this simple anti-inflammatory drug with a long-term established safety profile in patients with T2D. Despite the rapid and promising progress in establishing clinical efficacy, parallel progress to discover mechanisms of action for salsalate's glucose- and lipid-lowering and anti-inflammatory effects and potential side effects has lagged. Rationale. We have found that salicylic acid (SA), the active form of salsalate, simultaneously inhibits NF-:B and activates HSF-1 in cultured cells, rodent models, and patients with T2D. Both are transcription factors: NF-:B is a master regulator of inflammation while HSF-1 is a master regulator of stress responses. That salsalate upregulates one and down-regulates the other predicts antiparallel changes in the expression levels of transcriptional targets. This is readily apparent in cultured cells and tissues from treated animals and patients. That SA/salsalate affects the activities of two transcription factors further suggests that it could modulate other transcription factors. Because SA affects transcription, genome-wide expression profiling provides an ideal method for the global assessment of its effects. Research Plan: Blood samples for mRNA isolation (Paxgene) were collected during stage 1 of TINSAL-T2D, at baseline and after 14 weeks treatment (25-27 subjects each from placebo and 3 treatment groups). RNA will be isolated and used to determine genome-wide mRNA expression levels. Validated changes in leukocyte mRNA expression will be used as potential mechanism-based biomarkers that correlate with and predict efficacy and safety. These findings in conjunction with the results from additional response, pathway and network analyses will be used in attempts to identify responder subgroups and molecular mechanisms for efficacy and toxicity of salsalate in patients with T2D. PUBLIC HEALTH RELEVANCE: We have found that an old and safe drug (salicylate, salsalate) has a previously unrecognized capacity to lower blood glucose levels in patients with diabetes. Since clinical studies have progressed rapidly and the drug may be approved for use in patients, is important to know how it works in greater detail. Proposed studies provide biomarkers that correlate with and potentially predict efficacy and safety, and may help to identify mechanisms of action.

描述（由申请人提供）：TINSAL-T2D 是一项多中心、随机、安慰剂对照、剂量范围的临床试验，旨在确定水杨酸对 T2D 患者的血糖功效、安全性和耐受性。审判分为两个阶段。第一阶段，为期 14 周的治疗期，比较 3 剂双水杨酸与安慰剂，现已完成；第二阶段正在进行中，比较单剂量的水杨酸与安慰剂 48 周的暴露时间。第一阶段的结果表明 HbA1c 降低以及血糖控制的其他参数得到改善。甘油三酯水平也降低，脂联素水平升高，表明潜在的心脏保护作用。因此，TINSAL-T2D 第一阶段的结果支持了这种简单的抗炎药物在 T2D 患者中的潜在用途，该药物具有长期确定的安全性。尽管在建立临床疗效方面取得了快速且有希望的进展，但发现双水杨酸降糖、降脂、抗炎作用和潜在副作用的作用机制的并行进展却滞后。理由。我们发现水杨酸 (SA)（水杨酸的活性形式）在培养细胞、啮齿动物模型和 T2D 患者中同时抑制 NF-:B 并激活 HSF-1。两者都是转录因子：NF-:B 是炎症的主要调节因子，而 HSF-1 是应激反应的主要调节因子。水杨酸盐上调其中一种并下调另一种，这预示着转录靶标表达水平的反向平行变化。这在来自接受治疗的动物和患者的培养细胞和组织中显而易见。 SA/水杨酸影响两种转录因子的活性，进一步表明它可以调节其他转录因子。由于 SA 影响转录，因此全基因组表达谱分析为全面评估其影响提供了理想的方法。研究计划：在 TINS​​AL-T2D 第 1 阶段、基线时和治疗 14 周后（安慰剂组和 3 个治疗组各 25-27 名受试者）收集用于 mRNA 分离 (Paxgene) 的血液样本。 RNA 将被分离并用于确定全基因组 mRNA 表达水平。经过验证的白细胞 mRNA 表达变化将被用作与功效和安全性相关并预测功效和安全性的潜在的基于机制的生物标志物。这些发现与其他反应、通路和网络分析的结果相结合，将用于尝试确定 T2D 患者中水杨酸疗效和毒性的反应者亚组和分子机制。 公共健康相关性：我们发现一种古老而安全的药物（水杨酸盐、双水杨酸盐）具有以前未被认识到的降低糖尿病患者血糖水平的能力。由于临床研究进展迅速，并且该药物可能被批准用于患者，因此更详细地了解其作用原理非常重要。拟议的研究提供了与功效和安全性相关并可能预测功效和安全性的生物标志物，并可能有助于确定作用机制。