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

描述（由申请人提供）：TINSAL-T2D是一项多中心、随机、安慰剂对照、剂量范围临床试验，旨在确定水杨酸盐对T2D患者的降糖功效、安全性和耐受性。试验分为两个阶段。第一阶段，为期14周的治疗期，比较3种剂量的水杨酸盐和安慰剂，已经完成；第二阶段，正在进行中，比较单剂量水杨酸盐和安慰剂48周的暴露。一期结果显示HbA1c降低，血糖控制的其他参数也有所改善。甘油三酯水平也降低，脂联素水平升高，表明可能有心脏保护作用。因此，TINSAL-T2D的1期研究结果支持这种简单的抗炎药在T2D患者中的潜在应用，并具有长期的安全性。尽管在建立临床疗效方面取得了迅速而有希望的进展，但在发现水杨酸盐降血糖、降脂、抗炎作用及其潜在副作用的作用机制方面却进展缓慢。基本原理。我们发现水杨酸（SA），水杨酸盐的活性形式，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是炎症的主要调节剂，而HSF-1是应激反应的主要调节剂。salsalate上调其中一个，下调另一个，这预示着转录目标表达水平的反平行变化。这在接受治疗的动物和病人的培养细胞和组织中很明显。SA/salsalate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，全基因组表达谱为评估其影响提供了一种理想的方法。研究计划：在TINSAL-T2D第一阶段、基线和治疗14周后（安慰剂组和3个治疗组各25-27名受试者）收集血样进行mRNA分离（Paxgene）。RNA将被分离并用于测定全基因组mRNA的表达水平。经过验证的白细胞mRNA表达变化将被用作潜在的基于机制的生物标志物，与预测疗效和安全性相关。这些发现与其他应答、通路和网络分析的结果将用于试图确定应答亚组和水杨酸盐对T2D患者的疗效和毒性的分子机制。

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.