Intestinal Mechanisms and Molecular Predictors of Type 2 Diabetes Remission After Roux-en-Y Gastric Bypass Surgery

项目总结 虽然Roux-en-Y胃分流术(RYGB)是治疗肥胖症和2型的最有效方法之一 糖尿病(T2 DM)，每三名患者中就有一名，术后仍患有T2 DM。确定那些 没有达到T2 DM缓解的患者在机制上都很重要，以帮助发现RYGB是如何 改善血糖，并在临床上在术后早期开始额外的治疗或避免 整个行动。在动物模型和人类中的研究强调了肠道作为一种 RYGB后代谢改善机制的关键解剖底物。建议的项目将构建 基于并扩展了我们最近的前瞻性、纵向、观察性临床试验的结果 (ClinicalTrials.gov ID NCT02710370)，其目标是表征RYGB的性质和时机- 诱导人类肠道适应性改变。这项试验产生的三个主要影响是 A)肠道燃料利用率的提高对1- 术后一年HbA1c的下降，将肠道定位为RYGB诱导的改善的关键器官 血糖，b)术前肠道生物学似乎与术后反应有关，因此 这可以被利用作为一种预测性的临床工具，以及c)SIRT6-HIF1a途径，它是 葡萄糖代谢将能量底物代谢与功能联系起来，似乎在 RYGB的血糖控制。拟议的项目是基础研究和临床研究的独特结合。 并包含进一步评估增强肠道新陈代谢的作用所需的复杂性 作为RYGB的关键作用机制之一，并可作为预测T2 DM缓解的临床工具。我们会 在人类受试者身上进行3项研究。在具体目标1中，我们将进行病例对照研究，以检验 RYGB治疗后没有T2 DM缓解的患者表现出较低程度的肠道代谢的假说 有效激活SIRT6-HIF1a途径的能力较低。在具体目标2中，我们将进行 前瞻性的纵向研究，以测试是否有考虑到 单独或联合应用术前基因表达水平有助于预测术后糖化血红蛋白的变化 与其他临床、代谢或激素因素有关。在特定的目标3中，我们将执行单细胞RNA- RYGB前后受试者活检组织的测序。这些研究将进一步阐明 RYGB诱导的血糖控制中的肠道代谢和SIRT6-HIF1a途径。他们会允许我们 对肠道细胞底物、调节网络和机制有前所未有的了解 与T2 DM缓解相关的基因。它们还可能为发展 分子预测，可以帮助指导减肥手术候选人的临床决定。最后，他们会 生成独特的资源、生物库和数据集，以进一步实现对肠道的机械性研究 减肥手术的生物学和作用机制至今无法获得。

PROJECT SUMMARY Although Roux-en-Y Gastric Bypass (RYGB) is one of the most effective treatments for obesity and type 2 Diabetes Mellitus (T2DM), one out of three patients, still suffer from T2DM after the operation. Identifying those patients who do not achieve T2DM remission is important both mechanistically to help discover how RYGB improves glycemia, and clinically to initiate additional postoperative treatments early after surgery or to avoid the operation altogether. Studies in animal models and humans have emphasized the role of the intestine as a key anatomic substrate of the mechanisms of metabolic improvement after RYGB. The proposed project builds upon and expands the findings of our recent, prospective, longitudinal, observational clinical trial (ClinicalTrials.gov ID NCT02710370) the goal of which was to characterize the nature and the timing of RYGB- induced intestinal adaptive changes in humans. The three main implications that emerged from this trial were a) the enhancement of intestinal fuel utilization contributes in a significant and quantifiable manner to the 1- year postoperative decrement in HbA1c, positioning the gut as a key organ for RYGB-induced improved glycemia, b) the preoperative intestinal biology appears to be correlated with postoperative response, and thus this could be harnessed as a predictive clinical tool, and c) SIRT6-HIF1A pathway, a master gatekeeper of glucose metabolism linking energy substrate metabolism to function, appears to play a prominent role in the glycemic control of RYGB. The proposed project is a unique synergy between basic and clinical research teams and contains the requisite sophistication to further evaluate the role of augmented intestinal metabolism as one of the key mechanisms of action of RYGB and as a clinical tool to predict T2DM remission. We will perform 3 studies on human subjects. In Specific Aim 1, we will conduct a case control study to test the hypothesis that patients without T2DM remission post-RYGB exhibit a lower degree of intestinal metabolic activity and lower ability to engage SIRT6-HIF1A pathway effectively. In Specific Aim 2, we will conduct a prospective, longitudinal study to test whether specific composite metrics that take into account the preoperative gene expression levels could help predict postoperative HbA1c change, alone or in combination with other clinical, metabolic or hormonal factors. In Specific Aim 3, we will perform single cell RNA- Sequencing in biopsies from subjects before and after RYGB. These studies will further clarify the role of intestinal metabolism and the SIRT6-HIF1A pathway in RYGB-induced glycemic control. They will allow us to gain unprecedented insight into the intestinal cellular substrates, the regulatory networks and the mechanisms that are relevant for T2DM remission. They may also, potentially pave the way for the development of molecular predictors that could help guide clinical decisions for bariatric surgery candidates. Finally, they will generate unique resources, biobanks and datasets that will further enable mechanistic studies of intestinal biology and the mechanisms of action of bariatric surgery unobtainable to date.