Central and direct role of the small intestine in the improvement of type 2 diabetes following RYGB

小肠在 RYGB 后改善 2 型糖尿病中的核心和直接作用

• 批准号: 10398156
• 负责人: Nima Saeidi
• 金额: $ 44.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398156
• 关键词: Ablation; Achievement; Adult; Basic Science; Biodistribution; Biology; Blood Glucose; Body Weight decreased; Cell Differentiation process; Cell Proliferation; Cells; Citric Acid Cycle; Consensus; Data; Development; Diabetes Mellitus; Diet; Disease; Enzymes; Etiology; Event; FRAP1 gene; Fatty acid glycerol esters; Fructose; Gastric Bypass; Glucose; Glycolysis; Goals; Graph; Health; Height; Hormones; Human; Hyperplasia; Intestines; Investigation; Lead; Length; Light; Long-Term Effects; Matched Group; Mathematics; Measures; Mediating; Metabolic; Metabolic Pathway; Molecular; Morphology; Muscle; Network-based; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Overweight; PET/CT scan; Pathway Analysis; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmaceutical Preparations; Physiological; Play; Population; Prevalence; Proliferating; Proteomics; Rattus; Research; Research Design; Resolution; Reverse engineering; Rodent Model; Role; SLC2A1 gene; Short Bowel Syndrome; Signal Transduction; Small Intestines; Testing; Therapeutic; Therapeutic Effect; Thick; Tissues; Tracer; Transgenic Mice; Villus; Weight; X-Ray Computed Tomography; aerobic glycolysis; bariatric surgery; comorbidity; computational platform; effective therapy; fluorodeoxyglucose; glucose metabolism; glucose uptake; glycemic control; hormonal signals; improved; intestinal epithelium; metabolomics; microbiome; multiple omics; novel; novel therapeutics; obesity treatment; relating to nervous system; stem cells; surgery outcome; therapeutically effective; translational impact

ABSTRACT Obesity impacts approximately 40% of the adult population in the US, and another 32% are overweight. It is also the major cause of a host of other debilitating diseases, such as type II diabetes mellitus (T2DM). For example, over 90% of T2DM patients are also obese, and the prevalence of T2DM is approximately 21 million in the US alone. Therefore, obesity and T2DM are significant health crises, and given the sub-optimal outcomes of available medications, the development of effective therapies is urgent. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB), has been recognized as an extremely potent and durable treatment for obesity. For example, RYGB leads to approximately 30% weight loss within the first year which is maintained at 21% at ten years. Equally intriguing, RYGB resolves or improves T2DM in approximately 70% of patients. Considering the profound therapeutic effects of RYGB, elucidating the mechanisms by which it improves T2DM and obesity could potentially offer new strategies for developing effective therapeutics. While rigorous research over the past two decades has indicated a myriad of neural, metabolic, and hormonal signals that may mediate the physiological outcomes of the surgery, there is still a lack of mechanistic understanding and consensus as to which mechanisms are responsible for the beneficial effects of RYGB. Our team, and subsequently others, have recently demonstrated that RYGB triggers a profound intestinal metabolic and morphologic remodeling – that is manifested by significant augmentation of intestinal glucose utilization and hyperplasia. The hallmark of this remodeling is the induction of a GLUT1- and PKM2-mediated hyperactivation of glycolysis and redirection of its byproducts to anabolic pathways, to meet the energetic demand of the rapidly proliferating cells. These observations strongly suggest that RYGB increases glucose demand in the small intestine causing it to assume an active and direct role in the glycemic control following surgery. However, despite these intriguing observations, the potential role of the intestine in the improvement of T2DM is yet unknown. The objective of this proposal is to elucidate the role of the small intestine in the improvement of T2DM post-RYGB, and to shed light on the molecular and cellular mechanisms that underlie the intestinal metabolic and morphologic remodeling. Our approach will be pursued in the following Specific Aims: Aim 1 will determine the causality of the increased intestinal glucose metabolism on glycemic control following RYGB; Aim 2 will elucidate whether increased cellular proliferation underlies the augmented glucose demand; and Aim 3 will determine the key molecular mechanisms underlying the augmented metabolic demand and tissue hyperplasia. Successful achievement of our proposal’s goals is expected to be a detailed understanding of the contribution of the small intestine to amelioration of T2DM following RYGB, as well as the fundamental cellular and molecular mechanisms that underlie the RYGB-induced intestinal metabolic and morphologic remodeling.

抽象的 肥胖影响着美国大约 40% 的成年人口，另外 32% 的人体重超重。 是许多其他使人衰弱的疾病的主要原因，例如 II 型糖尿病 (T2DM)。 超过 90% 的 T2DM 患者也患有肥胖症，美国 T2DM 患病率约为 2100 万 因此，肥胖和 T2DM 是严重的健康危机，而且其结果并不理想。 由于现有药物的存在，迫切需要开发有效的治疗方法，包括 Roux-en-Y 手术。 胃绕道术（RYGB）已被认为是一种极其有效且持久的肥胖治疗方法。 例如，RYGB 在第一年内使体重减轻约 30%，到 10 岁则维持在 21% 同样有趣的是，RYGB 解决或改善了大约 70% 的 T2DM 患者。 RYGB 具有广泛的治疗作用，阐明了它改善 T2DM 和肥胖的机制 在过去两年的严格研究的同时，可能为开发有效的治疗方法提供新的策略。 几十年来已经表明无数的神经、代谢和激素信号可能介导生理学 对于手术的结果，目前仍缺乏机制上的理解和共识。 RYGB 的有益效果由我们的团队以及随后的其他团队负责。 最近证明 RYGB 触发了深刻的肠道代谢和形态重塑——即 表现为肠道葡萄糖利用和增生的显着增加。 重塑是诱导 GLUT1 和 PKM2 介导的糖酵解过度激活及其重定向 合成代谢途径的副产品，以满足快速增殖细胞的能量需求。 观察结果强烈表明，RYGB 增加了小肠中的葡萄糖需求，导致其假设 然而，尽管这些令人感兴趣，但它在手术后的血糖控制中发挥着积极和直接的作用。 观察结果显示，肠道在改善 T2DM 中的潜在作用尚不清楚。 提案旨在阐明小肠在 RYGB 后改善 T2DM 中的作用，并阐明 研究肠道代谢和形态重塑的分子和细胞机制。 我们的方法将追求以下具体目标： 目标 1 将确定增加的因果关系 RYGB 后肠道葡萄糖代谢对血糖控制的影响；目标 2 将阐明是否增加 细胞增殖是葡萄糖需求增加的基础；目标 3 将决定关键分子 代谢需求增加和组织增生的成功实现的机制。 我们提案的目标预计是详细了解小肠对 RYGB 后 T2DM 的改善，以及基本的细胞和分子机制 是 RYGB 诱导的肠道代谢和形态重塑的基础。