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: 10624230
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624230
• 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; Length; Light; Long-Term Effects; Matched Group; Mathematics; Measures; Mediating; Metabolic; Metabolic Pathway; Molecular; Morphology; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Overweight; PET/CT scan; PIK3CG gene; 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; neural; novel; novel therapeutics; obesity treatment; stem; 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 肥胖影响了美国大约40％的成年人口，而另外32％的人也超重 主机的主要原因其他使人衰弱的疾病 超过90％的T2DM patials也肥胖，在美国，T2DM的患病率约为2100万 因此，肥胖和T2DM是重大的健康危机 可用的药物，有效疗法的开发是紧迫的。 胃旁路（RYGB）已被认为是一种极有效且耐用的观察。 例如，RYGB在第一年内大约导致30％的体重减轻，该体重减轻为21％ 年份。 RYGB的深刻治疗作用，阐明了它改善T2DM和肥胖的机制 有可能提供开发有效治疗剂的新策略。 几十年来表明可能介导硫代的神经，代谢和激素标志 手术的结果，仍然缺乏机械理解和共识 机制是RYGB的有益效果。 最近证明，RYGB触发了深刻的肠道代谢和形态重塑 - 也就是说 表现出大量的增强葡萄糖利用率和增生。 重塑是GLUT1和PKM2密西西学的糖酵解和重定向的指示 合成代谢途径的副产品满足快速增殖细胞的能量需求 观察结果强烈表明，RYGB在小肠中增加了葡萄糖需求，导致它假设 然而，尽管这些有趣 观察，肠道在T2DM的改善中的潜在作用尚不清楚。 提案是阐明小肠在T2DM后rygb改善中的作用，并散发出光线 在肠道代谢和形态学重塑的基础的分子和细胞机制上。 我们的方法将在以下具体目的中进行：AIM 1将确定增加的混蛋 RYGB后血糖控制的肠道葡萄糖代谢； AIM 2将阐明是否增加 细胞增殖是增强的葡萄糖需求的基础； 增强代谢需求和组织增生的机制 我们的提议的目标是通过对小肠对 RYGB后T2DM的改善 RYGB诱导的肠道代谢和形态重塑的基础。

项目成果

PhaseFIT: live-organoid phase-fluorescent image transformation via generative AI.

• DOI: 10.1038/s41377-023-01296-y
• 发表时间: 2023-12-14
• 期刊: LIGHT-SCIENCE & APPLICATIONS
• 影响因子: 19.4
• 作者: Zhao, Junhan;Wang, Xiyue;Zhu, Junyou;Chukwudi, Chijioke;Finebaum, Andrew;Zhang, Jun;Yang, Sen;He, Shijie;Saeidi, Nima
• 通讯作者: Saeidi, Nima