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

摘要 肥胖影响了美国大约40%的成年人口，另外32%的人超重。也是 它是许多其他使人衰弱的疾病，如II型糖尿病（T2 DM）的主要原因。比如说， 超过90%的T2 DM患者也是肥胖的，在美国，T2 DM的患病率约为2100万 一个人因此，肥胖和T2 DM是重大的健康危机，并且考虑到 在现有药物的基础上，迫切需要开发有效的治疗方法。减肥手术，包括Roux-en-Y 胃旁路术（RYGB）已被认为是一种非常有效和持久的肥胖症治疗方法。为 例如，RYGB在第一年内导致大约30%的体重减轻，而在第十年保持在21%。 年同样有趣的是，RYGB在大约70%的患者中解决或改善了T2 DM。考虑 RYGB的深刻治疗作用，阐明其改善T2 DM和肥胖的机制， 可能为开发有效的治疗方法提供新的策略。虽然过去两年的严格研究 几十年来的研究表明，无数的神经，代谢和激素信号可能介导生理 手术的结果，仍然缺乏机械的理解和共识， 这些机制是RYGB的有益效果的原因。我们的团队，以及随后的其他团队， 最近证明，RYGB触发了深刻的肠道代谢和形态重塑-也就是说， 表现为肠葡萄糖利用和增生的显著增加。这个的特点是 重塑是诱导GLUT 1和PKM 2介导的糖酵解的过度激活和其糖酵解的重定向。 合成代谢途径的副产品，以满足快速增殖细胞的能量需求。这些 观察结果强烈表明，RYGB增加小肠中的葡萄糖需求，导致其假设 在手术后血糖控制中发挥积极和直接的作用。然而，尽管这些有趣的 然而，根据观察，肠道在改善T2 DM中的潜在作用尚不清楚。的目的 建议阐明小肠在RYGB后改善T2 DM中的作用，并阐明 对肠道代谢和形态重塑的分子和细胞机制的研究。 我们的方法将遵循以下具体目标：目标1将确定增加的因果关系。 肠道葡萄糖代谢对RYGB后血糖控制的影响;目的2将阐明是否增加 细胞增殖是葡萄糖需求增加的基础; Aim 3将决定关键分子 代谢需求增加和组织增生的潜在机制。成功实现 我们的建议的目标是详细了解小肠的作用， RYGB后T2 DM的改善，以及基本的细胞和分子机制， RYGB诱导的肠代谢和形态重建的基础。

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.