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

摘要 在美国，肥胖影响了大约40%的成年人口，另有32%的人超重。它也是 这是其他许多使人衰弱的疾病的主要原因，如II型糖尿病(T2 DM)。例如, 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 独自一人。因此，肥胖和2型糖尿病是严重的健康危机，考虑到 在现有药物的情况下，开发有效的治疗方法迫在眉睫。减肥手术，包括Roux-en-Y 胃旁路手术(RYGB)已被公认为是一种非常有效和持久的肥胖症治疗方法。为 例如，RYGB在第一年内会导致大约30%的体重下降，在10岁时保持在21% 好几年了。同样耐人寻味的是，RYGB在大约70%的患者中解决或改善了T2 DM。考虑到 RYGB的深刻疗效，阐明其改善T2 DM和肥胖的机制可能 有可能为开发有效的治疗方法提供新的策略。虽然在过去的两年里进行了严格的研究 几十年的研究表明，无数的神经、新陈代谢和荷尔蒙信号可能调节生理 对于手术的结果，目前还缺乏机械性的理解和共识 RYGB的有益效果是由机制决定的。我们的团队，以及随后的其他团队， 最近证明，RYGB触发了一种深刻的肠道代谢和形态重塑-即 表现为肠道葡萄糖利用显著增强和增生。这件事的特点是 重塑是GLUT1和PKM2介导的糖酵解过度激活和其重定向的诱导 副产物到合成代谢途径，以满足快速增殖的细胞的能量需求。这些 观察有力地表明，RYGB增加了小肠的葡萄糖需求，导致它假设 在手术后的血糖控制中发挥积极和直接的作用。然而，尽管有这些耐人寻味的事情 观察到，肠道在改善T2 DM中的潜在作用尚不清楚。这样做的目的是 建议阐明小肠在RYGB术后改善T2 DM中的作用，并阐明 关于肠道代谢和形态重塑的分子和细胞机制。 我们的做法将在以下具体目标中进行：目标1将确定增加的 RYGB后肠道葡萄糖代谢对血糖控制的影响；AIM 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将确定关键分子 代谢需求增加和组织增生的潜在机制。成功地实现了 我们的计划的目标是详细了解小肠对 RYGB对T2 DM的改善，以及基本的细胞和分子机制 RYGB诱导的肠道代谢和形态重塑是其基础。

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.