Electronic Bypass for Diabetes

糖尿病影响了超过9%的美国人，2012年在美国造成了超过2450亿美元的损失。最近在减肥 手术，如Roux-en-Y胃搭桥术和袖状胃切除术，已经被提出用于治疗糖尿病 肥胖患者因其降血糖作用而对餐后血糖有明显的减肥作用。 提出一种新的肠道电刺激(IES)治疗糖尿病的方法。 申请。在这种方法中，IES被设计用来改变胃肠道转运和激素，包括胰岛素 激素，如胰高血糖素样肽-1(GLP-1)。我们的初步研究证明了加速 在肠道转运方面，餐后GLP-1增加，口服葡萄糖后血糖下降。 长期以来，建议的IES已导致血糖控制的改善和胰腺的改善 胰岛起作用。根据这些发现，我们假设IES在糖尿病大鼠体内的急性降血糖作用 餐后状态归因于IES诱导的GLP-1的释放增加，可能还有其他 激素，如Ghrelin，以及IES在空腹和饮食中的慢性降血糖作用 状态归因于β细胞功能的改善，归因于预防有害影响 IES诱导的升高的GLP-1对β细胞功能的改善作用。 该项目将使用先进技术(无线刺激和记录笼子，以及 自主和持续的食物摄入量监测)，使IES能够在自由活动的动物中进行。 自发性2型糖尿病最具特征性的动物模型--Goto-Kakizaki(GK)大鼠 实现以下具体目标：1)优化IES参数，开发按需IES并执行 闭环式IES。首先，我们将系统地优化刺激参数，以最大限度地降低血糖 IES的效果。然后我们将开发一个算法来自动检测食物摄入量，然后在 食物摄取。它将基于肠道固有肌电活动和人工神经的特征 网络。膳食引发的IES将避免过度刺激。最后，一种闭环式IES方法(每个 刺激与固有的肠道肌电活动同步)将被开发以进一步增加 IES对糖尿病的疗效。2)研究胰岛素参与的急性IES的降糖机制 激素，如GLP-1和Ghrelin，以及参与IES诱导的肠道转运机制 刺激胰岛素的胃肠激素升高。3)探讨慢性IES的细胞机制 长期血糖控制。将进行慢性IES以研究IES的长期降糖效果 在禁食和进食状态下，以及涉及胰岛功能的机制，β细胞凋亡和 增殖，以及一些参与调控β细胞发育的转录因子， 分化和功能。L细胞在远端肠道的可能参与也将被调查。

Diabetes affects more than 9% of Americans and costs over $245 billion in 2012 in USA. Recently bariatric surgery, such as Roux-en-Y gastric bypass and sleeve gastrectomy, has been proposed for treating diabetic patients with obesity due to its hypoglycemic effect on postprandial blood glucose and significant weight loss. A novel method of intestinal electrical stimulation (IES) is proposed for the treatment of diabetes in this application. In this method, IES is designed to alter gastrointestinal transit and hormones, including incretin hormones, such as glucagon like peptide-1 (GLP-1). Our preliminary studies have demonstrated acceleration of intestinal transit, an increase in postprandial GLP-1 and a reduction in blood glucose after oral glucose. Chronically, the proposed IES has resulted in improvement in glycemic control and improvement in pancreatic islets functions. According to these findings, we hypothesize that the acute hypoglycemic effect of IES in the postprandial state is attributed to IES-induced enhancement in the release of GLP-1 and possibly other hormones as well, such as ghrelin, and that the chronic hypoglycemic effect of IES in both fasting and fed states is attributed to improvement in beta-cell functions, attributed to the prevention of the detrimental effects of hyperglycemia and the ameliorating effect of IES-induced elevated GLP-1 on beta-cell functions. The project will be performed using advanced technologies (wireless stimulation and recording cages, and autonomic and continuous food intake monitoring) that allow IES to be conducted in freely moving animals. The best characterized animal model of spontaneous Type 2 diabetes, the Goto-Kakizaki (GK) rat will be used to accomplish following specific aims: 1) To optimize IES parameters, develop on-demand IES and perform closed-loop IES. First, we will systematically optimized stimulation parameters to maximize the hypoglycemic effect of IES. Then we will develop an algorithm to automatically detect food intake and then trigger IES upon food ingestion. It will be based on characteristics of intrinsic intestinal myoelectrical activity and artificial neural network. The meal triggered IES will avoid excessive stimulation. Finally, a closed-loop IES method (each stimulus is synchronized with intrinsic intestinal myoelectrical activity) will be developed to further increase the efficacy of IES for diabetes. 2) To study the hypoglycemic mechanisms of acute IES involving incretin hormones, such as GLP-1, and ghrelin, and the intestinal transit mechanisms involved in the IES-induced elevation of insulin-stimulating gastrointestinal hormones. 3) To explore cellular mechanisms of chronic IES on long-term glycemic control. Chronic IES will be performed to investigate long-term hypoglycemic effects of IES in both fasting and fed states, and mechanisms involving pancreatic islets functions, beta-cell apoptosis and proliferation, and a number of transcription factors involved in the regulation of β-cell development, differentiation and function. Possible involvement of L-cells in the distal gut will also be investigated.