Electronic Bypass for Diabetes

糖尿病影响超过9%的美国人，2012年在美国花费超过2450亿美元。最近减肥 已经提出手术，例如Roux-en-Y胃旁路术和袖状胃切除术，用于治疗糖尿病 肥胖患者因其对餐后血糖有降糖作用而体重明显减轻。 本研究提出了一种新的肠电刺激（IES）治疗糖尿病的方法。 应用程序.在这种方法中，IES旨在改变胃肠运输和激素，包括肠促胰岛素 激素，如胰高血糖素样肽-1（GLP-1）。我们的初步研究表明 肠转运，餐后GLP-1增加和口服葡萄糖后血糖降低。 长期而言，所提出的IES已导致血糖控制的改善和胰腺炎的改善。 胰岛功能。根据这些发现，我们推测IES的急性降血糖作用可能与其对糖尿病患者的作用有关。 餐后状态归因于IES诱导的GLP-1和可能的其他 激素，如生长激素释放肽，以及IES的慢性降血糖作用，无论是空腹和进食 国家是由于β细胞功能的改善，由于预防的不利影响， 高血糖症和IES诱导的GLP-1升高对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， 自主和连续的食物摄入监测），允许IES在自由移动的动物中进行。 将使用自发性2型糖尿病的最佳表征动物模型Goto-Kakizaki（GK）大鼠 具体目标如下：1）优化IES参数，开发按需IES， 闭环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， 的影响。然后，我们将开发一种算法，自动检测食物摄入量，然后触发IES， 食物摄取它将基于固有的肠肌电活动和人工神经网络的特点， 网络进餐触发的IES将避免过度刺激。最后，一个闭环IES方法（每个 刺激与内在肠肌电活动同步）将进一步增加 IES对糖尿病的疗效。2)探讨肠促胰岛素参与的急性IES降血糖机制 激素，如GLP-1和ghrelin，以及参与IES诱导的肠转运机制。 胰岛素刺激胃肠激素升高。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的长期降血糖作用 在空腹和进食状态下，以及涉及胰岛功能、β细胞凋亡和 增殖，以及参与β细胞发育调节的许多转录因子， 分化和功能。还将研究远端肠道中L细胞的可能参与。

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.