Electronic Bypass for Diabetes

糖尿病电子旁路

基本信息

批准号：
10179364
负责人：
Jiande Chen
金额：
$ 45.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179364
关键词：
Acceleration Acute Affect Algorithms American Animal Model Animals Apoptosis B-Cell Development Beta Cell Blood Glucose Body Weight decreased Bypass Cell physiology Characteristics Chronic Clinical Colon Controlled Study Conventional Surgery Development Diabetes Mellitus Distal Eating Electric Stimulation Excision Fasting Food GLP-I receptor GLUT-2 protein Gastrectomy Gastric Bypass Gastric Emptying Gastric Inhibitory Polypeptide Gastrointestinal Hormones Gastrointestinal Transit Gastroparesis Glucose Goals Hormonal Hormones Hunger Hyperglycemia Hypoglycemia Individual Ingestion Insulin Intestinal Absorption Intestinal Bypasses Intestines Islets of Langerhans L Cells Medical Methodology Methods Monitor Morbid Obesity Morphology Movement Non-Insulin-Dependent Diabetes Mellitus Nutrient Oral Pancreas Plasma Play Prevention Procedures Rattus Regulation Rodent Model Role Small Intestines Speed Stimulus Stomach Surface System Technology Weight Wireless Technology algorithm development analog artificial neural network bariatric surgery base blood glucose regulation cost design diabetic patient diabetic rat experimental study ghrelin glucagon-like peptide 1 glycemic control ileum improved incretin hormone insulin secretion novel obese patients pancreatic islet function prevent protective effect transcription factor

项目摘要

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.

糖尿病在2012年在美国影响超过9％的美国人，成本超过2450亿美元。最近减肥已经提出了手术，例如roux-en-y胃旁路和袖子切除术，已提出用于治疗糖尿病的手术肥胖症患者由于其降血糖对餐后血糖和大量体重减轻的影响。提出了一种新型的肠电刺激方法（IE），以治疗糖尿病应用。在这种方法中，IES旨在改变胃肠道交通和激素，包括增加激素，例如胰高血糖素（如肽-1）（GLP-1）。我们的初步研究表明加速肠道的肠道，餐后GLP-1的增加和口服葡萄糖后血糖的降低。长期以来，提出的IES导致血糖控制和胰腺的改善改善胰岛功能。根据这些发现，我们假设IES在餐后状态归因于IES诱导的GLP-1发行和其他可能的增强骑马素（例如生长素释放），以及在禁食和喂养中IE的慢性降血糖作用状态归因于β细胞功能的改善，归因于预防检测器效应高血糖和IES诱导的GLP-1升高对β细胞功能的改善作用。该项目将使用高级技术（无线刺激和记录笼子，以及自主和连续的食物摄入监测），可以在自由移动的动物中进行IE。 goto-kakizaki（GK）大鼠的赞助2型糖尿病的动物模型最佳的动物模型将被使用完成以下特定目标：1）优化IES参数，开发点播IES并执行闭环IE。首先，我们将系统地优化模拟参数，以最大化降血糖 IES的效果。然后，我们将开发一种算法以自动检测食物摄入，然后触发IES 食物摄入。它将基于内在的肠肌电活动和人工神经的特征网络。触发的餐将避免过多刺激。最后，闭环IES方法（每种将开发与内在肠肌电活动同步的刺激），以进一步增加 IES对糖尿病的功效。 2）研究涉及肠降血糖素的急性IE的降血糖机制 Horsemones，例如GLP-1和Ghrelin，以及IES诱导的肠道过境机制胰岛素刺激的胃肠道激素的升高。 3）探索慢性IES的细胞机制长期血糖控制。将进行慢性IE，以研究IES的长期降血糖作用在禁食状态和联邦状态下，以及涉及胰岛功能的机制，β细胞凋亡和增殖以及β细胞发育调节的许多转录因子，分化和功能。 L细胞可能参与远端肠道。