Automated Intestinal Electrical Stimulation for Diabetes

描述（由申请人提供）：糖尿病影响超过8%的美国人，2007年在美国花费超过1740亿美元。最近，减肥手术，如Roux-en-Y胃旁路术，已被提出用于治疗糖尿病患者的肥胖，由于其对餐后血糖的降血糖作用和显着的体重减轻。 在这个建议中，我们提出了一种新的方法，自动肠道电刺激（IES）治疗糖尿病。基于我们小组先前发表的研究，我们发现IES以类似于胃旁路手术的方式改变胃肠动力，生理和激素：它减少食物摄入和营养吸收，抑制胃饥饿素并增加餐后状态下的胰高血糖素样肽（GLP-1）。基于这些发现，我们假设急性IES改善餐后高血糖，慢性IES改善长期血糖控制。如果被证明有效，与减肥手术相比，建议的IES具有可调节、可逆和侵入性小的优点。 Goto-Kakizaki（GK）大鼠是自发性2型糖尿病最具特征的动物模型之一，也是最广泛用于研究减肥手术抗糖尿病机制的动物模型，本项目将使用GK大鼠来证明以下假设并实现以下特定目标。1)优化IES方法，使IES的降血糖作用最大化。特别是，IES的刺激参数将进行系统的研究和优化。将仔细检查急性优化IES对餐后血糖和胰岛素敏感性的影响。2)探讨IES急性降糖作用的可能机制。设计实验以检验以下假设：IES诱导的餐后血糖降低是通过延迟胃排空和加速肠转运机械介导的，并且是通过减少胃饥饿素和增加GLP-1的释放来介导的。3)研究慢性IES对长期血糖控制的影响及其机制。慢性实验旨在检验以下假设：餐后高血糖症的改善预防/减少慢性高血糖症对β细胞功能和全身胰岛素敏感性的有害影响，从而改善长期血糖控制。将为慢性实验开发自动食物摄入检测算法。 一个多学科小组已经成立，以执行这项任务。PI在胃肠电刺激治疗胃肠动力、肥胖和糖尿病方面具有丰富的经验。顾问Abate博士是胰岛素抵抗和糖尿病方面的专家。小型企业拥有设计和开发建议的自动反馈控制IES系统所需的所有专业知识和设施。

DESCRIPTION (provided by applicant): Diabetes affects more than 8% of Americans and costs over $174 billion in 2007 in USA. Recently bariatric surgery, such as Roux-en-Y gastric bypass, has been proposed for treating diabetic patients with obesity due to its hypoglycemic effect on postprandial blood glucose and significant weight loss. In this proposal, we propose a novel method of automated intestinal electrical stimulation (IES) for the treatment of diabetes. Based on previous published studies in our group, we have discovered that IES alters gastrointestinal motility, physiology and hormones in a way similar to the gastric bypass procedure: it reduces food intake and nutrient absorption, inhibits gastric ghrelin and increases glucagon-like peptide (GLP-1) in the postprandial state. Based on these findings, we hypothesize that acute IES improves postprandial hyperglycemia and chronic IES results in improvement in long-term glycemic control. If proven effective, the proposed IES has advantages of being adjustable, reversible and less invasive, compared with bariatric surgery. The Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous Type 2 diabetes and most widely used in studying anti-diabetic mechanisms of bariatric surgeries will be used in this project to prove following hypotheses and accomplish following specific aims. 1) To optimize IES methodology such that the hypoglycemic effect of IES is maximized. Particularly, the stimulation parameters of IES will be systematically investigated and optimized. The effects of acute optimized IES on postprandial blood glucose and insulin sensitivity will be carefully examined. 2) To investigate possible mechanisms involved in the hypoglycemic effect of acute IES. Experiments are designed to test the hypothesis that IES-induced reduction in postprandial blood glucose is mediated mechanically by delayed gastric emptying and accelerated intestinal transit, and hormonally by reduced ghrelin and increased release of GLP-1. 3) To study effects and mechanisms of chronic IES on long-term glycemic control. Chronic experiments are designed to test the hypothesis that improvement in postprandial hyperglycemia prevents/reduces the detrimental effect of chronic hyperglycemia on beta-cell function and systemic insulin sensitivity, leading to improvement of long-term glucose control. An automatic food intake detection algorithm will be developed for the chronic experiments. A multi-disciplinary team has been assembled to undertake the task. The PI has extensive experience in gastrointestinal electrical stimulation on gastrointestinal motility, obesity and diabetes. The consultant Dr. Abate is an expert from in insulin resistance and diabetes. The small business has all required expertise and facilities to design and develop the proposed automatic feedback controlled IES system.