Glucagon Pump Therapy for Post-Bariatric Hypoglycemia: Merging Physiology and Engineering

项目总结/摘要 减肥手术是治疗肥胖相关代谢性疾病的有效方法，可显著改善血糖 控制T2 D。然而，沿着的是代谢的成功，严重低血糖的风险增加 （称为减肥后低血糖，或PBH），估计患病率高达30%的患者， 胃旁路术和袖状胃切除术。目前用于PBH的疗法是有限的并且不完全有效，并且 严重低血糖和无意识的个体在快速发作前缺乏足够的警告进行治疗。 神经性低血糖和安全性受损。 我们小组和其他人以前对PBH的研究已经证明了在这种情况下低血糖的潜在驱动因素。 条件：（1）胰岛素分泌增加，与餐后肠促胰岛素分泌（包括GLP 1）相关，（2）增加 胰岛素非依赖性葡萄糖摄取，（3）胰高血糖素和其他反调节激素分泌减少， （4）肠道代谢改变。预防和治疗PBH严重低血糖的一种有希望的方法 是闭环胰高血糖素疗法在之前的研究中，我们与工程同事合作开发并 测试闭环系统，该闭环系统利用CGM结合新颖闭环算法来检测 并通过贴片泵输送大剂量胰高血糖素。使用双盲， 在临床研究单位的安慰剂对照交叉试点研究中，我们证明了这种药物的有效性和安全性。 闭环胰高血糖素泵系统，混合餐后最低血糖增加，急救需求减少 葡萄糖在这些以膳食为中心的研究的成功鼓舞下，我们现在建议进一步定义胰高血糖素 敏感性，分泌，和营业额和糖原代谢的PBH，以发展一个增强的，更 有效闭环胰高血糖素算法和响应血糖波动的临床治疗系统 其不仅发生在餐后期间，而且发生在夜间和活动期间/之后。 为了实现这一目标，我们组建了一个多学科团队，包括具有专业知识的临床研究人员 在PBH和胰高血糖素和葡萄糖代谢，和生物医学工程师的专业知识和既定的轨道 在闭环泵系统开发和临床测试和实施方面有记录。因此，拟议的 研究将解决PBH的重要知识和治疗差距，并提供四个创新的 可交付成果，以促进我们对这一具有挑战性的患者群体的理解和临床护理：（1）关键 胰高血糖素敏感性、分泌和转换以及糖原代谢的定量数据， PBH中餐后、吸收后和活动后状态下的低血糖，（2）计算机模拟的发展 PBH患者的模型，允许实施和测试新的CLG算法，（3）实施 在驱动由CGM数据引导的微剂量胰高血糖素的体上泵输送的系统中的CLG算法， 和（4）在监管部门批准后，完成了一项随机门诊、基于酒店的临床试验， PBH患者的CLG系统。

Project Summary/Abstract Bariatric surgery is a potent treatment for obesity-related metabolic disease and markedly improves glucose control in T2D. However, along with this metabolic success comes an increased risk of severe hypoglycemia (termed post-bariatric hypoglycemia, or PBH), with estimated prevalence of up to 30% of patients after both gastric bypass and sleeve gastrectomy. Current therapies for PBH are limited and incompletely effective, and individuals with severe hypoglycemia and unawareness lack sufficient warning to treat before rapid onset of neuroglycopenia and impaired safety. Previous studies of PBH by our group and others have demonstrated potential drivers of hypoglycemia in this condition: (1) increased insulin secretion, linked to postprandial incretin secretion (including GLP1), (2) increased insulin-independent glucose uptake, (3) reduced secretion of glucagon and other counterregulatory hormones, and (4) altered intestinal metabolism. One promising approach to prevent and treat severe hypoglycemia in PBH is closed-loop glucagon therapy. In prior studies, we collaborated with engineering colleagues to develop and test a closed-loop system which utilized CGM in combination with a novel closed-loop algorithm to detect incipient meal-related hypoglycemia and deliver boluses of glucagon via a patch pump. Using a double-blind, placebo-controlled crossover pilot study in the clinical research unit, we demonstrated efficacy and safety of this closed-loop glucagon pump system, with increased nadir glucose after mixed meal and reduced need for rescue glucose. Buoyed by the success of these meal-focused studies, we now propose to further define glucagon sensitivity, secretion, and turnover and glycogen metabolism in PBH, in order to develop an enhanced, more effective, closed-loop glucagon algorithm and clinical therapeutic system responsive to glycemic excursions which occur not only during the postprandial period, but also during overnight hours and during/after activity. To achieve this goal, we have assembled a multidisciplinary team including clinical investigators with expertise in PBH and glucagon and glucose metabolism, and biomedical engineers with expertise and an established track record in closed-loop pump system development and clinical testing and implementation. Thus, the proposed studies will address an important knowledge and therapeutic gap in PBH, and provide four innovative deliverables to advance our understanding of and the clinical care of this challenging patient population: (1) key quantitative data for glucagon sensitivity, secretion and turnover and glycogen metabolism as contributors to hypoglycemia during postprandial, postabsorptive, and post-activity states in PBH, (2) development of an in silico model of the PBH patient, allowing implementation and testing of a novel CLG algorithm, (3) implementation of the CLG algorithm in a system driving on-body pump delivery of microdoses of glucagon guided by CGM data, and (4) after regulatory approval, completion of a pilot randomized outpatient, hotel-based clinical trial of the CLG system in patients with PBH.