Closed-loop Glucose Control System Research Articles

112-LB: Proof-of-Concept Testing of an Artificial Intelligence–Based Fully Closed-Loop System in Hospitalized Patients with Diabetes

Objective: Achieving tight glucose control safely and effectively is challenging in the Intensive Care Unit (ICU). We conducted the first-in-human test of an artificial intelligence (AI)-based fully autonomous glucose control system in a simulated ICU setting. Methods: We admitted seven participants with type1 and type 2 (n=6) diabetes mellitus for 24-hour closed-loop glucose control sessions that included three unannounced meals. The AI-based system uses glucose control software that controls intravenous insulin and glucose infusions based on real-time continuous glucose monitoring derived data from two real-time CGM devices. The primary efficacy endpoint was the percentage of glucose values within the range of 70-180 mg/dL. The primary safety endpoint was the percentage of glucose values < 70 mg/dL. Results: Participants were on average 48±9.7 years-old, 71% female, and BMI 36±7.8 m/kg2. Mean time in the target range (70-180 mg/dl) was 87.8%. Mean time in the hypoglycemic range (< 70 mg/dL) was 0.2%, Figure. No adverse events occurred. Conclusion: This first in-human results show this novel fully autonomous closed-loop glucose control system designed for the ICU setting has the potential to achieve unparalleled glycemic control with minimal risk of hypoglycemia and paves the way for further research in the actual ICU setting. Disclosure F. Zahedi tajrishi: None. F. J. Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies. G. Davis: Consultant; Medscape, Research Support; Insulet Corporation. M. Perez-guzman: None. L. I. Guerrero arroyo: None. G. Blanco: None. J. Varghese: None. S. Zahid: None. J. Dejournett: Stock/Shareholder; Ideal Medical Technologies. L. Dejournett: Employee; Ideal Medical Technologies. Funding Ideal Medical Technologies; Dexcom, Inc.

Time With Glucose Level in Target Range Among Children and Adolescents With Type 1 Diabetes After a Software Update to a Closed-Loop Glucose Control System

Time With Glucose Level in Target Range Among Children and Adolescents With Type 1 Diabetes After a Software Update to a Closed-Loop Glucose Control System

Performance of a closed-loop glucose control system, comprising a continuous glucose monitoring system and an AI-based controller in swine during severe hypo- and hyperglycemic provocations

Intensive care unit (ICU) patients develop stress induced insulin resistance causing hyperglycemia, large glucose variability and hypoglycemia. These glucose metrics have all been associated with increased rates of morbidity and mortality. The only way to achieve safe glucose control at a lower glucose range (e.g., 4.4–6.6 mmol/L) will be through use of an autonomous closed loop glucose control system (artificial pancreas). Our goal with the present study was to assess the safety and performance of an artificial pancreas system, composed of the EIRUS (Maquet Critical Care AB) continuous glucose monitor (CGM) and novel artificial intelligence-based glucose control software, in a swine model using unannounced hypo- and hyperglycemia challenges. Fourteen piglets (6 control, 8 treated) underwent sequential unannounced hypoglycemic and hyperglycemic challenges with 3 IU of NovoRapid and a glucose infusion at 17 mg/kg/min over the course of 5 h. In the Control animals an experienced ICU physician used every 30-min blood glucose values to maintain control to a range of 4.4–9 mmol/L. In the Treated group the artificial pancreas system attempted to maintain blood glucose control to a range of 4.4–6.6 mmol/L. Five of six Control animals and none of eight Treated animals experienced severe hypoglycemia (< 2.22 mmol/L). The area under the curve 3.5 mmol/L was 28.9 (21.1–54.2) for Control and 4.8 (3.1–5.2) for the Treated animals. The total percent time within tight glucose control range, 4.4–6.6 mmol/L, was 32.8% (32.4–47.1) for Controls and 55.4% (52.9–59.4) for Treated (p < 0.034). Data are median and quartiles. The artificial pancreas system abolished severe hypoglycemia and outperformed the experienced ICU physician in avoiding clinically significant hypoglycemic excursions.

1036-P: Closed-Loop Glucose Control System for In-Hospital Use: Extended Control Trials

Background: Optimal in-hospital glucose control is a requirement for reducing mortality, morbidity and duration of admission. Present glucose concentrations in critical care are characterized by marked variability and episodes of hypoglycemia due to inadequate sensing and treatment technologies. We have previously shown (ADA 2016), that a prototype closed loop system (Admetsys™) infusing insulin/dextrose is capable of controlling blood glucose. Aim: The aim of this study was to assess the ability of the Admetsys™ Insulin Based Infusion Systems (IBIS) (totally closed loop system) to lower, stabilize and maintain desired glucose levels and to avoid episodes of hypoglycemia for an extended period of time of up to 24 hours in patients “during admission to hospital.” Methodology: 12 people with diabetes (ten with type 1 diabetes, two with type 2 diabetes) ranging from 26-49 years of age were admitted to our clinical research unit. The duration of the study was up to 24 hours, and at beginning of the study blood glucose levels were betwee 150 and 300 mg/dl. Through a three-way connector the Admetsys™ IBIS was connected to insulin and glucose/dextrose pumps and linked to an intravenous automated glucose sensor (VIA Glucoscout), which sent the data to the treatment system. A saline solution was infused to insure vein patency. The therapeutic target range was set to 80-125 mg/dl. Results: Results from all twelve subjects were collected and analyzed. Mean time to reach the normoglycemic target range (80-125 mg/dl) was 2.36 hours. When target range was achieved the mean blood glucose level was 107.0 mg/dl (SD 8.6 mg/dl). No incidence of hypoglycemia (&amp;lt;70 mg/dl) occurred during the course of the trial. Conclusion: The Admetsys™ IBIS system proved accurate, safe and reliable in this study. However, further studies in greater patient populations are needed to validate the full performance of this closed loop system designed for hospital use. Disclosure N. Hashemi: None. T. Valk: Other Relationship; Self; Admetsys. K. Houlind: None. N. Ejskjaer: None.

Free-living use of artificial pancreas for children with type 1 diabetes: systematic review

BACKGRAUND: A closed-loop glucose control system or artificial pancreas consists of three components a Continuous Glucose Monitor (CGM), infusion pumps to deliver hormone(s) and a sophisticated dosing algorithm to control hormone delivery. In the past years, numerous studies with closed-loop system devices were conducted with gradual shift to out-of-hospital environment and with lengthening study duration.&#x0D; AIMS: To compare efficacy and safety of closed-loop insulin pump use in children with type 1 diabetes mellitus in compare with conventional insulin treatment (continuous subcutaneous insulin infusion (CSII) with our without CGM) based on randomized control trials data (RCT).&#x0D; METHODS: In the systematic review we have include 28 randomized controlled trials results indexed in PubMed, Medline databases published till 15 June 2017. The efficacy on metabolic control in this study evaluated by the proportion of time within target range (preferably 70 to 180 mg/dl if reported) and mean (median) glucose based on sensor measurements, and the safety evaluated by time in hypoglycemia (below 70 mg/dl if reported).&#x0D; RESULTS: Increased time in range in the night period was observed in all RCT. Only 3 RCT showed decrease of the time in range within 24 h evaluation period. In one RCT the significant positive differences have been shown in the time in range for dual hormone closed-loop glucose control system in compare with insulin-only artificial pancreas. Mean glycaemia and glucose variability changes were not in the same manner in different RCT, both in the night only and in 24 h estimation period. Night hypoglycemia duration decreased in most RCT with closed-loop control in compare with CSII, and increased only in 2 RCT. When all-day estimation period the time in hypoglycemia changed not in the same manner in different RCT. Valuable methodology differences of the glycaemic control estimation within observed RCT brought significant complications in the data analysis and made impossible the results quantitative estimation to prepare a metaanalysis.&#x0D; CONCLUSIONS: Much work has been done to develop effective and safe artificial pancreas, but not all RCTs confirmed advantages of closed-loop glucose control in compare with CSII in children and adolescents in real life. More research with prospective randomized control design required to prove benefits of closed-loop glucose control. Further RCTs should have an uniform methodology for glycemic control assessment and long duration that will allow to use cumulative measures in a closed-loop efficacy estimation (HbA1c).

Insulin Estimation and Prediction: A Review of the Estimation and Prediction of Subcutaneous Insulin Pharmacokinetics in Closed-Loop Glucose Control

Patients affected by type 1 diabetes (T1D) suffer from lack of insulin secretion by the pancreas, due to the autoimmune destruction of the insulin-producing beta cells. This translates into elevated plasma glucose concentration with deleterious effects in the cardiovascular system, leading to serious long-term complications. With the improvement of continuous glucose monitoring (CGM) technology, a significant amount of research has been focused in the last decade on the development of an artificial pancreas (AP), that is, a closed-loop glucose control system that automatically dispenses insulin. The AP is now closer to reality [1]. An AP system was first approved by the U.S. Food and Drug Administration (FDA) in 2016 [2]. The system still requires user intervention at mealtime, as currently done in openloop insulin pump therapy, to administer an insulin bolus based on carbohydrate counting (a hybrid closed-loop system).

Wearable systems and mobile applications for diabetes disease management

Diabetes is a chronic metabolic disorder requiring the active and continuous participation of diabetic individuals, their caregivers and physicians in order to be managed and well-controlled. Diabetes care has evolved considerably over the years with the development of advanced medical technologies and therapeutics. In the first part of this paper, we present the state of the art in wearable medical devices for monitoring and controlling blood glucose levels with special emphasis on continuous glucose monitoring (CGM) devices and insulin pumps. Moreover, a description is made of the significant steps taken towards a portable fully automated closed-loop glucose control system (artificial pancreas) suitable for outpatient use. The second part of this paper is concerned with mobile self-management support interventions in diabetes care. Advances in mobile computing and wireless communications have enabled the development of efficient mobile applications for self-monitoring diabetes and providing feedback. Both literature and digital distribution stores demonstrate a plethora of such paradigms with, admittedly, obvious variety in their functionalities, design and validity. The way in which mobile health technology has contributed to improvements in diabetes health outcomes and life is also discussed and future directions for research are identified.

Evaluating the Performance of a Novel Embedded Closed-loop System.

The objective was to assess the reliability of a novel automated closed-loop glucose control system developed within the AP@home consortium in adults with type 1 diabetes. Eight adults with type 1 diabetes on insulin pump therapy (3 men; ages 40.5 ± 14.3 years; HbA1c 8.2 ± 0.8%) participated in an open-label, single-center, single-arm, 12-hour overnight study performed at the clinical research facility. A standardized evening meal (80 g CHO) accompanied by prandial insulin boluses were given at 19:00 followed by an optional snack of 15 g at 22:00 without insulin bolus. Automated closed-loop glucose control was started at 19:00 and continued until 07:00 the next day. Basal insulin delivery (Accu-Chek Spirit, Roche) was automatically adjusted by Cambridge model predictive control algorithm, running on a purpose-built embedded device, based on real-time continuous glucose monitor readings (Dexcom G4 Platinum). Closed-loop system was operational as intended over 99% of the time. Overnight plasma glucose levels (22:00 to 07:00) were within the target range (3.9 to 8.0 mmol/l) for 75.4% (37.5, 92.9) of the time without any time spent in hypoglycemia (<3.9 mmol/l). Mean overnight glucose was 7.8 ± 1.3 mmol/l. For the entire 12-hour closed-loop period (19:00 until 07:00) plasma glucose levels were within the target range (3.9 to 10.0 mmol/l) for 84.4% (63.3, 100) of time. There were no adverse events noted during the trial. We observed a high degree of reliability of the automated closed-loop system. The time spent in target glucose level overnight was comparable to results of previously published studies. Further developments to miniaturize the system for home studies are warranted.

The future of open- and closed-loop insulin delivery systems

We have analysed several aspects of insulin-dependent diabetes mellitus, including the glucose metabolic system, diabetes complications, and previous and ongoing research aimed at controlling glucose in diabetic patients. An expert review of various models and control algorithms developed for the glucose homeostasis system is presented, along with an analysis of research towards the development of a polymeric insulin infusion system. Recommendations for future directions in creating a true closed-loop glucose control system are presented, including the development of multivariable models and control systems to more accurately describe and control the multi-metabolite, multi-hormonal system, as well as in-vivo assessments of implicit closed-loop control systems.

Pharmacodynamics And Stability of Subcutaneously Infused Glucagon in A Type 1 Diabetic Swine Model In Vivo

The objective of this study was to determine the in vivo pharmacodynamics of glucagon and to test its glycemic effect over days by assessing its time course of activity and potency in a type 1 diabetic swine model. Individual experiments were conducted in different pigs using glucagon preparations that were reconstituted on different days and stored at room temperature or near body temperature before usage. All experiments involved a subcutaneous bolus of glucagon to counter impending hypoglycemia induced by an earlier bolus of fast-acting insulin. Frequent blood-glucose measurements, using a standard in vitro hand-held meter, were taken during each experiment to track variations in blood-glucose concentration. Significant glucagon action was observed as early as 5 min after administration, as evidenced by an effective halt to declining blood glucose and a subsequent twofold rise in blood glucose after approximately 20 min. Results also indicate that the consumption of glucagon from the subcutaneous depot is substantially faster than that of fast-acting insulin. Furthermore, no significant depreciation was observed in glucagon efficacy across aging preparations as old as 7 days. These results suggest profound utility of subcutaneous glucagon in a closed-loop glucose control system, especially since glucagon would provide an effective safeguarding measure to stave off impending hypoglycemia, an application where the rapid effect of subcutaneous glucagon is both serendipitous and essential. Despite the notion that the stability of glucagon in solution at room temperature is inferior to that of fast-acting insulin, its subcutaneous administration has promising prospects for long-term closed-loop ambulatory care.

Dynamic Modeling of Free Fatty Acid, Glucose, and Insulin: An Extended "Minimal Model"

The mathematical models for patients with diabetes proposed in the literature since the late 1970s are mainly glucocentric (glucose-based); hence, the contribution of free fatty acid (FFA) metabolism in the body and its glucose-insulin interactions have been largely ignored. However, approximately 90% of the muscle energy is derived from FFA metabolism when the body is at rest. Furthermore, significant interactions exist among FFA, glucose, and insulin. With the long-term goal of developing a closed-loop glucose control system, a model of the major energy-providing substrate dynamics is required. The Bergman minimal model was extended to include plasma FFA dynamics, and its interaction with glucose and insulin dynamics, with a primary focus on patients with Type 1 diabetes. Differential equations were developed for plasma FFA concentrations and "remote" FFA effects on glucose uptake, as well as "remote" insulin effects on plasma FFA concentrations. Parameters for the model were estimated from experimental data provided in the scientific literature. The minimal model was extended in order to capture three major metabolic aspects: the antilipolytic effect of insulin; the lipolytic effect of prolonged hyperglycemia; and the impairing effect of FFA on glucose uptake rate. The dynamic fit of glucose, FFA, and insulin profiles is consistent with published data. The extended minimal model successfully captured the plasma FFA concentration behavior, the plasma insulin and glucose concentrations, and the physiological interactions that exist among these species. This more comprehensive description of energy-providing substrate dynamics may provide a novel simulation test-bed for analysis of patients with insulin dependent diabetes and controller design.