Closed-loop Insulin Delivery System Research Articles

Ultrafast glucose-responsive, high loading capacity erythrocyte to self-regulate the release of insulin

Insulin (INS) delivery system that can mimic normal insulin secretion to maintain the blood glucose level (BGL) in the normal range is an ideal treatment for diabetes. However, most of the existing closed-loop INS delivery systems respond slowly to the changes in BGL, resulting in a time lag between the abnormal BGL and the release of INS, which is not suitable for practical application. In this study, glucose oxidase (GOx)-modified erythrocytes are used as INS carriers (GOx-INS-ER) that can rapidly self-regulate the release of INS upon the changes in BGL. In this system, glucose can be broken down into gluconic acid and hydrogen peroxide by GOx-INS-ER, and the latter will rupture the erythrocyte membrane to release INS within minutes. A pulsatile release of INS can be achieved upon the changes in the glucose concentration. This GOx-INS-ER enables diabetic rats to overcome hyperglycemia within 1 h, and a single injection of this GOx-INS-ER into the STZ-induced diabetic rats can maintain the BGL in the normal range up to 9 days. Statement of SignificanceDiabetes mellitus has been a major public health threatener with global prevalence. Although, glucose-responsive carriers that can release insulin (INS) in a closed loop have been explored greatly in recent years, their sluggish glucose-responsive property and low INS-loading content greatly restrict their practical application [ACS Nano, 2013, 7, 4194].In this work, we reported INS-loaded erythrocytes featuring ultrafast glucose-responsive property and high INS loading content, which could release INS in a closed loop. These GOX-INS-ERs could respond to the changes in glucose level within several minutes and self-regulate the release of INS for a long time. Single injection of GOX-INS-ER can overcome hyperglycemia in diabetic mice within 1 h and maintain the baseline level of glucose up to 9 days. We think our method may provide a robust way to potentiate diabetes treatment.

Recent Advances in Closed-Loop and Smart Insulin Delivery Systems

Recent Advances in Closed-Loop and Smart Insulin Delivery Systems

Review of a commercially available hybrid closed-loop insulin-delivery system in the treatment of Type 1 diabetes.

Type 1 diabetes is an important medical condition causing significant burden and morbidity to those persons affected by it. Improvements in insulin products, insulin delivery and glucose monitoring technology have all contributed to reductions in long-term complications and hypoglycemia. This article reviews the Medtronic 670G device and summarizes the data supporting how this product reduces the burden and increases the safety of insulin dosing in Type 1 diabetes.

A Novel Three-Compartmental Model for Artificial Pancreas: Development and Validation.

Closed-loop insulin delivery system, also known as artificial pancreas (AP), provides the blood glucose control in diabetic patients, enabling the automatic blood-sugar management and reducing the risks and improving the lives of people with diabetes. A new three-compartmental model of glucose-insulin interaction for AP is presented and tested in this paper. The glucose and insulin "spaces" are split into a plasma compartment and interstitial fluids compartment, respectively. The model includes an additional subcutaneous compartment and provides three explicit delays and three parameters influencing the regulatory system and correlating with the physiopathology of the patients. Two delays are related with hepatic glucose production and insulin secretion; the third delay represents the lag time in the absorption of exogenous insulin in subcutaneous tissue. The parameters regulate the system dynamics acting on the glucose utilization and the insulin secretion. The clinical data (including information on food ingestion and exogenous insulin injection) from five case studies of Type 1 diabetics are presented and used to validate the mathematical model. After training the parameters for each case study, the model well simulates the glucose level during a 4-day test. The estimated values are physiologically meaningful and provide a further insight on the subject's dysfunctions and on the state of the disease. The results have been also compared with a parallel simulation carried out by implementing a previous two-compartmental model. The proposed algorithm produces a lower sum of the squared error between the simulated and the measured glucose concentrations over time.

Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: a randomised controlled crossover trial

Aims/hypothesisHypoglycaemia during and after exercise remains a challenge. The present study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes.MethodsA randomised, two-arm, open-label, in-hospital, crossover clinical trial was performed at a single site in Slovenia. The order was randomly determined using an automated web-based programme with randomly permuted blocks of four. Allocation assignment was not masked. Children and adolescents with type 1 diabetes who were experienced insulin pump users were eligible for the trial. During four separate in-hospital visits, the participants performed two unannounced exercise protocols: moderate intensity (55% of overset{cdot }{V}{mathrm{O}}_{2max } ) and moderate intensity with integrated high-intensity sprints (55/80% of overset{cdot }{V}{mathrm{O}}_{2max } ), using the same study device either for closed-loop or open-loop insulin delivery. We investigated glycaemic control during the exercise period and the following night. The closed-loop insulin delivery was applied from 15:00 h on the day of the exercise to 13:00 h on the following day.ResultsBetween 20 January and 16 June 2016, 20 eligible participants (9 female, mean age 14.2 ± 2.0 years, HbA1c 7.7 ± 0.6% [60.0 ± 6.6 mmol/mol]) were included in the trial and performed all trial-mandated activities. The median proportion of time spent in hypoglycaemia below 3.3 mmol/l was 0.00% for both treatment modalities (p = 0.7910). Use of the closed-loop insulin delivery system increased the proportion of time spent within the target glucose range of 3.9–10 mmol/l when compared with open-loop delivery: 84.1% (interquartile range 70.0–85.5) vs 68.7% (59.0–77.7), respectively (p = 0.0057), over the entire study period. This was achieved with significantly less insulin delivered via the closed-loop (p = 0.0123).Conclusions/interpretationClosed-loop insulin delivery was safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia.Trial registrationClinicaltrials.gov NCT02657083FundingUniversity Medical Centre Ljubljana, Slovenian National Research Agency, and ISPAD Research Fellowship

Numerical simulation of a glucose sensitive composite membrane closed-loop insulin delivery system.

Closed-loop insulin delivery system works on pH modulation by gluconic acid production from glucose, which in turn allows regulation of insulin release across membrane. Typically, the concentration variation of gluconic acid can be numerically modeled by a set of non-linear, non-steady state reaction diffusion equations. Here, we report a simpler numerical approach to time and position dependent diffusivity of species using finite difference and differential quadrature (DQ) method. The results are comparable to that obtained by analytical method. The membrane thickness directly determines the concentrations of the glucose and oxygen in the system, and inversely to the gluconic acid. The advantage with the DQ method is that its parameter values need not be altered throughout the analysis to obtain the concentration profiles of the glucose, oxygen and gluconic acid. Our work would be useful for modeling diabetes and other systems governed by such non-linear and non-steady state reaction diffusion equations.

Asymptotic tracking and disturbance rejection of the blood glucose regulation system

Type 1 diabetes patients need external insulin to maintain blood glucose within a narrow range from 65 to 108 mg/dl (3.6 to 6.0 mmol/l). A mathematical model for the blood glucose regulation is required for integrating a glucose monitoring system into insulin pump technology to form a closed-loop insulin delivery system on the feedback of the blood glucose, the so-called “artificial pancreas”. The objective of this paper is to treat the exogenous glucose from food as a glucose disturbance and then develop a closed-loop feedback and feedforward control system for the blood glucose regulation system subject to the exogenous glucose disturbance. For this, a mathematical model for the glucose disturbance is proposed on the basis of experimental data, and then incorporated into an existing blood glucose regulation model. Because all the eigenvalues of the disturbance model have zero real parts, the center manifold theory is used to establish blood glucose regulator equations. We then use their solutions to synthesize a required feedback and feedforward controller to reject the disturbance and asymptotically track a constant glucose reference of 90 mg/dl. Since the regulator equations are nonlinear partial differential equations and usually impossible to solve analytically, a linear approximation solution is obtained. Our numerical simulations show that, under the linear approximate feedback and feedforward controller, the blood glucose asymptotically tracks its desired level of 90 mg/dl approximately.

Chitosan Microgels Embedded with Catalase Nanozyme-Loaded Mesocellular Silica Foam for Glucose-Responsive Drug Delivery.

A glucose-responsive closed-loop insulin delivery system represents an ideal form of treatment for type 1 diabetes mellitus. Here, we develop a glucose-responsive protein delivery system based on chitosan microgels loaded with enzyme-mimicking inorganic nanoparticles. The pH-sensitive chitosan microgels, integrated with glucose-mediated pH-lowering enzymatic large-pore mesoporous silica (MCF), were fabricated via an electrospray process. Ceria nanoparticles (CeNPs), which is a catalase-mimicking inorganic artificial enzyme with a substantial stability compared to that of catalase, were incorporated into the MCF along with glucose oxidase. In hyperglycemic conditions, CeNPs successfully decomposed the toxic hydrogen peroxide that was generated from the glucose oxidation reaction mediated by glucose oxidase and regenerate oxygen; this protected glucose oxidase from denaturation. The pH-lowering induced by the enzymatic MCF in high glucose concentration resulted in swelling of the chitosan microgels and the subsequent release of the encapsulated model protein drug, such as bovine serum albumin and insulin. Finally, we successfully demonstrated self-regulated repetitive protein release from the chitosan microgels, which showed a basal release rate under normoglycemic conditions and an enhanced release rate under hyperglycemic conditions.

Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes.

Background: The safety and effectiveness of the in-home use of a hybrid closed-loop (HCL) system that automatically increases, decreases, and suspends insulin delivery in response to continuous glucose monitoring were investigated.Methods: Adolescents (n = 30, ages 14–21 years) and adults (n = 94, ages 22–75 years) with type 1 diabetes participated in a multicenter (nine sites in the United States, one site in Israel) pivotal trial. The Medtronic MiniMed® 670G system was used during a 2-week run-in phase without HCL control, or Auto Mode, enabled (Manual Mode) and, thereafter, with Auto Mode enabled during a 3-month study phase. A supervised hotel stay (6 days/5 nights) that included a 24-h frequent blood sample testing with a reference measurement (i-STAT) occurred during the study phase.Results: Adolescents (mean ± standard deviation [SD] 16.5 ± 2.29 years of age and 7.7 ± 4.15 years of diabetes) used the system for a median 75.8% (interquartile range [IQR] 68.0%–88.4%) of the time (2977 patient-days). Adults (mean ± SD 44.6 ± 12.79 years of age and 26.4 ± 12.43 years of diabetes) used the system for a median 88.0% (IQR 77.6%–92.7%) of the time (9412 patient-days). From baseline run-in to the end of study phase, adolescent and adult HbA1c levels decreased from 7.7% ± 0.8% to 7.1% ± 0.6% (P < 0.001) and from 7.3% ± 0.9% to 6.8% ± 0.6% (P < 0.001, Wilcoxon signed-rank test), respectively. The proportion of overall in-target (71–180 mg/dL) sensor glucose (SG) values increased from 60.4% ± 10.9% to 67.2% ± 8.2% (P < 0.001) in adolescents and from 68.8% ± 11.9% to 73.8% ± 8.4% (P < 0.001) in adults. During the hotel stay, the proportion of in-target i-STAT® blood glucose values was 67.4% ± 27.7% compared to SG values of 72.0% ± 11.6% for adolescents and 74.2% ± 17.5% compared to 76.9% ± 8.3% for adults. There were no severe hypoglycemic or diabetic ketoacidosis events in either cohort.Conclusions: HCL therapy was safe during in-home use by adolescents and adults and the study phase demonstrated increased time in target, and reductions in HbA1c, hyperglycemia and hypoglycemia, compared to baseline. Trial Registration: Clinicaltrials.gov identifier: NCT02463097.

Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery.

A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h.

Stem Cell Derived Beta Cells: The State of the Science.

Stem Cell Derived Beta Cells: The State of the Science.

Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes.

Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes.

Modeling Day-to-Day Variability of Glucose-Insulin Regulation Over 12-Week Home Use of Closed-Loop Insulin Delivery.

Parameters of physiological models of glucose-insulin regulation in type 1 diabetes have previously been estimated using data collected over short periods of time and lack the quantification of day-to-day variability. We developed a new hierarchical model to relate subcutaneous insulin delivery and carbohydrate intake to continuous glucose monitoring over 12 weeks while describing day-to-day variability. Sensor glucose data sampled every 10-min, insulin aspart delivery and meal intake were analyzed from eight adults with type 1 diabetes (male/female 5/3, age 39.9 ± 9.5 years, BMI 25.4 ± 4.4kg/m2, HbA1c 8.4 ± 0.6% ) who underwent a 12-week home study of closed-loop insulin delivery. A compartment model comprised of five linear differential equations; model parameters were estimated using the Markov chain Monte Carlo approach within a hierarchical Bayesian model framework. Physiologically, plausible a posteriori distributions of model parameters including insulin sensitivity, time-to-peak insulin action, time-to-peak gut absorption, and carbohydrate bioavailability, and good model fit were observed. Day-to-day variability of model parameters was estimated in the range of 38-79% for insulin sensitivity and 27-48% for time-to-peak of insulin action. In conclusion, a linear Bayesian hierarchical approach is feasible to describe a 12-week glucose-insulin relationship using conventional clinical data. The model may facilitate in silico testing to aid the development of closed-loop insulin delivery systems.

Management of Hypoglycemia in Children and Adolescents with Type 1 Diabetes Mellitus.

Hypoglycemia and fear of hypoglycemia limit appropriate glycemic control in many children and adolescents with type 1 diabetes. Traditional approaches to the prevention of hypoglycemia including patient education about modifiable risk factors for hypoglycemia (changes in insulin, diet, and exercise) and frequency of self glucose monitoring remain important for hypoglycemia prevention. Continuous glucose monitoring systems with or without a partial closed-loop control of insulin infusion have been very useful in the prevention of hypoglycemia. Oral carbohydrate and parenteral glucagon continue to be the mainstays of hypoglycemia treatment. In the future, we can look forward to regulatory approval of closed-loop insulin delivery and glucose monitoring systems to facilitate euglycemia, as well as glucagon administered by the intranasal route to treat hypoglycemia.

Intelligent semi-IPN chitosan–PEG–PAAm hydrogel for closed-loop insulin delivery and kinetic modeling

Design of an intelligent semi-IPN chitosan–PEG–PAAm hydrogel using glucose oxidase (GOx) and catalase (CAT) to improve closed-loop insulin delivery systems.

Home Use of an Artificial Beta Cell in Type 1 Diabetes

BackgroundThe feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established.MethodsIn two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents.ResultsAmong adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, −11 mg per deciliter; 95% CI, −17 to −6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, −0.3%; 95% CI, −0.5 to −0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, −29 mg per deciliter; 95% CI, −39 to −20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use.ConclusionsAmong patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.)

Metabolic Control With the Bio-inspired Artificial Pancreas in Adults With Type 1 Diabetes: A 24-Hour Randomized Controlled Crossover Study.

The Bio-inspired Artificial Pancreas (BiAP) is a closed-loop insulin delivery system based on a mathematical model of beta-cell physiology and implemented in a microchip within a low-powered handheld device. We aimed to evaluate the safety and efficacy of the BiAP over 24 hours, followed by a substudy assessing the safety of the algorithm without and with partial meal announcement. Changes in lactate and 3-hydroxybutyrate concentrations were investigated for the first time during closed-loop. This is a prospective randomized controlled open-label crossover study. Participants were randomly assigned to attend either a 24-hour closed-loop visit connected to the BiAP system or a 24-hour open-loop visit (standard insulin pump therapy). The primary outcome was percentage time spent in target range (3.9-10 mmol/l) measured by sensor glucose. Secondary outcomes included percentage time in hypoglycemia (<3.9 mmol/l) and hyperglycemia (>10 mmol/l). Participants were invited to attend for an additional visit to assess the BiAP without and with partial meal announcements. A total of 12 adults with type 1 diabetes completed the study (58% female, mean [SD] age 45 [10] years, BMI 25 [4] kg/m(2), duration of diabetes 22 [12] years and HbA1c 7.4 [0.7]% [58 (8) mmol/mol]). The median (IQR) percentage time in target did not differ between closed-loop and open-loop (71% vs 66.9%, P = .9). Closed-loop reduced time spent in hypoglycemia from 17.9% to 3.0% (P < .01), but increased time was spent in hyperglycemia (10% vs 28.9%, P = .01). The percentage time in target was higher when all meals were announced during closed-loop compared to no or partial meal announcement (65.7% [53.6-80.5] vs 45.5% [38.2-68.3], P = .12). The BiAP is safe and achieved equivalent time in target as measured by sensor glucose, with improvement in hypoglycemia, when compared to standard pump therapy.

The Artificial β Cell in Type 1 Diabetes

In a closed-loop insulin-delivery system (the “artificial β cell”), a diabetic patient's blood glucose is monitored continuously by a subcutaneous sensor, and an algorithm continuously adjusts insulin infusion rates though an insulin pump; wireless communication connects the sensor and pump. Early studies of this technology have been conducted in highly controlled environments for short periods of time (NEJM JW …

Technology to Reduce Hypoglycemia.

Hypoglycemia is a major barrier toward achieving glycemic targets and is associated with significant morbidity (both psychological and physical) and mortality. This article reviews technological strategies, from simple to more advanced technologies, which may help prevent or mitigate exposure to hypoglycemia. More efficient insulin delivery systems, bolus advisor calculators, data downloads providing information on glucose trends, continuous glucose monitoring with alarms warning of hypoglycemia, predictive algorithms, and finally closed loop insulin delivery systems are reviewed. The building blocks to correct use and interpretation of this range of available technology require patient education and appropriate patient selection.

Abstracts from ATTD 20158th International Conference on Advanced Technologies &amp; Treatments for DiabetesParis, France—February 18–21, 2015

Abstracts from ATTD 20158th International Conference on Advanced Technologies &amp; Treatments for DiabetesParis, France—February 18–21, 2015