Dual-hormone Closed-loop Systems Research Articles

Dual-hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions.

Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.

215-OR: Performance of a Dual Hormone Closed-Loop System vs. an Insulin-Only Closed-Loop System during Challenging Inpatient Conditions: A Single-Blinded Randomized Controlled Crossover Trial

Objective: To assess the efficacy and safety of an insulin-glucagon dual-hormone (DH) compared with an insulin-only single-hormone (SH) closed-loop system. Methods: In a 33-h, randomized, crossover, inpatient study, 13 participants with type 1 diabetes used two modes of the DiaCon Artificial Pancreas system: DH and SH closed-loop control. During each study period, participants had two overnight stays, received an underbolus (50%) for their breakfast, normal bolus (100%) for lunch, overbolus (130%) for dinner and performed unannounced exercise for 45 min (bicycled at estimated 50% V02max). The co-primary endpoints were sensor-based percentage of time in hypoglycemia (<3.9 mmol/L) and the number of 15 g carbohydrate rescues whenever plasma glucose <3.0 mmol/L from 0 to 33 h after initiation of the systems. Results: Overall, the average number of carbohydrate rescues was significantly lower during DH compared with SH (mean±SD: 0.8±1.3 vs. 1.4±1.4 per 33 h, p = 0.04). The percentages of time in hypoglycemia (3.6±2.1% vs. 3.8±3.3%, p = 0.46), target range (3.9-10.0 mmol/L: 67.2±15.4% vs. 65.3±12.4%, p = 0.41) and hyperglycemia (>10.0 mmol/L: 26.8±16.0% vs. 28.7±12.7%, p = 0.41) were similar between study arms. Mean glucose was lower for DH than SH (8.3±1.2 vs. 8.6±1.0 mmol/L, p = 0.04) with similar coefficient of variation (40±8.3 vs. 38±5.0%, p = 0.30). From exercise start and 4 h onwards, DH achieved more time in range (86.7±11.7 vs. 74.7±16.5%, p = 0.01), but similar time in hypoglycemia (10.5±18.7 vs. 12.6±24.3%, p = 0.32) and numbers of carbohydrate rescues (5±0.7 vs. 6±0. 7, p = 0.38). No differences were observed on visual analog scale-measured nausea (p = 0.47), headache (p = 0.77), hunger (p = 0.66), and palpitation (p = 0.11). Conclusions: During challenging inpatient conditions, the DH system achieved similar glucose control but significantly reduced need for carbohydrate rescue compared with SH. Disclosure A. G. Ranjan: None. D. Boiroux: Consultant; Self; Novo Nordisk A/S, Employee; Spouse/Partner; Novo Nordisk A/S. C. Laugesen: None. S. Schmidt: None. A. T. Reenberg: None. J. B. Jørgensen: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. Funding Danish Diabetes Association; Danish Diabetes Academy (PD002-19)

New uses and formulations of glucagon for hypoglycaemia.

Hypoglycaemia is the more frequent complication of insulin therapy and the main barrier to tight glycaemic control. Injectable glucagon and oral intake of carbohydrates are the recommended treatments for severe and non-severe hypoglycaemia episodes, respectively. Nasal glucagon is currently being developed as a ready-to-use device, to simplify severe hypoglycaemia rescue. Stable forms of liquid glucagon could open the field for different approaches for mild to moderate hypoglycaemia treatment, such as mini-doses of glucagon or continuous subcutaneous glucagon infusion as a part of dual-hormone closed-loop systems. Pharmaceutical companies are developing stable forms of native glucagon or glucagon analogues for that purpose.

1038-P: Results of Interim Analysis of a Randomized Crossover Study in Type 1 Diabetes (T1D) of a Dual-Hormone Closed-Loop System with Xerisol™ Glucagon vs. Insulin-Only Closed-Loop System vs. a Predictive Low Glucose Suspend System

Dual-hormone systems show promise to reduce hypoglycemia, but require a stable liquid glucagon formulation. XeriSol™ glucagon is a shelf-stable glucagon product for this use. Nineteen subjects with T1D are completing a single-center three-day outpatient study comparing control modes of the Oregon Artificial Pancreas system: 1) dual hormone (DH) closed-loop with Novolog™ insulin and XeriSol™ glucagon, 2) insulin-only single hormone (SH) closed-loop, 3) insulin-only predictive low glucose suspend system (PLGS). In clinic aerobic exercise (45 minutes at 60% VO2max) and home exercise was completed with each arm. SH and DH used automated exercise detection to adaptively dose insulin/glucagon for predicted hypoglycemia and tailored mealtime dosing based on past meal responses with an adaptive algorithm. An interim analysis after 7 subjects was completed for safety. The primary outcome measures are % time 70-180 mg/dL and % time <70 mg/dL for the 3-day study and the 4-hour period from start of exercise until the next meal. From start of exercise until the next meal, DH showed a clinically meaningful reduction of time in hypoglycemia compared with PLGS and SH. For the entire study, DH showed a clinically meaningful lower time <70mg/dL. No serious events or unexpected side effects occurred. Disclosure L.M. Wilson: None. P.G. Jacobs: Stock/Shareholder; Self; Pacific Diabetes Technologies. N. Resalat: None. R. Reddy: None. J. El Youssef: None. D. Branigan: None. J.A. Leitschuh: Other Relationship; Self; AgaMatrix. B. Senf: None. V. Gabo: None. J.R. Castle: Advisory Panel; Self; Novo Nordisk Inc., Zealand Pharma A/S. Consultant; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Funding JDRF

Technology in the management of type 1 diabetes mellitus - current status and future prospects.

Type 1 diabetes mellitus (T1DM) represents 5-10% of diabetes cases worldwide. The incidence of T1DM is increasing, and there is no immediate prospect of a cure. As such, lifelong management is required, the burden of which is being eased by novel treatment modalities, particularly from the field of diabetes technologies. Continuous glucose monitoring has become the standard of care and includes factory-calibrated subcutaneous glucose monitoring and long-term implantable glucose sensing. In addition, considerable progress has been made in technology-enabled glucose-responsive insulin delivery. The first hybrid insulin-only closed-loop system has been commercialized, and other closed-loop systems are under development, including dual-hormone glucose control systems. This Review focuses on well-established diabetes technologies, including glucose sensing, pen-based insulin delivery, data management and data analytics. We also cover insulin pump therapy, threshold-based suspend, predictive low-glucose suspend and single-hormone and dual-hormone closed-loop systems. Clinical practice recommendations for insulin pump therapy and continuous glucose monitoring are presented, and ongoing research and future prospects are highlighted. We conclude that the management of T1DM is improved by diabetes technology for the benefit of the majority of people with T1DM, their caregivers and guardians and health-care professionals treating patients with T1DM.

Randomized Outpatient Trial of Single- and Dual-Hormone Closed-Loop Systems That Adapt to Exercise Using Wearable Sensors.

OBJECTIVEAutomated insulin delivery is the new standard for type 1 diabetes, but exercise-related hypoglycemia remains a challenge. Our aim was to determine whether a dual-hormone closed-loop system using wearable sensors to detect exercise and adjust dosing to reduce exercise-related hypoglycemia would outperform other forms of closed-loop and open-loop therapy.RESEARCH DESIGN AND METHODSParticipants underwent four arms in randomized order: dual-hormone, single-hormone, predictive low glucose suspend, and continuation of current care over 4 outpatient days. Each arm included three moderate-intensity aerobic exercise sessions. The two primary outcomes were percentage of time in hypoglycemia (<70 mg/dL) and in a target range (70–180 mg/dL) assessed across the entire study and from the start of the in-clinic exercise until the next meal.RESULTSThe analysis included 20 adults with type 1 diabetes who completed all arms. The mean time (SD) in hypoglycemia was the lowest with dual-hormone during the exercise period: 3.4% (4.5) vs. 8.3% (12.6) single-hormone (P = 0.009) vs. 7.6% (8.0) predictive low glucose suspend (P < 0.001) vs. 4.3% (6.8) current care where pre-exercise insulin adjustments were allowed (P = 0.49). Time in hypoglycemia was also the lowest with dual-hormone during the entire 4-day study: 1.3% (1.0) vs. 2.8% (1.7) single-hormone (P < 0.001) vs. 2.0% (1.5) predictive low glucose suspend (P = 0.04) vs. 3.1% (3.2) current care (P = 0.007). Time in range during the entire study was the highest with single-hormone: 74.3% (8.0) vs. 72.0% (10.8) dual-hormone (P = 0.44).CONCLUSIONSThe addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.

Stable Liquid Glucagon: Beyond Emergency Hypoglycemia Rescue.

Glycemic control is the mainstay of preventing diabetes complications at the expense of increased risk of hypoglycemia. Severe hypoglycemia negatively impacts the quality of life of patients with type 1 diabetes and can lead to morbidity and mortality. Currently available glucagon emergency kits are effective at treating hypoglycemia when correctly used, however use is complicated especially by untrained persons. Better formulations and devices for glucagon treatment of hypoglycemia are needed, specifically stable liquid glucagon. Out of the scope of this review, other potential uses of stable liquid glucagon include congenital hyperinsulinism, post-bariatric surgery hypoglycemia, and insulinoma induced hypoglycemia. In the 35 years since Food and Drug Administration (FDA) approval of the first liquid stable human recombinant insulin, we continue to wait for the glucagon counterpart. For mild hypoglycemia, a commercially available liquid stable glucagon would enable more widespread implementation of mini-dose glucagon use as well as glucagon in dual hormone closed-loop systems. This review focuses on the current and upcoming pharmaceutical uses of glucagon in the treatment of type 1 diabetes with an outlook on stable liquid glucagon preparations that will hopefully be available for use in patients in the near future.

Safety of Overestimation of a Meal Insulin Bolus in the Context of Closed-Loop Operation Combined with a Simplified Semi-Quantitative Carbohydrate Intake Estimation

A closed-loop system (CLS) combined with a simplified meal bolus has been shown to achieve comparable glucose control as CLS with carbohydrate (CHO) counting for patients with type 1 diabetes. It is, however, important to establish the safety of this meal bolus approach. We compared in a randomized inpatient trial: 1) Dual-hormone CLS with an adequately estimated CHO intake, 2) Dual-hormone CLS with an overestimated CHO intake. The simplified strategy tested involved a meal bolus based on a semi-quantitative meal CHO-content size assessment (regular, large or very large). A large size standardized meal of 75 g of CHO was provided to participants and was either adequately categorized (large meal 60 to 90 g of CHO; bolus for 65 g) or overestimated (very large meal >90 g of CHO; bolus for 95 g). The primary outcome was time below 4.0 mmol/L over a 4-hour postprandial period. We aim to recruit 10 participants who will be tested for the 75 g CHO meal and 10 participants for a 45 g CHO meal. Six participants completed the study for the 75 g meal so far (40.4±17.2 years old; HbA1c 7.4±0.5%). Similar mean sensor glucose level was achieved with the adequate meal category and the overestimation (median [IQR]: 10.8 [8.4 to 12.5] vs. 10.2 [8.5 to 10.5] mmol/L; p=0.46). No participant spent any time <4.0 mmol/L in both interventions and no difference was observed in the amount of glucagon infused (p=0.91). These preliminary analyses show that the dual-hormone CLS with a simplified meal bolus calculation is able to avoid hypoglycaemia in the event of overestimation of the meal insulin bolus.

A Simplified Semi-Quantitative Meal Bolus Strategy Combined with Single- and Dual-Hormone Closed-Loop Delivery in Patients with Type 1 Diabetes: A Pilot Study

Single- and dual-hormone closed-loop systems (CLS) have the potential to reduce carbohydrate-counting burden for patients with type 1 diabetes; however, simplification of meal insulin calculation should not compromise glycemic control. We compared in a randomized outpatient pilot trial: 1) single-hormone CLS accompanied with carbohydrate-content matched boluses vs. accompanied with a simplified meal bolus strategy, and 2) dual-hormone CLS accompanied with carbohydrate-content matched boluses vs. accompanied with a simplified meal bolus strategy. Carbohydrate-matched boluses were based on participant's carbohydrate meal content estimation while the simplified strategy involved the selection, by participants, of a semi-quantitative meal carbohydrate-content size; snack, regular, large or very large meal. Participants also underwent sensor-augmented pump therapy. Basal insulin delivery was more aggressive with the simplified bolus. Twelve participants were recruited (48.2±16.0 years old; HbA1c 7.4±0.9%) to compare the 2 bolus strategies during single- and dual-hormone closed-loop delivery. Similar mean sensor glucose level (15-hour period; primary outcome) was achieved with the carbohydrate-matched boluses and simplified strategy using single-hormone (median [IQR]: 7.6 [7.2 to 8.1] vs. 8.0 [7.0 to 8.6] mmol/L; p=0.90) and dual-hormone CLS (7.6 [7.2 to 8.1] vs. 7.0 [6.4 to 8.2] mmol/L; p=0.08). Exploratory analyses showed that, as compared to sensor-augmented pump therapy, there was an increased time spent in hypoglycemia with the simplified strategy but not with the carbohydrate-matched boluses. Though the algorithm employed in this pilot study may lead to an increased risk for hypoglycemia, this strategy has the potential to reduce the carbohydrate counting burden in patients with type 1 diabetes while generally maintaining adequate glucose control.

A Simplified Semiquantitative Meal Bolus Strategy Combined with Single- and Dual-Hormone Closed-Loop Delivery in Patients with Type 1 Diabetes: A Pilot Study.

Single- and dual-hormone closed-loop systems can improve glycemic control and have the potential to reduce carbohydrate-counting burden for patients with type 1 diabetes; however, simplification of meal insulin calculation should not compromise glycemic control. We compared in a randomized outpatient pilot trial: (1) a single-hormone closed-loop system accompanied with carbohydrate-content matched boluses versus accompanied with a simplified meal bolus strategy, and (2) a dual-hormone closed-loop system accompanied with carbohydrate-content matched boluses versus accompanied with a simplified meal bolus strategy. Carbohydrate-matched boluses were based on the participant's carbohydrate meal content estimation whereas the simplified strategy involved the selection, by participants, of a semi-quantitative meal carbohydrate-content size: snack, regular, large, or very large meal. Each participant also underwent sensor-augmented pump therapy. Basal insulin delivery was more aggressive with the simplified bolus. The primary outcome was mean sensor glucose level over a 15-h daytime period. Twelve participants were recruited (48.2 ± 16.0 years old; HbA1c 7.4% ± 0.9%) to compare the two bolus strategies during single- and dual-hormone closed-loop delivery. A similar mean sensor glucose level (15 h) was achieved with the carbohydrate-matched boluses and simplified strategy using single-hormone (median [interquartile]: 7.6 [7.2-8.1] vs. 8.0 [7.0-8.6] mmol/L; P = 0.90) and dual-hormone closed-loop systems (7.6 [6.7-9.1] vs. 7.0 [6.4-8.2] mmol/L; P = 0.08). Exploratory analyses showed that, as compared with sensor-augmented pump therapy, there was an increased time spent in hypoglycemia with the simplified strategy but not with the carbohydrate-matched boluses. Though the algorithm employed in this pilot study may lead to an increased risk for hypoglycemia, this strategy has the potential to reduce the carbohydrate-counting burden in patients with type 1 diabetes while generally maintaining adequate glucose control. Longer outpatient studies with an improved algorithm are needed.

Continuous Glucose Monitoring, Future Products, and Update on Worldwide Artificial Pancreas Projects.

The development of accurate and easy-to-use continuous glucose monitoring (CGM) improved diabetes treatment by providing additional temporal information on glycemia and glucose trends to patient and physician. Although CGM enables users to lower their average glucose level without an increased incidence of hypoglycemia, this comes at the price of additional patient effort. Automation of insulin administration, also known as closed-loop (CL) or artificial pancreas treatment, has the promise to reduce patient effort and improve glycemic control. CGM data serve as the conditional input for insulin automation devices. The first commercial product for partial automation of insulin administration used insulin delivery shutoff at a predefined glucose level. These systems showed a reduction in hypoglycemia. Insulin-only CL devices show increased time spent in euglycemia and a reduction of hypo- and hyperglycemia. Improved glycemic control, coinciding with a minor decrease in hemoglobin A1c level, was confirmed in recent long-term home studies investigating these devices, paving the way for pivotal studies for commercialization of the artificial pancreas. Although the first results from dual-hormone CL systems are promising, because of increased cost of consumables of these systems, long-term head-to-head studies will have to prove superiority over insulin-only approaches. Now CL glucose control for daily use might finally become reality. Improved continuous glucose sensing technology, miniaturization of electrical devices, and development of algorithms were key in making this possible. Clinical adoption challenges, including device usability and reimbursement, need to be addressed. Time will tell for which patient groups CL systems will be reimbursed and whether these devices can deliver the promise that they hold.

Closing the loop

Closing the loop