Dual-hormone Artificial Pancreas Research Articles

Recent advances in the precision control strategy of artificial pancreas.

The scientific diagnosis and treatment of patients with diabetes require frequent blood glucose testing and insulin delivery to normoglycemia. Therefore, an artificial pancreas with a continuous blood glucose (BG) monitoring function is an urgent research target in the medical industry. The problem of closed-loop algorithmic control of the BG with a time delay is a key and difficult issue that needs to be overcome in the development of an artificial pancreas. Firstly, the composition, structure, and control characteristics of the artificial pancreas are introduced. Subsequently, the research progress of artificial pancreas control algorithms is reviewed, and the characteristics, advantages, and disadvantages of proportional-integral-differential control, model predictive control, and artificial intelligence control are compared and analyzed to determine whether they are suitable for the practical application of the artificial pancreas. Additionally, key advancements in areas such as blood glucose data monitoring, adaptive models, wearable devices, and fully automated artificial pancreas systems are also reviewed. Finally, this review highlights that meal prediction, control safety, integration, streamlining the optimization of control algorithms, constant temperature preservation of insulin, and dual-hormone artificial pancreas are issues that require further attention in the future.

Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Systematic Review

The artificial pancreas (AP) is equipped with a glucose monitoring sensor, an insulin pump and an integrated mathematical algorithm that determines insulin infusion based on the glucose levels detected by the sensor. Research has shown that AP can help patients with type-1 Diabetes Mellitus (T1DM) to improve the control of their glucose levels, but the occurrence of postprandial hyperglycemia is still considerable. The addition of pramlintide (a synthetic derivative analog of amylin) in a dual-hormone AP could improve postprandial glycemic control. This systematic review aims to evaluate and synthesize the evidence on the safety, efficacy and cost-effectiveness of the dual insulin- and pramlintide-releasing AP. The electronic databases MEDLINE, Embase, Web of Science and ClinicalTrials.gov were consulted up to 6 June 2021. We identified four small crossover studies (n = 59) and two ongoing crossover trials, all of them carried out by the same research group. The four studies observed more gastrointestinal adverse effects with the dual system. One study found that the dual system improved outcomes compared to insulin alone, with precise carbohydrate counting (CC) in both groups. Another study showed that a fully closed-loop system (without CC) was equivalent to an insulin-alone AP (with CC) on time in the target range but performed worse in hyperglycemia during the daytime. These preliminary results suggest that the control of postprandial hyperglycemia remains a challenge.

Dual‐hormone artificial pancreas for glucose control in type 1 diabetes: A meta‐analysis

AimTo evaluate the efficacy and safety of a dual‐hormone artificial pancreas (DH) in type 1 diabetes.Material and MethodsPubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for studies published up to February 16, 2022. We included randomized controlled trials that compared DH with single­hormone artificial pancreas (SH), continuous subcutaneous insulin infusion (CSII) or sensor‐augmented pumps (SAP), and predictive low glucose suspend systems (PLGS) in type 1 diabetes. The primary outcome was percent time in target (3.9‐10 mmol/L [70‐180 mg/dL]). Data were summarized as mean differences (MDs) or risk differences (RDs).ResultsA total of 17 randomized crossover trials (438 participants) were included. There were nine trials of DH versus SH, 13 trials of DH versus SAP/CSII, and two trials of DH versus PLGS. For time in target, DH showed no significant difference in time in target compared with SH (MD 2.69%, 95% confidence interval [CI] −0.38 to 5.76) but resulted in 16.05% (95% CI 12.06 to 20.05) and 6.89% (95% CI 2.63 to 11.14) more time in target range compared with SAP/CSII and PLGS, respectively. DH slightly reduced time in hypoglycaemia (MD −1.20%, 95% CI −1.85 to −0.56) but increased the risk of gastrointestinal symptoms (RD 0.18, 95% CI 0.08 to 0.27) compared with SH.ConclusionsThe results of this study suggest that DH has a comparable effect on time in target compared with SH, but is associated with a longer time in target range compared with SAP/CSII and PLGS. The DH slightly reduced time in hypoglycaemia but may increase the risk of gastrointestinal symptoms compared with the SH. PROSPERO registration number: CRD42022314015.

Nonlinear Model Predictive Control and System Identification for a Dual-hormone Artificial Pancreas

In this work, we present a switching nonlinear model predictive control (NMPC) algorithm for a dual-hormone artificial pancreas (AP), and we use maximum likelihood estimation (MLE) to identify the model parameters. A dual-hormone AP consists of a continuous glucose monitor (CGM), a control algorithm, an insulin pump, and a glucagon pump. The AP is designed with a heuristic to switch between insulin and glucagon as well as state-dependent constraints. We extend an existing glucoregulatory model with glucagon and exercise for simulation, and we use a simpler model for control. We test the AP (NMPC and MLE) using in silico numerical simulations on 50 virtual people with type 1 diabetes. The system is identified for each virtual person based on data generated with the simulation model. The simulations show a mean of 89.3% time in range (3.9–10 mmol/L) and no hypoglycemic events.

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.

Intraperitoneal and subcutaneous glucagon delivery in anaesthetized pigs: effects on circulating glucagon and glucose levels

Glucagon is a pancreatic hormone and increases the blood glucose levels. It may be incorporated in a dual hormone artificial pancreas, a device to automatically and continuously control blood glucose levels of individuals with diabetes. Artificial pancreas systems have been developed for use in the subcutaneous tissue; however, the systems are not fully automated due to slow dynamics. The intraperitoneal space is therefore investigated as an alternative location for an artificial pancreas. Glucose dynamics after subcutaneous and intraperitoneal glucagon delivery in ten anaesthetized pigs were investigated. The pigs received intraperitoneal boluses of 0.3 µg/kg and 0.6 µg/kg and a subcutaneous bolus of 0.6 µg/kg in randomized order. They also received an intraperitoneal bolus of 1 mg given at the end of the experiments to test the remaining capacity of rapid glucose release. Six pigs were included in the statistical analysis. The intraperitoneal glucagon bolus of 0.6 µg/kg gave a significantly higher glucose response from 14 to 30 min compared with the subcutaneous bolus. The results indicate that glucagon induces a larger glucose response after intraperitoneal delivery compared with subcutaneous delivery and is encouraging for the incorporation of glucagon in an intraperitoneal artificial pancreas.

Co-administration of Pramlintide and Insulin Via an Automated Dual-hormone Artificial Pancreas System in Adults With Type 1 Diabetes

Co-administration of Pramlintide and Insulin Via an Automated Dual-hormone Artificial Pancreas System in Adults With Type 1 Diabetes

A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial.

The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes but daytime control remains suboptimal. We propose two novel dual-hormone artificial pancreas systems. We conducted a randomized crossover trial comparing a rapid insulin-alone artificial pancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintide artificial pancreas systems in adults with type 1 diabetes. Participants were assigned to the interventions in random order during three 24-h inpatient visits. Each visit was preceded by an outpatient hormonal open-loop run-in period of 10-14 days. The dual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio relative to insulin. The primary outcome was time in the range 3.9-10.0 mmol/L. Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84% (13%) (P = 0.0014), whereas the regular insulin-and-pramlintide system did not change the time in range (69% [19%]; P = 0.22). The increased time in range with the rapid insulin-and-pramlintide system was due to improved daytime control (daytime time in range increased from 63% [23%] to 78% [16%], P = 0.0004). There were 11 (1 per 2.5 days) hypoglycemic events (<3.3 mmol/L with symptoms or <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system, compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid and regular insulin-and-pramlintide systems, respectively. Gastrointestinal symptoms were reported after 0% (0 of 112) of meals with the rapid insulin-alone system, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid and regular insulin-and-pramlintide systems, respectively; none of the symptoms were severe. A novel rapid insulin-and-pramlintide artificial pancreas improves glucose control compared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov number NCT02814123).

Insulin-and-Glucagon Artificial Pancreas Versus Insulin-Alone Artificial Pancreas: A Short Review.

IN BRIEF The advantage of the insulin-and-glucagon artificial pancreas is based on the rapid effect of subcutaneous glucagon delivery in preventing hypoglycemia compared to suspension of insulin delivery. In short-term studies, the dual-hormone artificial pancreas reduced daytime hypoglycemia, especially during exercise, compared to the insulin-alone artificial pancreas, but the insulin-alone system seemed sufficient in eliminating nocturnal hypoglycemia. The comparative benefits of the single- and dual-hormone systems for improving A1C and preventing severe hypoglycemia remain unknown.

Coordinated dual-hormone artificial pancreas with parallel control structure

Concomitant glucagon delivery in a dual-hormone artificial pancreas system might overcome the limitations of insulin-only systems, potentially leading to improved hypoglycemia mitigation. However, current dual-hormone systems have not shown clearly its superiority. This work presents a novel dual-hormone system based on a parallel control structure with intrinsic coordination among insulin and glucagon delivery. The proposed coordinated controller (CC) was compared with its non-coordinated counterpart (NCC) based on independent loops for the insulin and glucagon controllers, as done in current systems. To evaluate the benefits of coordination, CC and NCC shared the same insulin controller, differing solely on how glucagon is administered. An in-silico study using the UVA-Padova simulator, extended with variability sources, was performed. Three scenarios were considered, comprising meals, snacks and exercise. CC achieved superior performance with better values of times in ranges. Moreover, CC delivered lower glucagon doses than the two NCC tuning alternatives considered.

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: a randomized controlled crossover trial

ObjectiveHypoglycemia is a frequent and potentially dangerous event among patients with diabetes mellitus type 1. Subcutaneous glucagon is an emergency treatment to counteract severe hypoglycemia. The effect of intraperitoneal glucagon...

Low Doses of Dasiglucagon Consistently Increase Plasma Glucose (PG) Levels in Hypoglycemia and Euglycemia in People with Type 1 Diabetes Mellitus (T1DM)

To develop a dual hormone artificial pancreas (DHAP) a liquid stable glucagon component is needed. Currently available glucagon products have limited stability after reconstitution and are therefore not suited for DHAP usage. Dasiglucagon is a novel liquid stable glucagon analog, which does not require mixing prior to use. In this randomized double-blind trial 17 patients with T1DM received four single subcutaneous doses (0.03, 0.08, 0.2 and 0.6 mg) of dasiglucagon (4 mg/ml) under hypoglycemic (plasma glucose (PG) 56-66 mg/dL) or euglycemic (PG 100 mg/dL) conditions. For comparison, identical doses of Lilly GlucagonTM (GLUCA) were investigated at euglycemia. In the euglycemic setting dasiglucagon showed rapid and dose-dependent PG-increases of mean 39, 56, 72 and 80 mg/dL at 30 minutes post-dosing (30, 49 and 71 mg/dl for GLUCA) (Figure). During hypoglycemia, dasiglucagon provided similar PG-increases of 24, 64, 87 and 94 mg/dL 30 minutes post dose and rapidly corrected PG levels to normoglycemia (PG ?70 mg/dL) with a median time of 14, 10, 6 and 6 minutes. In conclusion, low doses of dasiglucagon rapidly and effectively increase PG from euglycemia and hypoglycemia in a titratable manner. Therefore, dasiglucagon should be a good candidate for use in dual-hormone closed-loop AP systems.Figure. Different Doses of Dasiglucagon and GLUCA, PG Levels (Mean ±SEM). Disclosure U. Hovelmann: None. M. Braendholt Olsen: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Zealand Pharma A/S. U. Mouritzen: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D. Lamers: None. B. Kronshage: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research &amp; Development, MedImmune, Merck Sharp &amp; Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi.

Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analog

Several groups are developing fully integrated dual-hormone artificial pancreas systems, which deliver insulin or glucagon in response to changes in glucose to maintain euglycemia. These systems hold the potential to transform management of type 1 diabetes, but in order to be realized these systems require a stable-in-solution glucagon analog suitable for chronic use. Dasiglucagon is a novel glucagon analog stable in liquid formulation. The present studies evaluated safety and tolerability of chronically administered dasiglucagon in rats and dogs. Rats and dogs were dosed s.c. daily for 26 and 39 weeks, respectively, in 4 groups of 20 rats with 0 (vehicle), 0.5, 2, or 8 mg/kg/day; 4 groups of 4 beagle dogs with 0, 0.02, 0.1, or 0.3 mg/kg/day. Glucose and insulin levels increased in a dose-dependent manner in all treated animals. In dogs, heart rate increased at the 0.1 and 0.3 mg/kg/day dose level. Liver and kidney weights increased at all dose levels for in both species, and microscopic pathology demonstrated increase in hepatocyte glycogen vacuolation and increase in chronic progressive nephropathy (a normal finding in aging rats). Heart weights increased with no histopathological correlate. All findings showed full/partial recovery after 4-week treatment free periods. Some animals developed anti-drug-antibodies but with no apparent effect on pharmacodynamics. The NOAEL (no observed adverse effect level) dose of 2 mg/kg/day in rats and 0.1 mg/kg/day in dogs represents exposure multiples (AUC) of 22 and 2 compared to anticipated human doses of up to 1 mg/day. Chronic administration of dasiglucagon multiple times above relevant human doses was well tolerated. All findings were consistent with the known pharmacological effects of glucagon. The risk of glycogen accumulation is not considered relevant for humans treated with dasiglucagon to maintain euglycemia. These findings support long-term human testing of dasiglucagon in dual-hormonal artificial pancreas systems. Disclosure J.R. Castle: Consultant; Self; Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk Inc. M. Elander: Employee; Self; Zealand Pharma A/S. S.A. O'Halloran: None.

Insulin-plus-Pramlintide Artificial Pancreas in Type 1 Diabetes—Randomized Controlled Trial

We conducted a randomized crossover comparison between i) dual-hormone, rapid insulin and amylin (Pramlintide), artificial pancreas (DAP), ii) regular insulin (Humulin R) and amylin artificial pancreas (R-DAP), and iii) rapid insulin-alone artificial pancreas (AP) in 12 adults with type 1 diabetes. Insulin and amylin were delivered simultaneously, in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio (6 µg/u), mimicking a co-formulation. Participants were admitted three times for 24 hours and ingested three meals and a bedtime snack. Prior to closed-loop study, amylin was delivered for two weeks, and basal rates and carb ratios were optimized. Over the 24-hour study, DAP increased time spent in target range [3.9-10.0 mmol/L] compared to AP from 71% to 85% (P=0.03) and decreased glucose variability (CV) from 34% to 25% (P=0.01), without increasing the risk of hypoglycemia (P=NS). Overnight, DAP and AP achieved high and similar time in tight target range [3.9-7.8 mmol/L; 77%, 71%, P=NS]. Moderate nausea was reported by two participants (16%) on DAP compared to 0 (0%) on AP. There was no benefits associated with R-DAP compared to AP during day or night period. We conclude that a dual-hormone artificial pancreas delivering rapid insulin and amylin with fixed ratio improves glucose control and reduces glucose variability compared to insulin-alone, first-generation, artificial pancreas.Table 1.Comparisons between AP, DAP, and R-DAP (mean±SD)OutcomeAPDAPR-DAPP-value DAP vs. APP-value R-DAP vs. APTime spent between 3.9 and 10.0 mmol/L during 24-hour study period (%)71 ± 1985 ± 1072 ± 160.030.86Mean glucose level during 24-hour study period (mmol/L)8.2 ± 1.37.4 ± 1.17.7 ± 0.80.070.38Coefficient of variance during 24-hour study period (%)34 ± 1125 ± 635 ± 80.010.65Time spent between 3.9 and 10.0 mmol/L during daytime period (%)58 ± 2678 ± 1666 ± 210.020.58Mean glucose level during daytime period (mmol/L)9.1 ± 1.97.8 ± 1.58.4 ± 1.50.020.34Time spent between 3.9 and 7.8 mmol/L during overnight period (%)77 ± 2071 ± 2965 ± 190.470.16Mean glucose level during overnight period (mmol/L)6.6 ± 0.96.8 ± 0.96.6 ± 1.20.510.87 Disclosure A. Haidar: Consultant; Self; Eli Lilly and Company. Research Support; Self; AgaMatrix, Medtronic MiniMed, Inc. M. Tsoukas: Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. S. Twardy: None. N. Strauss: None. J. Yale: Advisory Panel; Self; Medtronic, Abbott. Speaker's Bureau; Self; Abbott. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Takeda Canada Inc.. Speaker's Bureau; Self; Takeda Canada Inc.. Advisory Panel; Self; Merck &amp; Co., Inc.. Speaker's Bureau; Self; Merck &amp; Co., Inc., Bayer AG. Research Support; Self; Mylan, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Sanofi. J. Rutkowski: None. A. Bossy: Other Relationship; Self; Insulet Corporation, Medtronic. E. Pytka: Consultant; Self; Animas Corporation. H.T. Nguyen: None. L. Legault: Advisory Panel; Self; Insulet Corporation. Research Support; Self; Merck &amp; Co., Inc., Sanofi. Advisory Panel; Self; Medtronic. Other Relationship; Self; Eli Lilly and Company.

Adaptive model predictive control for a dual-hormone artificial pancreas

We report the closed-loop performance of adaptive model predictive control (MPC) algorithms for a dual-hormone artificial pancreas (AP) intended for patients with type 1 diabetes. The dual-hormone AP measures the interstitial glucose concentration using a subcutaneous continuous glucose monitor (CGM) and administers glucagon and rapid-acting insulin subcutaneously. The discrete-time transfer function models used in the insulin and glucagon MPCs comprise a deterministic part and a stochastic part. The deterministic part of the MPC model is individualized using patient-specific information and describes the glucose-insulin and glucose-glucagon dynamics. The stochastic part of the MPC model describes the uncertainties that are not included in the deterministic part of the MPC model. Using closed-loop simulation of the MPCs, we evaluate the performance obtained using the different deterministic and stochastic models for the MPC on three virtual patients. We simulate a scenario including meals and daily variations in the model parameters for two settings. In the first setting, we try five different models for the deterministic part of the MPC model and use a fixed model for the stochastic part of the MPC model. In the second setting, we use a second-order model for the deterministic part of the MPC model and estimate the stochastic part of the MPC model adaptively. The results show that the controller is robust to daily variations in the model parameters. The numerical results also suggest that the deterministic part of the MPC model does not play a major role in the closed-loop performance of MPC. This is ascribed to the availability of feedback and the poor prediction capability of the model, i.e. the large disturbances and model-patient mismatch. Moreover, a second order adaptive model for the stochastic part of the MPC model offers a marginally better performance in closed-loop, in particular if the model-patient mismatch is large.

Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis

ObjectiveTo evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes.DesignSystematic review and meta-analysis of randomised controlled trials.Data sourcesMedline, Embase, Cochrane Library, and grey...

Impact of erroneous meal insulin bolus with dual-hormone artificial pancreas using a simplified bolus strategy - A randomized controlled trial

Postprandial glucose control remains challenging for patients with type 1 diabetes (T1D). A simplified meal bolus approach with a dual-hormone (insulin and glucagon) closed-loop system (DH-CLS) has been tested; yet, the impact of categorization errors with this strategy is unknown. The objective was to compare, in a randomized controlled inpatient trial, DH-CLS with the simplified meal bolus approach for two different meals properly categorized or overestimated. We tested, in patients with T1D, the simplified strategy with two standardized breakfasts (n = 10 per meal) adequately categorized or overestimated: (1) 75 g and (2) 45 g of carbohydrate. No difference was observed for percentage of time <4.0 mmol/L over a 4-hour post-meal period (primary outcome; median [IQR]: 0[0–0] vs. 0[0–0] for both comparisons, p = 0.47 and 0.31 for the 75 g and 45 g meals, respectively). Despite higher meal insulin boluses with overestimation for both meals (9.2 [8.2–9.6] vs. 8.1 [7.3–9.1] U and 8.4 [7.2–10.4] vs. 4.8 [3.7–5.6] U; p < 0.05), mean glycemia, percentage of time in target range and glucagon infusion did not differ. Additional scenarios were tested in silico with comparable results. These results suggest that the DH-CLS with a simplified meal bolus calculation is probably able to avoid hypoglycemia in the event of meal size misclassification.

Overnight Glucose Control with Dual- and Single-Hormone Artificial Pancreas in Type 1 Diabetes with Hypoglycemia Unawareness: A Randomized Controlled Trial.

The dual-hormone (insulin and glucagon) artificial pancreas may be justifiable in some, but not all, patients. We sought to compare dual- and single-hormone artificial pancreas systems in patients with hypoglycemia unawareness and documented nocturnal hypoglycemia. We conducted a randomized crossover trial comparing the efficacy of dual- and single-hormone artificial pancreas systems in controlling plasma glucose levels over the course of one night's sleep. We recruited 18 adult participants with hypoglycemia unawareness and 17 participants with hypoglycemia awareness, all of whom had documented nocturnal hypoglycemia during 2 weeks of screening. Outcomes were calculated using plasma glucose. In participants with hypoglycemia unawareness, the median (interquartile range [IQR]) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on dual-hormone artificial pancreas nights and 0% (0-10) on single-hormone artificial pancreas nights (P = 0.20). Additionally, participants with hypoglycemia unawareness experienced two hypoglycemic events (<3.0 mmol/L) on dual-hormone artificial pancreas nights and three hypoglycemic events on single-hormone artificial pancreas nights. In participants with hypoglycemia awareness, the median (IQR) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on both dual- and single-hormone artificial pancreas nights. Hypoglycemia awareness participants experienced zero hypoglycemic events on dual-hormone artificial pancreas nights and one event on single-hormone artificial pancreas nights. In this study, dual-hormone and single-hormone systems performed equally well in preventing nocturnal hypoglycemia in participants with hypoglycemia unawareness. Longer studies over the course of multiple days and nights may be needed to explore possible specific benefits in this population. ClinicalTrials.gov No. NCT02282254.

Design of Switched Model Predictive Control Algorithms for a Dual-Hormone Artificial Pancreas

Abstract In this paper, we evaluate the closed-loop performance of two switching strategies for a dual-hormone artificial pancreas (AP). The dual-hormone AP administers insulin and glucagon subcutaneously. Since insulin and glucagon have opposite effects, we want to avoid simultaneous injections of these two hormones. To handle non-simultaneous injections of insulin and glucagon, we compare model predictive control (MPC) algorithms using a hysteresis switch between insulin and glucagon controllers with a multiple-input single-output (MISO) formulation. Although the closed-loop performance of these two control strategies is similar, the hysteresis switch is preferable due to (i) its greater flexibility in control design and tuning and (ii) a more straightforward way to avoid simultaneous injections of insulin and glucagon.

Stability of Commercially Available Glucagon Formulation for Dual-Hormone Artificial Pancreas Clinical Use.

Available glucagon formulations are approved for immediate use after reconstitution for severe hypoglycemia emergency treatment. However, they are used in dual-hormone artificial pancreas (insulin and glucagon) studies through subcutaneous infusion pumps over 24 h. Chemical and physical stability of such glucagon use have not been reported in a comprehensive manner. Recombinant Glucagon DNA (Eli Lilly) was used. Compatibility and sterility of glucagon delivery through subcutaneous pump systems were verified. Glucagon degradation through liquid chromatography with tandem mass spectrometry (LC-MS/MS), fibrillation using intrinsic tryptophan fluorescence shift, and bioactivity through a cell-protein kinase A-based fluorescent bioassay were assessed over a range of different physical conditions (temperature, movement, and air bubbles). Subcutaneous infusion pump systems administered glucagon in sterile conditions and with comparable accuracy to insulin delivery; mean absolute relative difference of actual versus expected weights were 1.2% ± 1.1% for glucagon and 1.1% ± 0.5% for insulin (P = 0.9). In comparison to freshly reconstituted samples, glucagon analyzed through LC-MS/MS was intact at 93.0% ± 7.0% after 24 h (P = 0.42) and 83.04% ± 6.0% after 48 h (P = 0.02) of incubation in pumps at 32°C. Peak wavelengths for Trp fluorescence did not differ from samples exposed to air bubbles or movement whether incubated (in infusion sets for 24 h at 32°) immediately or 24- and 48-h poststorage at 4°C (P = 0.10, 0.70 and 0.80, respectively) and no significant differences in bioactivity (shifts in EC50) were found for the same conditions (P = 0.13, 0.83, and 0.63). Available glucagon formulations are chemically and physically stable, as well as compatible with delivery through subcutaneous infusion pumps over 24 h and can be used in long-term clinical trials.