OBJECTIVE Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks. RESEARCH DESIGN AND METHODS Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A_1c (HbA_1c). Outcomes are reported adhering to consensus recommendations on reporting of AP trials. RESULTS Twenty-nine patients completed the trial. HbA_1c, 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (−0.3, 95% CI −0.5 to −0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (−3.1, 95% CI −4.1 to −2.1, P < 0.001) and overnight from 4.1 to 1.1% (−3.1, 95% CI −4.2 to −1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events. CONCLUSIONS Use of our novel adaptive AP yielded significant reductions in HbA_1c and hypoglycemia.

Continuous Glucose Monitoring (CGM) has been a springboard of new diabetes management technologies such as integrated sensor-pump systems, the artificial pancreas, and more recently, smart pens. It also allows patients to make better informed decisions compared to a few measurements per day from a glucometer. However, CGM accuracy is reportedly affected during exercise periods, which can impact the effectiveness of CGM-based treatments. In this review, several studies that used CGM during exercise periods are scrutinized. An extensive literature review of clinical trials including exercise and CGM in type 1 diabetes was conducted. The gathered data were critically analysed, especially the Mean Absolute Relative Difference (MARD), as the main metric of glucose accuracy. Most papers did not provide accuracy metrics that differentiated between exercise and rest (non-exercise) periods, which hindered comparative data analysis. Nevertheless, the statistic results confirmed that CGM during exercise periods is less accurate.

Background: Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. Methods: Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 μg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. Results: Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. Conclusion: A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. Clinical Trials Registration: NCT03255629

Background: We investigated the safety and efficacy of the addition of a trust index to enhanced Model Predictive Control (eMPC) Artificial Pancreas (AP) that works by adjusting the responsiveness of the controller's insulin delivery based on the confidence intervals around predictions of glucose trends. This constitutes a dynamic adaptation of the controller's parameters in contrast with the widespread AP implementation of individualized fixed controller tuning. Materials and Methods: After 1 week of sensor-augmented pump (SAP) use, subjects completed a 48-h AP admission that included three meals/day (carbohydrate range 29–57 g/meal), a 1-h unannounced brisk walk, and two overnight periods. Endpoints included sensor glucose percentage time 70–180, 180 mg/dL, number of hypoglycemic events, and assessment of the trust index versus standard eMPC glucose predictions. Results: Baseline characteristics for the 15 subjects who completed the study (mean ± SD) were age 46.1 ± 17.8 years, HbA1c 7.2% ± 1.0%, diabetes duration 26.8 ± 17.6 years, and total daily dose (TDD) 35.5 ± 16.4 U/day. Mean sensor glucose percent time 70–180 mg/dL (88.0% ± 8.0% vs. 74.6% ± 9.4%), <70 mg/dL (1.5% ± 1.9% vs. 7.8% ± 6.0%), and number of hypoglycemic events (0.6 ± 0.6 vs. 6.3 ± 3.4), all showed statistically significant improvement during AP use compared with the SAP run-in (P < 0.001). On average, the trust index enhanced controller responsiveness to predicted hyper- and hypoglycemia by 26% (P < 0.005). Conclusions: In this population of well-controlled patients, we conclude that eMPC with trust index AP achieved nearly 90% time in the target glucose range. Additional studies will further validate these results.

Background: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. Methods: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. Results: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 μg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 μg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). Conclusions: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.

Model predictive control (MPC) performance depends on the accuracy of the prediction model implemented by the controller. Complex physiology and modeling limitations often prevent the ability to provide long and accurate glucose predictions, which results in the need to account for prediction errors. Optimal insulin dosage by Zone-MPC is calculated by solving an optimization problem in which a scalar index is minimized by penalizing relative input deviations and glucose predictions out of the reference zone. The controller’s tuning parameters are the penalties on the input variable (insulin). Positive and negative relative inputs are penalized differently. A dynamic adaptation of the tuning parameters based on the accuracy of the model in recent history is implemented in this article and compared in silico to aggressive and conservative tunings of the same controller structure. Similar average glucose and time in the safe glucose range (70-180 mg/dL) are achieved for the adaptive design and traditional controller configurations. However, percentage time under 70 mg/dL is significantly reduced, both for announced meals using bolus compensation and unannounced meals with a meal detection algorithm triggered bolus. No differences in the average insulin delivered were observed between the adaptive design and the conservative or aggressive tuning for the bolus strategy, and the adaptive controller delivered less insulin in the other scenario considered. The adaptive strategy provides safe and effective glucose management as well as significant reduction of hypoglycemia events. No abnormal insulin delivery profiles were observed upon the application of the adaptive strategy.