OBJECTIVE To assess the efficacy and feasibility of a dual-hormone (DH) closed-loop system with insulin and a novel liquid stable glucagon formulation compared with an insulin-only closed-loop system and a predictive low glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In a 76-h, randomized, crossover, outpatient study, 23 participants with type 1 diabetes used three modes of the Oregon Artificial Pancreas system: 1) dual-hormone (DH) closed-loop control, 2) insulin-only single-hormone (SH) closed-loop control, and 3) PLGS system. The primary end point was percentage time in hypoglycemia (<70 mg/dL) from the start of in-clinic aerobic exercise (45 min at 60% VO2max) to 4 h after. RESULTS DH reduced hypoglycemia compared with SH during and after exercise (DH 0.0% [interquartile range 0.0–4.2], SH 8.3% [0.0–12.5], P = 0.025). There was an increased time in hyperglycemia (>180 mg/dL) during and after exercise for DH versus SH (20.8% DH vs. 6.3% SH, P = 0.038). Mean glucose during the entire study duration was DH, 159.2; SH, 151.6; and PLGS, 163.6 mg/dL. Across the entire study duration, DH resulted in 7.5% more time in target range (70–180 mg/dL) compared with the PLGS system (71.0% vs. 63.4%, P = 0.044). For the entire study duration, DH had 28.2% time in hyperglycemia vs. 25.1% for SH (P = 0.044) and 34.7% for PLGS (P = 0.140). Four participants experienced nausea related to glucagon, leading three to withdraw from the study. CONCLUSIONS The glucagon formulation demonstrated feasibility in a closed-loop system. The DH system reduced hypoglycemia during and after exercise, with some increase in hyperglycemia.
Purpose We introduce two validated single (SH) and dual hormone (DH) mathematical models that represent an in-silico virtual patient population (VPP) for type 1 diabetes (T1D). The VPP can be used to evaluate automated insulin and glucagon delivery algorithms, so-called artificial pancreas (AP) algorithms that are currently being used to help people with T1D better manage their glucose levels. We present validation results comparing these virtual patients with true clinical patients undergoing AP control and demonstrate that the virtual patients behave similarly to people with T1D. Methods A single hormone virtual patient population (SH-VPP) was created that is comprised of eight differential equations that describe insulin kinetics, insulin dynamics and carbohydrate absorption. The parameters in this model that represent insulin sensitivity were statistically sampled from a normal distribution to create a population of virtual patients with different levels of insulin sensitivity. A dual hormone virtual patient population (DH-VPP) extended this SH-VPP by incorporating additional equations to represent glucagon kinetics and glucagon dynamics. The DH-VPP is comprised of thirteen differential equations and a parameter representing glucagon sensitivity, which was statistically sampled from a normal distribution to create virtual patients with different levels of glucagon sensitivity. We evaluated the SH-VPP and DH-VPP on a clinical data set of 20 people with T1D who participated in a 3.5-day outpatient AP study. Twenty virtual patients were matched with the 20 clinical patients by total daily insulin requirements and body weight. The identical meals given during the AP study were given to the virtual patients and the identical AP control algorithm that was used to control the glucose of the virtual patients was used on the clinical patients. We compared percent time in target range (70–180 mg/dL), time in hypoglycemia (<70 mg/dL) and time in hyperglycemia (>180 mg/dL) for both the virtual patients and the actual patients. Results The subjects in the SH-VPP performed similarly vs. the actual patients (time in range: 78.1 ± 5.1% vs. 74.3 ± 8.1%, p = 0.11; time in hypoglycemia: 3.4 ± 1.3% vs. 2.8 ± 1.7%, p = 0.23). The subjects in the DH-VPP also performed similarly vs. the actual patients (time in range: 75.6 ± 5.5% vs. 71.9 ± 10.9%, p = 0.13; time in hypoglycemia: 0.9 ± 0.8% vs. 1.3 ± 1%, p = 0.19). While the VPPs tended to over-estimate the time in range relative to actual patients, the difference was not statistically significant. Conclusions We have verified that a SH-VPP and a DH-VPP performed comparably with actual patients undergoing AP control using an identical control algorithm. The SH-VPP and DH-VPP may be used as a simulator for pre-evaluation of T1D control algorithms.
Background: Despite new glucose sensing technologies, nocturnal hypoglycemia is still a problem for people with type 1 diabetes (T1D) as symptoms and sensor alarms may not be detected while sleeping. Accurately predicting nocturnal hypoglycemia before sleep may help minimize nighttime hypoglycemia. Methods: A support vector regression (SVR) model was trained to predict, before bedtime, the overnight minimum glucose and overnight nocturnal hypoglycemia for people with T1D. The algorithm was trained on continuous glucose measurements and insulin data collected from 124 people (22,804 valid nights of data) with T1D. The minimum glucose threshold for announcing nocturnal hypoglycemia risk was derived by applying a decision theoretic criterion to maximize expected net benefit. Accuracy was evaluated on a validation set from 10 people with T1D during a 4week trial under free-living sensor-augmented insulin-pump therapy. The primary outcome measures were sensitivity and specificity of prediction, the correlation between predicted and actual minimum nocturnal glucose, and root-meansquare error. The impact of using the algorithm to prevent nocturnal hypoglycemia is shown in-silico. Results: The algorithm predicted 94.1% of nocturnal hypoglycemia events (<3.9 mmol/L, 95% confidence interval [CI], 71.3-99.9) with an area under the receiver operating characteristic curve of 0.86 (95% CI, 0.75-0.98). Correlation between actual and predicted minimum glucose was high (R = 0.71, P < 0.001). In-silico simulations showed that the algorithm could reduce nocturnal hypoglycemia by 77.0% (P = 0.006) without impacting time in target range (3.9-10 mmol/L). Conclusion: An SVR model trained on a big data set and optimized using decision theoretic criterion can accurately predict at bedtime if overnight nocturnal hypoglycemia will occur and may help reduce nocturnal hypoglycemia.
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