Integrating metabolic expenditure information from wearable fitness sensors into an AI-augmented automated insulin delivery system: a randomised clinical trial.

BACKGROUND: Exercise can rapidly drop glucose in people with type 1 diabetes. Ubiquitous wearable fitness sensors are not integrated into automated insulin delivery (AID) systems. We hypothesised that an AID can automate insulin adjustments using real-time wearable fitness data to reduce hypoglycaemia during exercise and free-living conditions compared with an AID not automating use of fitness data. METHODS: Our study population comprised of individuals (aged 21-50 years) with type 1 diabetes from from the Harold Schnitzer Diabetes Health Center clinic at Oregon Health and Science University, OR, USA, who were enrolled into a 76 h single-centre, two-arm randomised (4-block randomisation), non-blinded crossover study to use (1) an AID that detects exercise, prompts the user, and shuts off insulin during exercise using an exercise-aware adaptive proportional derivative (exAPD) algorithm or (2) an AID that automates insulin adjustments using fitness data in real-time through an exercise-aware model predictive control (exMPC) algorithm. Both algorithms ran on iPancreas comprising commercial glucose sensors, insulin pumps, and smartwatches. Participants executed 1 week run-in on usual therapy followed by exAPD or exMPC for one 12 h primary in-clinic session involving meals, exercise, and activities of daily living, and 2 free-living out-patient days. Primary outcome was time below range (<3·9 mmol/L) during the primary in-clinic session. Secondary outcome measures included mean glucose and time in range (3·9-10 mmol/L). This trial is registered with ClinicalTrials.gov, NCT04771403. FINDINGS: Between April 13, 2021, and Oct 3, 2022, 27 participants (18 females) were enrolled into the study. There was no significant difference between exMPC (n=24) versus exAPD (n=22) in time below range (mean [SD] 1·3% [2·9] vs 2·5% [7·0]) or time in range (63·2% [23·9] vs 59·4% [23·1]) during the primary in-clinic session. In the 2 h period after start of in-clinic exercise, exMPC had significantly lower mean glucose (7·3 [1·6] vs 8·0 [1·7] mmol/L, p=0·023) and comparable time below range (1·4% [4·2] vs 4·9% [14·4]). Across the 76 h study, both algorithms achieved clinical time in range targets (71·2% [16] and 75·5% [11]) and time below range (1·0% [1·2] and 1·3% [2·2]), significantly lower than run-in period (2·4% [2·4], p=0·0004 vs exMPC; p=0·012 vs exAPD). No adverse events occurred. INTERPRETATION: AIDs can integrate exercise data from smartwatches to inform insulin dosing and limit hypoglycaemia while improving glucose outcomes. Future AID systems that integrate exercise metrics from wearable fitness sensors may help people living with type 1 diabetes exercise safely by limiting hypoglycaemia. FUNDING: JDRF Foundation and the Leona M and Harry B Helmsley Charitable Trust, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Dual-Hormone Closed-Loop System Using a Liquid Stable Glucagon Formulation Versus Insulin-Only Closed-Loop System Compared With a Predictive Low Glucose Suspend System: An Open-Label, Outpatient, Single-Center, Crossover, Randomized Controlled Trial.

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.

Leveraging a Big Dataset to Develop a Recurrent Neural Network to Predict Adverse Glycemic Events in Type 1 Diabetes.

Patients with type 1 diabetes (T1D) do not produce their own insulin. They must continuously monitor their glucose and make decisions about insulin dosing to avoid the consequences of adverse glucose excursions. Continuous glucose monitoring (CGM) systems and insulin pumps are state-of-the-art systems that can help people with T1D manage their glucose. Accurate glucose prediction algorithms are becoming critical components of CGM systems that can help people with T1D proactively avoid the occurrence of impending hyperglycemia and hypoglycemia events. We present Glucop30, a robust data-driven glucose prediction model that is trained on a big dataset (27,466 days) to forecast glucose concentration along a short-term prediction horizon of 30 minutes. Our proposed prediction method is composed of (i) a recurrent neural network with long-short-term-memory (LSTM) units that predicts the general trend of future glucose levels, followed by (ii) a patient-specific smoothing error correction step that accounts for inter- and intra-patient glucose variability. We retrospectively test our proposed method on a clinical dataset obtained from 10 T1D insulin pump users who were continuously monitored during a 4-week trial under free-living conditions (255 days), and assess the impact of the size of the training set on the accuracy of the proposed model. In addition, we report on the accuracy of our method when both CGM and insulin data are used for prediction; however we discovered that adding insulin as an additional input feature improves prediction accuracy by only 1%. Glucop30 achieves leading performance as measured by the RMSE of 7.55 (SD = 2.20 mg/dL) and MAE of 4.89 (SD = 1.43 mg/dL) for an effective prediction horizon of 27.50 (SD = 2.64) minutes. Moreover, Glucop30 accurately anticipates the occurrence of 97.79 (SD = 5.35)% of hyperglycemia events (glucose > 180 mg/dL), and 90.87 (SD = 6.79)% of hypoglycemia events (glucose < 70 mg/dL) with remarkably few false alerts (1 and 2 false alarms per week for hypoglycemia and hyperglycemia events, respectively).

A statistical virtual patient population for the glucoregulatory system in type 1 diabetes with integrated exercise model.

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.

Prediction of Hypoglycemia During Aerobic Exercise in Adults With Type 1 Diabetes.

BACKGROUND: Fear of exercise related hypoglycemia is a major reason why people with type 1 diabetes (T1D) do not exercise. There is no validated prediction algorithm that can predict hypoglycemia at the start of aerobic exercise. METHODS: We have developed and evaluated two separate algorithms to predict hypoglycemia at the start of exercise. Model 1 is a decision tree and model 2 is a random forest model. Both models were trained using a meta-data set based on 154 observations of in-clinic aerobic exercise in 43 adults with T1D from 3 different studies that included participants using sensor augmented pump therapy, automated insulin delivery therapy, and automated insulin and glucagon therapy. Both models were validated using an entirely new validation data set with 90 exercise observations collected from 12 new adults with T1D. RESULTS: Model 1 identified two critical features predictive of hypoglycemia during exercise: heart rate and glucose at the start of exercise. If heart rate was greater than 121 bpm during the first 5 min of exercise and glucose at the start of exercise was less than 182 mg/dL, it predicted hypoglycemia with 79.55% accuracy. Model 2 achieved a higher accuracy of 86.7% using additional features and higher complexity. CONCLUSIONS: Models presented here can assist people with T1D to avoid exercise related hypoglycemia. The simple model 1 heuristic can be easily remembered (the 180/120 rule) and model 2 is more complex requiring computational resources, making it suitable for automated artificial pancreas or decision support systems.

Adaptive Control of an Artificial Pancreas Using Model Identification, Adaptive Postprandial Insulin Delivery, and Heart Rate and Accelerometry as Control Inputs.

BACKGROUND: People with type 1 diabetes (T1D) have varying sensitivities to insulin and also varying responses to meals and exercise. We introduce a new adaptive run-to-run model predictive control (MPC) algorithm that can be used to help people with T1D better manage their glucose levels using an artificial pancreas (AP). The algorithm adapts to individuals' different insulin sensitivities, glycemic response to meals, and adjustment during exercise as a continuous input during free-living conditions. METHODS: A new insulin sensitivity adaptation (ISA) algorithm is presented that updates each patient's insulin sensitivity during nonmeal periods to reduce the error between the actual glucose levels and the process model. We further demonstrate how an adaptive learning postprandial hypoglycemia prevention algorithm (ALPHA) presented in the previous work can complement the ISA algorithm, and the algorithm can adapt in several days. We further show that if physical activity is incorporated as a continuous input (heart rate and accelerometry), performance is improved. The contribution of this work is the description of the ISA algorithm and the evaluation of how ISA, ALPHA, and incorporation of exercise metrics as a continuous input can impact glycemic control. RESULTS: Incorporating ALPHA, ISA, and physical activity into the MPC improved glycemic outcome measures. The adaptive learning postprandial hypoglycemia prevention algorithm combined with ISA significantly reduced time spent in hypoglycemia by 71.7% and the total number of rescue carbs by 67.8% to 0.37% events/day/patient. Insulin sensitivity adaptation significantly reduced model-actual mismatch by 12.2% compared to an AP without ISA. Incorporating physical activity as a continuous input modestly improved time in the range 70 to 180 mg/dL during high physical activity days from 84.4% to 84.9% and reduced the percentage time in hypoglycemia by 23.8% from 2.1% to 1.6%. CONCLUSION: Adapting postprandial insulin delivery, insulin sensitivity, and adapting to physical exercise in an MPC-based AP systems can improve glycemic outcomes.

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

OBJECTIVE: Automated 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 METHODS: Participants 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. RESULTS: The 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). CONCLUSIONS: The addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.

Design of a dual-hormone model predictive control for artificial pancreas with exercise model.

The Artificial Pancreas (AP) is a new technology for helping people with type 1 diabetes to better control their glucose levels through automated delivery of insulin and optionally glucagon in response to sensed glucose levels. In a dual hormone AP, insulin and glucagon are delivered automatically to the body based on glucose sensor measurements using a control algorithm that calculates the amount of hormones to be infused. A dual-hormone MPC may deliver insulin continuously; however, it must avoid continuous delivery of glucagon because nausea can occur from too much glucagon. In this paper, we propose a novel dual-hormone (DH) switching model predictive control and compare it with a single-hormone (SH) MPC. We extended both MPCs by integrating an exercise model and compared performance with and without the exercise model included. Results were obtained on a virtual patient population undergoing a simulated exercise event using a mathematical glucoregulatory model that includes exercise. Time spent in hypoglycemia is significantly less with the DH-MPC than the SH-MPC (p=0.0022). Additionally, including the exercise model in the DH-MPC can help prevent hypoglycemia (p <; 0.001).

Incorporating an Exercise Detection, Grading, and Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate.

In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients' glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event.