Estimation and Prediction of Glucose Appearance Rate for Use in a Fully Closed-Loop Dual-Hormone Intraperitoneal Artificial Pancreas.

OBJECTIVE: A fully automated artificial pancreas requires a meal estimator and predictions of blood glucose levels (BGL) to handle disturbances during meal times, all without relying on manual meal announcements and user interventions. This study introduces a technique for estimating the glucose appearance rate (GAR) and predicting BGL in people with type 1 diabetes and insulin and glucagon administration. It is demonstrated for intraperitoneal insulin and glucagon delivery but may be adapted to other delivery sites. METHOD: The estimator is designed based on the moving horizon estimation (MHE) approach, where the underlying cost function incorporates prior statistical information on the GAR in subjects over the course of a day. The proposed prediction scheme is developed to predict GAR using estimated states and an intestinal model, which is then used to predict BGL with the help of an animal glucose metabolic model. RESULTS: The intraperitoneal dual-hormone estimator was evaluated on three anesthetized animals, achieving a 21.8% mean absolute percentage error (MAPE) for GAR estimation and a 10.0% MAPE for BGL prediction when the future GAR is known. For a 120-minute prediction horizon, the proposed predictor achieved an 18.0% MAPE for GAR and a 28.4% MAPE for BGL. CONCLUSION: The findings demonstrate the effectiveness and reliability of the proposed estimator and its potential for use in a fully automated artificial pancreas and reducing user interventions. SIGNIFICANCE: This study represents advancements toward the development of a fully automated artificial pancreas, ultimately enhancing the quality of life for people with type 1 diabetes.

A Nonlinear State Observer for the Bi-Hormonal Intraperitoneal Artificial Pancreas.

Currently, continuous glucose monitoring sensors are used in the artificial pancreas to monitor blood glucose levels. However, insulin and glucagon concentrations in different parts of the body cannot be measured in real-time, and determining body glucagon sensitivity is not feasible. Estimating these states provides more information about the current system status, facilitating improved decision-making by the model-based controller. In this regard, the aim of this paper is to design a nonlinear high-gain observer for a bi-hormonal artificial pancreas in the presence of measurement noises, model uncertainties, and disturbances. The model used in the observer is based on an existing intraperitoneal nonlinear animal model in the literature. This model is modified by assuming that insulin can directly transfer from the peritoneal cavity to the bloodstream. Based on a set of realistic assumptions, one model is considered after each hormone infusion, and two observers are separately designed. The model is divided into the insulin-phase and glucagon-phase models based on a set of realistic assumptions. Thereafter, two high-gain observers are designed separately for these phases contributing to estimating the non-measurable states. The observer error is proven to be locally uniformly ultimately bounded, and it is verified that any asymptotically stable control laws remain stable in the presence of the observer. The performance of the observers with different gains is evaluated for a scenario with multiple insulin and glucagon infusions. The proposed observer converges to a finite error, according to the results. Clinical relevance- In Type 1 diabetic patients, the developed observer can be employed in a closed-loop artificial pan-creas to improve the performance of model-based controllers. It estimates the key states, which are necessary for forecasting the body's response to insulin and glucagon boluses.

Low-Order Nonlinear Animal Model of Glucose Dynamics for a Bihormonal Intraperitoneal Artificial Pancreas.

OBJECTIVE: The design of an Artificial Pancreas (AP) to regulate blood glucose levels requires reliable control methods. Model Predictive Control has emerged as a promising approach for glycemia control. However, model-based control methods require computationally simple and identifiable mathematical models that represent glucose dynamics accurately, which is challenging due to the complexity of glucose homeostasis. METHODS: In this work, a simple model is deduced to estimate blood glucose concentration in subjects with Type 1 Diabetes Mellitus (T1DM). Novel features in the model are power-law kinetics for intraperitoneal insulin absorption and a separate glucagon sensitivity state. Profile likelihood and a method based on singular value decomposition of the sensitivity matrix are carried out to assess parameter identifiability and guide a model reduction for improving the identification of parameters. RESULTS: A reduced model with 10 parameters is obtained and calibrated, showing good fit to experimental data from pigs where insulin and glucagon boluses were delivered in the intraperitoneal cavity. CONCLUSION: A simple model with power-law kinetics can accurately represent glucose dynamics submitted to intraperitoneal insulin and glucagon injections. The reduced model was found to exhibit local practical as well as structural identifiability. IMPORTANCE: The proposed model facilitates intraperitoneal bi-hormonal model-based closed-loop control in animal trials.

Modelling and simulation of occlusions in insulin pumps.

An open source simulation model of the mechanical properties of a fully functional insulin pump was made in Matlab Simscape. The model simulates realistic behavior of an insulin pump, parts of which are validated against real-world systems. Simulations include mechanical forces and internal pressures, and the following fluid dynamics. Failure modes, such as occlusions, can be simulated and the resulting simulations can give new insights on how these failures affect the pump and how to detect them.Clinical relevance- Realistic pump simulations can be used to analyze how pump failures affect the system and in turn how to most effectively detect them before posing a hazard to the user, increasing the safety and reliability of the system.

Physiological effects of intraperitoneal versus subcutaneous insulin infusion in patients with diabetes mellitus type 1: A systematic review and meta-analysis.

The intraperitoneal route of administration accounts for less than 1% of insulin treatment regimes in patients with diabetes mellitus type 1 (DM1). Despite being used for decades, a systematic review of various physiological effects of this route of insulin administration is lacking. Thus, the aim of this systematic review was to identify the physiological effects of continuous intraperitoneal insulin infusion (CIPII) compared to those of continuous subcutaneous insulin infusion (CSII) in patients with DM1. Four databases (EMBASE, PubMed, Scopus and CENTRAL) were searched beginning from the inception date of each database to 10th of July 2020, using search terms related to intraperitoneal and subcutaneous insulin administration. Only studies comparing CIPII treatment (≥ 1 month) with CSII treatment were included. Primary outcomes were long-term glycaemic control (after ≥ 3 months of CIPII inferred from glycated haemoglobin (HbA1c) levels) and short-term (≥ 1 day for each intervention) measurements of insulin dynamics in the systematic circulation. Secondary outcomes included all reported parameters other than the primary outcomes. The search identified a total of 2242 records; 39 reports from 32 studies met the eligibility criteria. This meta-analysis focused on the most relevant clinical end points; the mean difference (MD) in HbA1c levels during CIPII was significantly lower than during CSII (MD = -6.7 mmol/mol, [95% CI: -10.3 --3.1]; in percentage: MD = -0.61%, [95% CI: -0.94 -- 0.28], p = 0.0002), whereas fasting blood glucose levels were similar (MD = 0.20 mmol/L, [95% CI: -0.34-0.74], p = 0.47; in mg/dL: MD = 3.6 mg/dL, [95% CI: -6.1-13.3], p = 0.47). The frequencies of severe hypo- and hyper-glycaemia were reduced. The fasting insulin levels were significantly lower during CIPII than during CSII (MD = 16.70 pmol/L, [95% CI: -23.62 --9.77], p < 0.0001). Compared to CSII treatment, CIPII treatment improved overall glucose control and reduced fasting insulin levels in patients with DM1.

Intraperitoneal insulin administration in pigs: effect on circulating insulin and glucose levels.

INTRODUCTION: The effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses. There is a lack of studies comparing the insulin appearance in the systemic circulation after intraperitoneal compared with subcutaneous insulin delivery. Thus, we also aimed for a comparison with the subcutaneous route. RESEARCH DESIGN AND METHODS: Eight anesthetized, non-diabetic pigs were given three different intraperitoneal insulin boluses (2, 5 and 10 U). The order of boluses for the last six pigs was randomized. Endogenous insulin and glucagon release were suppressed by repeated somatostatin analog injections. The first pig was used to identify the infusion rate of glucose to maintain stable glucose values throughout the experiment. The estimated difference between insulin boluses was compared using two-way analysis of variance (GraphPad Prism V.8).In addition, a trial of three pigs which received subcutaneous insulin boluses was included for comparison with intraperitoneal insulin boluses. RESULTS: Decreased mean blood glucose levels were observed after 5 and 10 U intraperitoneal insulin boluses compared with the 2 U boluses. No changes in circulating insulin levels were observed after the 2 and 5 U intraperitoneal boluses, while increased circulating insulin levels were observed after the 10 U intraperitoneal boluses. Subcutaneously injected insulin resulted in higher values of circulating insulin compared with the corresponding intraperitoneal boluses. CONCLUSIONS: Smaller intraperitoneal boluses of insulin have an effect on circulating glucose levels without increasing insulin levels in the systemic circulation. By increasing the insulin bolus, a major increase in circulating insulin was observed, with a minor additive effect on circulating glucose levels. This is compatible with a close to 100% first-pass effect in the liver after smaller intraperitoneal boluses. Subcutaneous insulin boluses markedly increased circulating insulin levels.

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.

Pattern Recognition Reveals Characteristic Postprandial Glucose Changes: Non-Individualized Meal Detection in Diabetes Mellitus Type 1.

Accurate continuous glucose monitoring (CGM) is essential for fully automated glucose control in diabetes mellitus type 1. State-of-the-art glucose control systems automatically regulate the basal insulin infusion. Users still need to manually announce meals to dose the prandial insulin boluses. An automated meal detection could release the user and improve the glucose regulation. In this study, patterns in the postprandial CGM data are exploited for meal detection. Binary classifiers are trained to recognize the postprandial pattern in horizons of the estimated glucose rate of appearance and in CGM data. The appearance rate is determined by moving horizon estimation based on a simple model. Linear discriminant analysis (LDA) is used for classification. The proposed method is compared to methods that detect meals when thresholds are violated. Diabetes care data from 12 free-living pediatric patients was downloaded during regular screening. Experts identified meals and their start by retrospective evaluation. The classification was tested by cross-validation. Compared to the threshold-based methods, LDA showed higher sensitivity to meals with a low rate of false alarms. Classifying horizons outperformed the other methods also with respect to time of detection. The onset of meals can be detected by pattern recognition based on estimated model states and consecutive CGM measurements. No individual tuning is necessary. This makes the method easily adopted in the clinical practice.

Why intraperitoneal glucose sensing is sometimes surprisingly rapid and sometimes slow: A hypothesis.

The artificial pancreas requires fast and reliable glucose measurements. The peritoneal space has shown promising results, and in one of our studies we detected glucose changes in the peritoneal space already at the same time as in the femoral artery. The peritoneal lining is highly vascularised, covered by a single layer of mesothelial cells and therefore easily accessible for proper sensor technology, e.g. optical technology. We hypothesize that the rapid intraperitoneal glucose dynamics observed in our study was possible because the sensors were located directly at the peritoneal lining, at the point where the glucose molecules entered the peritoneal space. Glucose travels slowly in fluids by diffusion, and a longer distance between the sensor and the peritoneal lining would consequently result in slower dynamics. We therefore propose to place the glucose sensor in an artificial pancreas as closely to the peritoneal lining as possible, or even utilize appropriate sensor technology to measure glucose in the peritoneal lining itself.

Data driven filtering of bowel sounds using multivariate empirical mode decomposition.

BACKGROUND: The analysis of abdominal sounds can help to diagnose gastro-intestinal diseases. Sounds originating from the stomach and the intestine, the so-called bowel sounds, occur in various forms. They are described as loose successions or clusters of rather sudden bursts. Realistic recordings of abdominal sounds are contaminated with noise and artifacts from which the bowel sounds must be differentiated. METHODS: The proposed intrinsic mode function-fractal dimension (IMF-FD) filtering utilizes the property of the multivariate empirical mode decomposition (MEMD) to behave as a series of band pass filters. The MEMD decomposes the abdominal signal into its different frequency components. The resulting intrinsic mode functions (IMFs) are modulated in amplitude and frequency where transient sonic events occur. Based on the complexity of the IMFs, measured by their fractal dimension (FD) in sliding windows, the information-carrying IMFs are selected. The filtered signal is formed as the superposition of all selected IMFs. The IMF-FD filter not only enhances the non-linear components of the original signal but also segments them from the rest. Another important aspect of this work is that typical artifacts that occur in the same frequency range as bowel sounds can be subsequently eliminated by heuristic rules. CONCLUSIONS: The method is tested on a realistic, contaminated data set with promising performance: close to 100% of the manually labeled bowel sounds are identified.

Feasibility of Early Meal Detection Based on Abdominal Sound.

In classical approaches for an artificial pancreas, continuous glucose monitoring (CGM) is the only measured variable used for insulin dosing and additional control functions. The CGM values are subject to time delays and slow dynamics between blood and the sensing location. These time lags compromise the controller's performance in maintaining (near to) normal glucose levels. Meal information could enhance the control outcome. However, meal announcement by the user is not reliable, and it takes 30 min to 40 min from meal onset until a meal is detected by methods based on CGM. In this pilot study, the use of bowel sounds for meal detection was investigated. In particular, we focused on whether bowel sounds change qualitatively during or shortly after meal ingestion. After fasting for at least 4 h, 11 healthy volunteers ingested a lunch meal at their usual time. Abdominal sound was recorded by a condenser microphone that was attached to the right upper quadrant of the abdomen by medical tape. Features that describe the power distribution over the frequency spectrum were extracted and used for classification by support vector machines. These classifiers were trained in a leave-one-out cross-validation scheme. Meals could be detected on average 10 min (std: 4.4 min) after they had started. Half of these were detected without false alarms. This shows that abdominal sound monitoring could provide an early meal detection. Further studies should investigate this possibility on a larger population in more general settings.

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

OBJECTIVE: Hypoglycemia 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 delivery is sparsely studied. We performed a direct comparison of the blood glucose response following intraperitoneally, subcutaneously and intravenously administered glucagon. RESEARCH DESIGN AND METHODS: This is a prospective, randomized, controlled, open-label, crossover trial in 20 octreotide-treated rats. Three interventions, 1 week apart, in a randomized order, were done in each rat. All 20 rats were given intraperitoneal and subcutaneous glucagon injections, from which 5 rats were given intravenous glucagon injections and 15 rats received placebo (intraperitoneal isotonic saline) injection. The dose of glucagon was 5 µg/kg body weight for all routes of administration. Blood glucose levels were measured before and until 60 min after the glucagon/placebo injections. RESULTS: Compared with placebo-treated rats, a significant increase in blood glucose was observed 4 min after intraperitoneal glucagon administration (p=0.009), whereas after subcutaneous and intravenous glucagon administration significant increases were seen after 8 min (p=0.002 and p<0.001, respectively). In intraperitoneally treated compared with subcutaneously treated rats, the increase in blood glucose was higher after 4 min (p=0.019) and lower after 40 min (p=0.005) and 50 min (p=0.011). The maximum glucose response occurred earlier after intraperitoneal compared with subcutaneous glucagon injection (25 min vs 35 min; p=0.003). CONCLUSIONS: Glucagon administered intraperitoneally gives a faster glucose response compared with subcutaneously administered glucagon in rats. If repeatable in humans, the more rapid glucose response may be of importance in a dual-hormone artificial pancreas using the intraperitoneal route for administration of insulin and glucagon.

Effect of sensor location on continuous intraperitoneal glucose sensing in an animal model.

BACKGROUND: In diabetes research, the development of the artificial pancreas has been a major topic since continuous glucose monitoring became available in the early 2000's. A prerequisite for an artificial pancreas is fast and reliable glucose sensing. However, subcutaneous continuous glucose monitoring carries the disadvantage of slow dynamics. As an alternative, we explored continuous glucose sensing in the peritoneal space, and investigated potential spatial differences in glucose dynamics within the peritoneal cavity. As a secondary outcome, we compared the glucose dynamics in the peritoneal space to the subcutaneous tissue. MATERIAL AND METHODS: Eight-hour experiments were conducted on 12 anesthetised non-diabetic pigs. Four commercially available amperometric glucose sensors (FreeStyle Libre, Abbott Diabetes Care Ltd., Witney, UK) were inserted in four different locations of the peritoneal cavity and two sensors were inserted in the subcutaneous tissue. Meals were simulated by intravenous infusions of glucose, and frequent arterial blood and intraperitoneal fluid samples were collected for glucose reference. RESULTS: No significant differences were discovered in glucose dynamics between the four quadrants of the peritoneal cavity. The intraperitoneal sensors responded faster to the glucose excursions than the subcutaneous sensors, and the time delay was significantly smaller for the intraperitoneal sensors, but we did not find significant results when comparing the other dynamic parameters.

Differences Between Flash Glucose Monitor and Fingerprick Measurements.

Freestyle Libre (FL) is a factory calibrated Flash Glucose Monitor (FGM). We investigated Mean Absolute Relative Difference (MARD) between Self Monitoring of Blood Glucose (SMBG) and FL measurements in the first day of sensor wear in 39 subjects with Type 1 diabetes. The overall MARD was 12.3%, while the individual MARDs ranged from 4% to 25%. Five participants had a MARD ≥ 20%. We estimated bias and lag between the FL and SMBG measurements. The estimated biases range from -1.8 mmol / L to 1.4 mmol / L , and lags range from 2 min to 24 min . Bias is identified as a main cause of poor individual MARDs. The biases seem to persist in days 2⁻7 of sensor usage. All cases of MARD ≥ 20% in the first day are eliminated by bias correction, and overall MARD is reduced from 12.3% to 9.2%, indicating that adding support for voluntary user-supplied bias correction in the FL could improve its performance.

A Review of the Current Challenges Associated with the Development of an Artificial Pancreas by a Double Subcutaneous Approach.

INTRODUCTION: Patients with diabetes type 1 (DM1) struggle daily to achieve good glucose control. The last decade has seen a rush of research groups working towards an artificial pancreas (AP) through the application of a double subcutaneous approach, i.e., subcutaneous (SC) continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion. Few have focused on the fundamental limitations of this approach, especially regarding outcome measures beyond time in range. METHODS: Based on insulin physiology, the limitations of CGM, SC insulin absorption, meal challenge, and physical activity in DM1 patients, we discuss the limitations of the double SC approach. Finally, we discuss safety measures and the achievements reported in some recent AP studies that have utilized the double SC approach. RESULTS: Most studies show that a double SC AP increases the time in range compared to a sensor-augmented insulin pump and shortens the time in hypoglycemia. Despite these achievements, the proportion of time spent in hyperglycemia is still roughly 20-40%, and hypoglycemia is still present 1-4% of the time. The main factors limiting further progress are the latency of SC CGM (at least 5-10 min) and the slow pharmacokinetics of SC-delivered fast-acting insulin. The maximum blood insulin level is reached after 45 min and the maximum glucose-lowering effect is observed after 1.5-2 h, while the glucose-lowering effect lasts for at least 5 h. CONCLUSIONS: Although using a double SC AP leads to significant improvements in glucose control, the SC approach has severe limitations that hamper further progress towards a robust AP.