Background and Aims

Lipohypertrophy (LH) is a chronic complication of diabetes mellitus that caused by subcutaneous injections of insulin. Nowadays, on the basis of results of ultrasonography of subcutaneous fat prevalence of LH in diabetic patients is still high. The aim has been to develop prevention of insulin induced LH in diabetic patients.

Methods

This study was done on 140 diabetic patients on insulin therapy a mean 8 years. On first stage patients were divided into two groups. First–117 patients with LH, second–23 diabetics without LH. All known LH risk factors were statistically processed using Spearman rank correlation coefficients. Results were statistically significant when p<0,05. On second stage 65 patients from first group were divided into two subgroups. First–50 patients with LH and corrected risk factors, second (control)–15 diabetics with LH and uncorrected risk factors. Ultrasonography were used in assessing new LH in these subgroups after 3 and 6 month.

Results

10 factors were remained after statistic analysis on first stage (p>0,05). Further, in first subgroup only 2 patients (4%) had new LH, while in second–9 diabetics (60%) had new pathologic areas of subcutaneous fat after 3 month. And in first subgroup only 6 patients (12%) had new pathologic areas of subcutaneous fat, while in second–12 diabetics (80%) had new LH after 6 month.

Conclusions

There were stated that only 10 risk factors strongly influence on LH progress. Correction of these risk factors doesn`t lead to development of new subcutaneous fat pathological changes and could be used to prevent LH in diabetic patients in clinical daily practice.

Background and Aims

With the support of the University of Virginia, the ARG controller without pre-meal boluses was successfully tested on the DiAs platform in the first clinical trials in Latin America. To further develop the ARG algorithm, the design of an own platform was carried out in view of future trials.

Methods

The GluControl platform (Figure) is based on the Android APS (AAPS), which is in turn designed from the Open APS. Initially, the connection with the same commercial devices as those used in the clinical trials were considered: Roche Accu-Chek Spirit Combo insulin pump and DexCom G4 Platinum CGM. Thereafter, GluControl was also tested using Freestyle Libre and the MiaoMiao Bluetooth adapter. To run the system, Motorola Moto G5 and One cell-phones were used, in which the ARG controller and a user interface were developed. Multiple-patient remote monitoring and online registry of the main system variables were also implemented.

Results

The base system (GluControl, Dexcom G4 and Roche Spirit Combo) was tested during 240hs, showing adequate CL operation for 93% of total time. Regarding the algorithm, an ARG version with disconnection mitigation techniques was tested using the glucose measurements from the clinical trials. The average relative error in total delivered insulin with respect to Matlab controller implementation was 5,37%, while the difference compared to the clinical trials results with DiAs-based implementation was of 6,94%.

Conclusions

An open-source APS platform including a monitoring system for several patients was introduced. Results are comparable to those obtained by other well-known systems for clinical trials.

Background and Aims

Activation of the hexosamine pathway of glucose metabolism in hyperglycemia leads to the formation of glyoxal, methylglyoxal, and later malonic dialdehyde. These products have a negative effect on the blood vessels wall in patients with type 2 diabetes mellitus (T2DM). The aim of the study was to evaluate the effectiveness of the antioxidant drug N-acetylcysteine in patients with T2DM and lower extremities microangiopathy for correction of glyoxal, metiglyoxal and malonic dialdehyde levels.

Methods

20 men with T2DM and lower extremities microangiopathy with N-acetylcysteine treatment combined with recommended therapy ​​and 30 healthy men (control group) in the study were involved. N-acetylcysteine ​​administered in a daily dose of 600 mg intravenously for 7 days. Methods of high-performance liquid chromatography used.

Results

In patients with T2DM and lower extremities microangiopathy, the glyoxal level increased to the third day (by 56%) and decreased to the control values to the seventh day. The level of methylglyoxal did not change to the third day, but decreased by 5 times to the seventh day. The dynamics of the malonic dialdehyde level decreased on the third (by 15%) and seven (by 47%) days.

Conclusions

The use of N-acetylcysteine allows to decrease the amount of ketoaldehydes in the blood and, thereby, to reduce the manifestation of vascular complications.

Background and Aims

Chronic kidney disease (CKD) is considered as an important factor in the disruption of the synthesis and regulation of 25(OH) vitamin D. Also, in patients with CKD terminal stage the thyroid function decrease is considered as one of the risk factors of adverse outcomes. Comparative analysis of the vitamin 25(OH)D and thyroid hormones levels in patients with diabetes mellitus and CKD was this research aim

Methods

Patients with type 1 and type 2 diabetes mellitus (DM) (n = 14, average age 54.5 years) and comparison group without carbohydrate metabolism disorders (n = 17, average age 52 of the year) were examined. In both groups, patients had a terminal stage of CKD and received renal replacement (лучше substitution therapy) therapy. The thyroid-stimulating hormone, thyroxine levels and vitamin 25(OH)D in the blood were determined

Results

The incidence of severe deficiency of vitamin 25(OH)D in the group of patients with DM was higher (81.8%) compared with the group of patients without DM (45.5%) (p<0.05). Correlation analysis revealed the presence of a feedback relations between the content of vitamin 25(OH)D in the blood and the daily average glycaemia in patients with DM (r=-0.66, p<0.05). An analysis of the thyroid hormones profile revealed thyroid hypofunction - subclinical hypothyroidism in 28.5% of all examined patients. A comparative analysis of this parameters not detected statistically significant differences (p>0.05) between two groups.

Conclusions

High prevalence of vitamin 25(OH)D deficiency in patients with end-stage renal failure and DM were found. More than a quarter of patients receiving renal substitution therapy had subclinical hypothyroidism.

Background and Aims

Endogenous hyperinsulinism caused by an insulinoma is a rare condition, potentially causing severe hypoglycaemia. The definite therapy for insulinoma is a pancreas-sparing surgery. That is why accurate preoperative localization of the tumour is important. However, most insulinomas are solitary, benign and rather small in size, which often makes their localization difficult. In about 10% of insulinomas, conventional imaging (CT, EUS, MRI, somatostatin receptor scintigraphy) is negative. Glucagon-like peptide-1 receptors (GLP-1R) are expressed in high percentage and density in virtually all insulinomas. The aim of this study was to evaluate GLP-1R imaging with the use of [Lys⁴⁰(Ahx-HYNIC-^99mTc/EDDA)NH₂]-exendin-4 in localization of insulinoma, when conventional imaging was negative or inconclusive.

Methods

Whole-body GLP-1R SPECT/CT was performed four hours after administration of [Lys⁴⁰(Ahx-HYNIC-^99mTc/EDDA)NH₂]-exendin-4 in patients with suspected insulinoma and negative or inconclusive conventional imaging (CT/EUS/MRI/SRS). The results of the GLP-1R scintigraphy were evaluated by an experienced nuclear medicine physician. Following surgical excision of the lesion, the diagnostic performance of the GLP-1R scintigraphy was analysed using histopathological evaluation and patient’s symptoms resolution as the gold standard.

Results

Seven female patients with biochemically confirmed endogenous hyperinsulinism during fasting test were enrolled in our study. In all patients, focal uptake of the radiopharmaceutical in the pancreas was found and surgery was performed. No metastases were found. In all cases, insulin-producing neuroendocrine tumors were confirmed by histopathological analysis and patient’s symptoms resolved after surgery. The sensitivity and specificity of GLP-1R scintigraphy were 100%.

Conclusions

GLP-1R imaging with the use of [Lys⁴⁰(Ahx-HYNIC-^99mTc/EDDA)NH₂]-exendin-4 is a highly efficient diagnostic modality for localization of insulinoma.

Background and Aims

Advanced closed loop (ACL) algorithms combine automated basal rate with additional enhancement when correction is required, usually post meal. Preliminary studies have demonstrated increased time spent in target glucose range of 70-180 mg/dL (TIR) with reduction in post prandial excursion. Here, we assessi the effectiveness of the algorithm to overcome no premeal bolus.

Methods

Four participants were followed for 4 days in a protected free living environment, while consuming pre-defined meals consisting of either 40, 60 and 80 grams of carbohydrates each day. Participants consumed the same meals and either bolus or did not bolus before consuming the meals according to the following protocol: Day1, all meals announced. Day 2 , participants announce only the 80 gr carb meal. In days 3 and 4, all meals unannounced

Results

Preliminary results of 4 adult participants show that overall glycemia during the unannounced meal phase demonstrated a 73.2% (±9.6) TIR of 70-180 mg% and 0% time in hypoglycemia <70mg%. Reduction in total daily dose and requirements for glucose salvage was noted. Comparison between the post meal excursion of the announced versus unannounced meals demonstrated a separation of excursion, when the carbs was above 40 grams. The peak glucose levels of unannounced meals did not differ between the 40, 60 and 80 gram carbohydrate-containing meals,

Conclusions

MINIMED^TM 670G 4.0 system is programmed for meal announcement. Nevertheless, when meals containing < 80 gram of carbohydrates are consumed without meal announcement, the system is able to provide safe glycemic control with over 70% of TIR.

Background and Aims

An Artificial Pancreas usually involves subcutaneous (sc) devices to measure glucose and to infuse insulin with important delays. The intraperitoneal (ip) route is more physiological and would avoid the sc delays, improving glucose control[A]. In these last years, new ip devices have been designed[B] and new modalities of ip insulin delivery, e.g pulsatile, have been tested. The aim here is to present the new simulator and its first use in in silico trial comparing the ip vs. sc insulin delivery route.

[A]Dassau, E. et al. Diabetes,Obesity and Metabolism,19.12(2017):1698-1705.

[B]Iacovacci V. et al. Journal of Medical Devices,13.1(2019):011008.

Methods

The model of the UVA/Padova simulator has been modified to describe ip insulin administration. A Run-to-Run approach is used to adapt the Basal-Bolus Therapy (BBT) of the 100 in silico patients to the new ip site. A new version of the MPC controller [C] is synthesised using the new simulator and the optimized BBT.

[C] Soru P. et al. Annual Reviews in Control,36.1(2012):118-128.

Results

The intraperitoneal controller tested on a 2 days scenario maintains the glucose inside the target range for 93.5% of the time with no time spent below 70 mg/dl and 6.5% above 180 mg/dl. The MPC is able to keep the glycaemia inside the target range during all night.

Conclusions

The ip MPC results are much better than those obtained with the sc MPC. Future development of MPC involves the design of ad hoc constraints and safety. This new MPC in conjunctions with a new ip insulin pump will be tested in animals.

Background and Aims

Maintaining glucose concentration (GC) in the target range in spite of physical activities and events causing acute psychological stress (PS) is challenging for artificial pancreas (AP) systems. PS and physical activities affect GC in different ways; aerobic exercise decreases GC while PS can increase it. Many stressful events and physical activities cannot be manually entered to the AP in a timely manner. Hence, they are unknown disturbances for AP systems and reduce glycemic control. In this work, wristband biosignals are utilized in a novel algorithm to estimate the psychological and physiological state of a subject, and improve the GC prediction for use in AP systems.

Methods

Biosignals from Empatica E4 wristband are collected in real-time and machine learning algorithms are utilized to determine the physical state of a subject, obtain energy expenditure estimates, and predict her/his PS levels. These estimates are incorporated in a GC prediction model along with CGM readings and insulin infusion data from pump. These BGC estimates are compared to estimates from a model that uses only CGM readings and insulin infusion data.

Results

Data from 50 experiments with thirteen different subjects with T1D who performed physical activities and various PS causing events were used and proposed method improved to mean absolute percentage error of GC prediction by 6.5%.

Conclusions

Wristband biosignals used to determine the psychological and physiological state of people with T1D provide valuable information to improve GC estimates and the performance of an AP system in response to unannounced physical activities and stressful events.

Background and Aims

The aim of this study is to evaluate whether T1D patients’ characteristics such as age, body weight (BW), Sex, and time in physical activity (TPA) have effect on the performance of the Diabeloop Artificial Pancreas (AP) based on data from clinical trial (NCT02987556).

Methods

Linear correlation was computed between age, BW, and TPA (1) vs time in range (TIR (2)), and time in hypoglycemia (TIHYPO (3)), to demonstrate that there is not a linear dependency between performance and age, BW, and TPA. To demonstrate that patient's sex has no effect on performance of the Diabeloop AP the Kruskal-Wallis H-test was computed to evaluate statistical difference.

The dataset is composed of 24 women and 39 men wearing the Diabeloop AP during 3 months. Patients’ characteristics were (mean, std): age (49.21, 13.36) years old, BW (70.11, 11.17) kg, and TPA (1.38, 1.68) %.

Results

There is no linear correlation between TIR and age (r = 0.01), BW (r = 0.25), and TPA (r = 0.02) neither between TIHYPO and age (r = 0.09), BW (r = 0.15), and TPA (r = 0.01). We observe that there is no significant difference between the performance reached by the Diabeloop AP for women and men (p value of 0.38 and 0.6 for TIR and TIHYPO respectively).

Conclusions

The Diabeloop AP allowed to correctly perform on a variety of T1D patients despite their age, BW, TPA and sex, showing that the Diabeloop’s algorithm is not biased by these factors.

Background and Aims

Clinical trials in free-living conditions is key in the development of an Artificial Pancreas (AP) for T1D subjects. Since the scenario plays a key role in the synthesis and validation of AP control algorithms, a probabilistic approach is proposed to automatically design meal scenarios. In particular, we exploit our real-life data to design realistic in silico scenarios.

Methods

The amount and time-of-day of ingested carbohydrates in a 1-month in 13 patients for a total of 1500 meals. have been considered. The joint distribution of these variables has been estimated via a copula function, in order to model their dependence. The use of a copula allows to generate Monte Carlo scenarios by drawing random samples, which represent a pair of amount and time-of-day.

Results

A Gaussian copula resulted suitable for the description of the dependence in the meal dataset with a p-value of 0.005 according to the χ² test based on Rosenblatt’s transformation. A bootstrap version of the test shows that the estimate of the Spearman correlation coefficient (ρ) is sufficiently accurate with respect to the correlation (ρ) directly computed from the data (ρ=0.13, ρ=0.12).

Conclusions

The availability of a copula statistical model able to represent the food habits of a T1D population allows to design realistic eating patterns to run in silico simulations under free-living conditions.

Background and Aims

Glucagon has received renewed interest, particularly in the development of a dual hormone artificial pancreas (AP). Slow subcutaneous (SC) dynamics motivates for exploration of the intraperitoneal (IP) space both for glucose sensing and hormone delivery. We previously investigated IP glucagon delivery in rats [1]. Now we compared glucose dynamics after IP and SC glucagon delivery in a swine model.

Methods

Ten anaesthetized, non-diabetic, somatostatin-analogue treated pigs (35–50 kg) were, in random order, given glucagon boluses of 0.6 µg/kg IP, 0.3 µg/kg IP, and 0.6 µg/kg SC. At last, 1 mg IP glucagon was given to test maximum glucose response.

Results

Only 17 of 28 IP boluses and nine of 10 SC boluses had a glucose increasing effect. We believe this is due to prolonged fasting causing depletion of hepatic glycogen. Hence, we excluded four pigs from further analysis. The mean maximum effect on glucose for the remaining six pigs was 2.4, 2.2 and 1.6 mmol/L for 0.6 µg/kg IP, 0.3 µg/kg IP and 0.6 µg/kg SC glucagon, respectively.

Glucose increase after 14 to 30 minutes was significantly larger for the 0.6 µg/kg IP bolus compared to the equally sized SC bolus. In some pigs, a marked “first-pass-effect” is observed after IP glucagon.

Conclusions

Results indicates that adequate glucose responses by IP glucagon is achieved by smaller doses, potentially avoiding side effects of glucagon treatment by resembling physiologic glucagon secretion and distribution [2].

Further data on glucagon levels in blood following the different boluses will be presented.

References:

Background and Aims

To regulate blood glucose of a diabetic patient; artificial pancreas is used to externally infuse insulin in the patient body. This work presents the design and analysis of the nonlinear controller that enables the automatic regulation of blood glucose level in type-1 diabetic patients.

Methods

We have proposed a Lyapunov based nonlinear Backstepping controller. In Berman’s Minimal Model, the meal disturbance phenomenon is considered as fixed value. One of the enhancements that we have introduced is the annexure of the variable meal disturbance as a dynamic state to the existing BMM. The asymptotic stability of the system is proven via mathematical analysis using Lyapunov theory.

Results

To demonstrate the performance of the proposed controller, simulations are carried out through MATLAB/Simulink and results of the proposed controller has been compared with PID controller.

Conclusions

The propsed nonlinear controller enables the automatic regulation of blood glucose level far better than PID controller.