Proportional Insulin Infusion in Closed-Loop Control of Blood Glucose.
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ABSTRACT:
SUBMITTER: Grasman J
PROVIDER: S-EPMC5217952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundBlood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users.MethodsWavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16).ResultsGlycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals.ConclusionsSAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.
| S-EPMC9264430 | biostudies-literature
Project description:Current artificial pancreas systems (AP) operate via subcutaneous (SC) glucose sensing and SC insulin delivery. Due to slow diffusion and transport dynamics across the interstitial space, even the most sophisticated control algorithms in on-body AP systems cannot react fast enough to maintain tight glycemic control under the effect of exogenous glucose disturbances caused by ingesting meals or performing physical activity. Recent efforts made towards the development of an implantable AP have explored the utility of insulin infusion in the intraperitoneal (IP) space: a region within the abdominal cavity where the insulin-glucose kinetics are observed to be much more rapid than the SC space. In this paper, a series of canine experiments are used to determine the dynamic association between IP insulin boluses and plasma glucose levels. Data from these experiments are employed to construct a new mathematical model and to formulate a closed-loop control strategy to be deployed on an implantable AP. The potential of the proposed controller is demonstrated via in-silico experiments on an FDA-accepted benchmark cohort: the proposed design significantly outperforms a previous controller designed using artificial data (time in clinically acceptable glucose range: 97.3±1.5% vs. 90.1±5.6%). Furthermore, the robustness of the proposed closed-loop system to delays and noise in the measurement signal (for example, when glucose is sensed subcutaneously) and deleterious glycemic changes (such as sudden glucose decline due to physical activity) is investigated. The proposed model based on experimental canine data leads to the generation of more effective control algorithms and is a promising step towards fully automated and implantable artificial pancreas systems.
| S-EPMC6548466 | biostudies-literature
Project description:AimTo compare bolus insulin delivery patterns during closed-loop home studies in adults with suboptimally [HbA1c 58-86 mmol/mol (7.5%-10%)] and well-controlled [58 mmol/mol (< 7.5%)] Type 1 diabetes.MethodsRetrospective analysis of daytime and night-time insulin delivery during home use of closed-loop over 4 weeks. Daytime and night-time controller effort, defined as amount of insulin delivered by closed-loop relative to usual basal insulin delivery, and daytime bolus effort, defined as total bolus insulin delivery relative to total daytime insulin delivery were compared between both cohorts. Correlation analysis was performed between individual bolus behaviour (bolus effort and frequency) and daytime controller efforts, and proportion of time spent within and below sensor glucose target range.ResultsIndividuals with suboptimally controlled Type 1 diabetes had significantly lower bolus effort (P = 0.038) and daily bolus frequency (P < 0.001) compared with those with well-controlled diabetes. Controller effort during both daytime (P = 0.007) and night-time (P = 0.005) were significantly higher for those with suboptimally controlled Type 1 diabetes. Time when glucose was within the target range (3.9-10.0 mmol/L) during daytime correlated positively with bolus effort (r = 0.37, P = 0.016) and bolus frequency (r = 0.33, P = 0.037). Time when glucose was below the target range during daytime was comparable in both groups (P = 0.36), and did not correlate significantly with bolus effort (r = 0.28, P = 0.066) or bolus frequency (r = -0.21, P = 0.19).ConclusionMore frequent bolusing and higher proportion of insulin delivered as bolus during hybrid closed-loop use correlated positively with time glucose was in target range. This emphasises the need for user input and educational support to benefit from this novel therapeutic modality.
| S-EPMC5788742 | biostudies-literature
Project description:Advances in diabetes technologies have enabled the development of automated closed-loop insulin delivery systems. Several hybrid closed-loop systems have been commercialised, reflecting rapid transition of this evolving technology from research into clinical practice, where it is gradually transforming the management of type 1 diabetes in children and adults. In this review we consider the supporting evidence in terms of glucose control and quality of life for presently available closed-loop systems and those in development, including dual-hormone closed-loop systems. We also comment on alternative 'do-it-yourself' closed-loop systems. We remark on issues associated with clinical adoption of these approaches, including training provision, and consider limitations of presently available closed-loop systems and areas for future enhancements to further improve outcomes and reduce the burden of diabetes management.
| S-EPMC8012332 | biostudies-literature
Project description:BackgroundIn outpatient studies of closed-loop insulin delivery systems, it is not typically practical to obtain blood glucose measurements for an outcome measure. Using a continuous glucose monitoring (CGM) device as both part of the intervention and as the outcome in a clinical trial can give a biased estimate of the treatment effect. A stochastic adjustment has been proposed to correct this problem.Materials and methodsWe performed Monte Carlo simulations to assess the performance of the stochastic adjustment in various scenarios where the CGM device was used passively and when it was used to inform insulin delivery. The resulting bias for using CGM to estimate the percentage of glucose values inside a target range was compared with and without the proposed stochastic adjustment.ResultsCGM bias for estimating the percentage of glucose values 70-180 mg/dL ranged from -6% to +4% in the various scenarios studied. In some circumstances, stochastic adjustment did indeed reduce this CGM bias. However, in other circumstances, stochastic adjustment made the bias worse. Stochastic adjustment tended to underestimate the true percentage of glucose values in range for most, but not all, scenarios considered in these simulations.ConclusionsStochastic adjustment is not a general solution to the problem of CGM bias. The proposed adjustment relies on an implicit assumption that usually does not hold. The appropriate level of adjustment depends on how efficacious the closed-loop system is, which is not typically known in practice.
| S-EPMC3934513 | biostudies-literature
Project description:Objective: To assess the efficacy and safety of closed-loop control (CLC) insulin delivery system in adolescents and young adults with type 1 diabetes. Research Design and Methods: Prespecified subanalysis of outcomes in adolescents and young adults aged 14-24 years old with type 1 diabetes in a previously published 6-month multicenter randomized trial. Participants were randomly assigned 2:1 to CLC (Tandem Control-IQ) or sensor augmented pump (SAP, various pumps+Dexcom G6 CGM) and followed for 6 months. Results: Mean age of the 63 participants was 17 years, median type 1 diabetes duration was 7 years, and mean baseline HbA1c was 8.1%. All 63 completed the trial. Time in range (TIR) increased by 13% with CLC versus decreasing by 1% with SAP (adjusted treatment group difference = +13% [+3.1 h/day]; 95% confidence interval [CI] 9-16, P < 0.001), which largely reflected a reduction in time >180 mg/dL (adjusted difference -12% [-2.9 h/day], P < 0.001). Time <70 mg/dL decreased by 1.6% with CLC versus 0.3% with SAP (adjusted difference -0.7% [-10 min/day], 95% CI -1.0% to -0.2%, P = 0.002). CLC use averaged 89% of the time for 6 months. The mean adjusted difference in HbA1c after 6 months was 0.30% in CLC versus SAP (95% CI -0.67 to +0.08, P = 0.13). There was one diabetic ketoacidosis episode in the CLC group. Conclusions: CLC use for 6 months was substantial and associated with improved TIR and reduced hypoglycemia in adolescents and young adults with type 1 diabetes. Thus, CLC has the potential to improve glycemic outcomes in this challenging age group. The clinical trial was registered with ClinicalTrials.gov (NCT03563313).
| S-EPMC8080922 | biostudies-literature
Project description:Aims/hypothesisThe aim of this work was to assess the relationship between meal nutrients and postprandial blood glucose response (PGR) in individuals with type 1 diabetes on a hybrid closed-loop system (HCLS).MethodsThe dietary composition of 1264 meals (398 breakfasts, 441 lunches and 425 dinners) was assessed by 7-day food records completed by 25 individuals with type 1 diabetes on HCLSs (12 men/13 women, mean ± SD age 40 ± 12 years, mean ± SD HbA1c 51 ± 10 mmol/mol [6.9 ± 0.2%]). For each meal, PGR (continuous glucose monitoring metrics, glucose incremental AUCs) and insulin doses (pre-meal boluses, post-meal microboluses automatically delivered by the pump and adjustment boluses) over 6 h were evaluated.ResultsBreakfast, lunch and dinner significantly differed with respect to energy and nutrient intake and insulin doses. The blood glucose postprandial profile showed an earlier peak after breakfast and a slow increase until 4 h after lunch and dinner (p < 0.001). Mean ± SD postprandial time in range (TIR) was better at breakfast (79.3 ± 22.2%) than at lunch (71.3 ± 23.9%) or dinner (70.0 ± 25.9%) (p < 0.001). Significant negative predictors of TIR at breakfast were total energy intake, per cent intake of total protein and monounsaturated fatty acids, glycaemic load and absolute amounts of cholesterol, carbohydrates and simple sugars consumed (p < 0.05 for all). No significant predictors were detected for TIR at lunch. For TIR at dinner, a significant positive predictor was the per cent intake of plant proteins, while negative predictors were glycaemic load and intake amounts of simple sugars and carbohydrate (p < 0.05 for all).Conclusions/interpretationThis study shows that nutritional factors other than the amount of carbohydrate significantly influence postprandial blood glucose control. These nutritional determinants vary between breakfast, lunch and dinner, with differing effects on postprandial blood glucose profile and insulin requirements, thus remaining a challenge to HCLSs.
| S-EPMC8660714 | biostudies-literature
Project description:Since the discovery of insulin 100 years ago, we have seen considerable advances across diabetes therapies. The more recent advent of glucose-responsive automated insulin delivery has started to revolutionise the management of type 1 diabetes in children and adults. Evolution of closed-loop insulin delivery from research to clinical practice has been rapid, and multiple systems are now commercially available. In this review, we summarise key evidence on currently available closed-loop systems and those in development. We comment on dual-hormone and do-it-yourself systems, as well as reviewing clinical evidence in special populations such as very young children, older adults and in pregnancy. We identify future directions for research and barriers to closed-loop adoption, including how these might be addressed to ensure equitable access to this novel therapy.
| S-EPMC8792215 | biostudies-literature
Project description:Homeostasis of metabolism by hormone production is crucial for maintaining physiological integrity, as disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibody-deficient mice and immunodeficiency patients have subphysiological blood glucose concentrations. Restoring blood glucose physiology required total IgG injections and insulin-specific IgG antibodies detected in total IgG preparations and in the serum of healthy individuals. In addition to the insulin-neutralizing anti-insulin IgG, we identified two fractions of anti-insulin IgM in the serum of healthy individuals. These autoreactive IgM fractions differ in their affinity to insulin. Interestingly, the low-affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose, whereas the high-affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG, thereby preventing blood glucose dysregulation. To demonstrate that anti-insulin IgMhigh acts as a protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of a high-affinity anti-insulin antibody as IgG and IgM. Remarkably, the recombinant anti-insulin IgMhigh normalized insulin function and prevented IgG-mediated insulin neutralization. These results suggest that autoreactive antibodies recognizing insulin are key regulators of blood glucose and metabolism, as they control the concentration of insulin in the blood. Moreover, our data suggest that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms generating high-affinity autoreactive IgM antibodies during memory responses.
| S-EPMC8833180 | biostudies-literature
Project description:Objective: Evaluating the feasibility of closed-loop insulin delivery with a zone model predictive control (zone-MPC) algorithm designed for pregnancy complicated by type 1 diabetes (T1D). Research Design and Methods: Pregnant women with T1D from 14 to 32 weeks gestation already using continuous glucose monitor (CGM) augmented pump therapy were enrolled in a 2-day multicenter supervised outpatient study evaluating pregnancy-specific zone-MPC based closed-loop control (CLC) with the interoperable artificial pancreas system (iAPS) running on an unlocked smartphone. Meals and activities were unrestricted. The primary outcome was the CGM percentage of time between 63 and 140 mg/dL compared with participants' 1-week run-in period. Early (2-h) postprandial glucose control was also evaluated. Results: Eleven participants completed the study (age: 30.6 ± 4.1 years; gestational age: 20.7 ± 3.5 weeks; weight: 76.5 ± 15.3 kg; hemoglobin A1c: 5.6% ± 0.5% at enrollment). No serious adverse events occurred. Compared with the 1-week run-in, there was an increased percentage of time in 63-140 mg/dL during supervised CLC (CLC: 81.5%, run-in: 64%, P = 0.007) with less time >140 mg/dL (CLC: 16.5%, run-in: 30.8%, P = 0.029) and time <63 mg/dL (CLC: 2.0%, run-in:5.2%, P = 0.039). There was also less time <54 mg/dL (CLC: 0.7%, run-in:1.6%, P = 0.030) and >180 mg/dL (CLC: 4.9%, run-in: 13.1%, P = 0.032). Overnight glucose control was comparable, except for less time >250 mg/dL (CLC: 0%, run-in:3.9%, P = 0.030) and lower glucose standard deviation (CLC: 23.8 mg/dL, run-in:42.8 mg/dL, P = 0.007) during CLC. Conclusion: In this pilot study, use of the pregnancy-specific zone-MPC was feasible in pregnant women with T1D. Although the duration of our study was short and the number of participants was small, our findings add to the limited data available on the use of CLC systems during pregnancy (NCT04492566).
| S-EPMC9464083 | biostudies-literature