Feasibility of a Portable Bihormonal Closed-Loop System to Control Glucose Excursions at Home Under Free-Living Conditions for 48 Hours

Bon, Arianne C. van; Luijf, Yoeri M.; Koebrugge, Rob; Koops, Robin; Hoekstra, J. B. L.; DeVries, J. Hans

doi:10.1089/dia.2013.0166

Cited by 73 publications

(66 citation statements)

References 15 publications

(18 reference statements)

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“…A 48-hour home study using a portable bi-hormonal closed loop system, combining the delivery of insulin with subcutaneous glucagon did not show any improvement in time spent within target range. Reduction of median glucose on the second day of closed loop period was shown, but at the expense of greater time spent in the hypoglycaemic range 30 . An interim analysis of overnight closed loop over four nights at home demonstrated improvements in hypoglycaemia endpoints, without improvement in the percentage of nights with normal mean glucose levels 31 .…”

Section: Figurementioning

confidence: 94%

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study

Thabit¹,

Lubina-Solomon²,

Stadler³

et al. 2014

The Lancet Diabetes & Endocrinology

145

105

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Summary Background We assessed whether overnight home use of automated closed loop insulin delivery (artificial pancreas) improves glucose control. Methods We studied 24 adults with type 1 diabetes in a multicentre crossover study design comparing four weeks of overnight closed loop using a model predictive control algorithm to direct insulin delivery, with four weeks of insulin pump therapy in which participants used real-time display of continuous glucose monitoring independent of their pumps as control. Primary outcome was time when glucose was in the target range of 3·9 and 8·0mmol/l between midnight to 07:00. Analyses were by intention to treat. Trial registration ClinicalTrials.gov NCT01440140. Findings Closed loop was utilised over median 8·3 (interquartile range 6·0, 9·6)hours on 555nights (86%). Proportion of time when overnight glucose was in target range was significantly higher during closed loop compared to control by 13·5% (95% CI, 7·3–19·7; p<0·001). Mean overnight glucose (8·2±0·9 vs. 9·0±1·3mmol/l; p=0·005) and time spent above target (44·3%±11·9 vs. 57·1%±15·6; p=0·001) were significantly lower during closed loop. Time spent below target was low and comparable [1·8%(0·6, 3·6) vs. 2·1%(0·7, 3·9); p=0·28]. Lower mean overnight glucose was brought about by increased overnight insulin delivery [6·4 (4·5, 8·1) vs. 4·9 (3·7, 6·3)units; p<0·001) without changing the total daily insulin amount [34·5 (29·3, 48·4) vs. 35·4 (29·7, 45·2)units; p=0·32]. No severe hypoglycaemia episodes occurred during control period and two during closed loop not related to algorithm instructions. Interpretation Unsupervised overnight closed loop at home is feasible and may improve glucose control in adults with type 1 diabetes.

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Section: Figurementioning

confidence: 94%

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study

Thabit¹,

Lubina-Solomon²,

Stadler³

et al. 2014

The Lancet Diabetes & Endocrinology

145

105

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“…While some investigators use insulin-only systems, [1][2][3][4][5] others have reported that, in addition to insulin, the automated delivery of glucagon when glucose is declining and approaching hypoglycemic levels reduces the frequency and duration of hypoglycemia. [6][7][8][9][10] However, glucagon is an unstable peptide and forms amyloid fibrils when aged in acidic aqueous solutions. [11][12][13][14] These fibrils, which can form gels, have been reported to be cytotoxic 13,15 and could occlude pump delivery catheters.…”

mentioning

confidence: 99%

A Novel, Stable, Aqueous Glucagon Formulation Using Ferulic Acid as an Excipient

Bakhtiani

Caputo

Castle

et al. 2014

J Diabetes Sci Technol

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Background: Commercial glucagon is unstable due to aggregation and degradation. In closed-loop studies, it must be reconstituted frequently. For use in a portable pump for 3 days, a more stable preparation is required. At alkaline pH, curcumin inhibited glucagon aggregation. However, curcumin is not sufficiently stable for long-term use. Here, we evaluated ferulic acid, a stable breakdown product of curcumin, for its ability to stabilize glucagon.Methods: Ferulic acid-formulated glucagon (FAFG), composed of ferulic acid, glucagon, L-methionine, polysorbate-80, and human serum albumin in glycine buffer at pH 9, was aged for 7 days at 37°C. Glucagon aggregation was assessed by transmission electron microscopy (TEM) and degradation by high-performance liquid chromatography (HPLC). A cell-based protein kinase A (PKA) assay was used to assess in vitro bioactivity. Pharmacodynamics (PD) of unaged FAFG, 7-day aged FAFG, and unaged synthetic glucagon was determined in octreotide-treated swine. Results:No fibrils were observed in TEM images of fresh or aged FAFG. Aged FAFG was 94% intact based on HPLC analysis and there was no loss of bioactivity. In the PD swine analysis, the rise over baseline of glucose with unaged FAFG, aged FAFG, and synthetic native glucagon (unmodified human sequence) was similar.Conclusions: After 7 days of aging at 37°C, an alkaline ferulic acid formulation of glucagon exhibited significantly less aggregation and degradation than that seen with native glucagon and was bioactive in vitro and in vivo. Thus, this formulation may be stable for 3-7 days in a portable pump for bihormonal closed-loop treatment of T1D.

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“…The MPC controller was tested with the same protocol in 5 patients in one center [87] and in a larger randomized study involving 4 centers and 20 subjects [88], showing significant reduction in the number of hypoglycemic episodes and on the rescue carbohydrate treatment assumed for hypoglycemia treatment with respect to CSII therapy, at the expense of slightly but statistically significant higher average blood glucose (152.1 vs. 161.13 mg/dl, p = 0.042) Finally, van Bon et al [89] reported a nonrandomized feasibility study of a portable bihormonal AP in home settings under free-living conditions for 48 h in 16 patients. Of the 11 patients analyzed, significantly lower median glucose levels were found on day 2 in the closed-loop mode with respect to the open-loop mode, at the expense of more time in hypoglycemia.…”

Section: Resultsmentioning

confidence: 93%

Artificial Pancreas: A Review of Fundamentals and Inpatient and Outpatient Studies

Favero¹,

Bruttomesso²,

Cobelli³

2014

Frontiers in Diabetes

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The artificial pancreas (AP) is a device for automated modulation of insulin infusion that aims to maintain blood glucose in a nearly normal range. The core of the AP is the control algorithm, which is in charge of computing an effective insulin dose on the basis of continuous glucose monitoring readings. In the last 6 years, AP prototypes based on subcutaneous glucose sensing and subcutaneous insulin delivery have been extensively studied in clinical trials first on hospitalized patients and, more recently, in an outpatient setting. In this chapter we review the state of the art of the field, starting with a description of the various AP system components. In particular, we focus on the control techniques employed in the AP and on the principles on which they are based. We then move to AP testing: the preclinical stage (mostly done in silico), the inpatient clinical studies, and finally the outpatient studies. We also discuss the technological requirements for an ambulatory AP. © 2015 S. Karger AG, BaselAlthough type 1 diabetes is associated with increased morbidity and decreased life expectancy, strong evidence indicates that good metabolic control decreases diabetes complications [1-3]. Tight glucose control, however, increases the risk of hypoglycemia. To make diabetes control easier, new insulin analogues have been developed and infusion devices have been improved. Glucose monitoring has improved, too, with the introduction of devices for continuous glucose monitoring (CGM) which detect in real time the rate and direction of glucose changes. More recently, pumps and CGM devices have been connected to form an integrated system, the so-called 'artificial pancreas' (AP), whose scope is to ensure better glycemic control by frequently changing the insulin infusion rate on the basis of past, present, and forecasted glucose readings, as computed by a suitable control algorithm ( fig. 1).The pathway that led to the present models of AP started with the development of the first portable insulin pump by Kadish [4] in 1964. Prototypes of the AP with intra-

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Feasibility of a Portable Bihormonal Closed-Loop System to Control Glucose Excursions at Home Under Free-Living Conditions for 48 Hours

Cited by 73 publications

References 15 publications

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study

A Novel, Stable, Aqueous Glucagon Formulation Using Ferulic Acid as an Excipient

Artificial Pancreas: A Review of Fundamentals and Inpatient and Outpatient Studies

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