Single-hormone Artificial Pancreas Research Articles

Single-Hormone Artificial Pancreas Use in Diabetes: Clinical Efficacy and Remaining Challenges.

IN BRIEF Artificial pancreas systems are rapidly developing and constitute the most promising technology for insulin-requiring diabetes management. Single-hormone systems (SH-AP) that deliver only insulin and have a hybrid design that necessitates patients' interventions around meals and exercise are the first to appear on the market. Trials with SH-AP have demonstrated improvement in time spent with blood glucose levels within target ranges, with a concomitant decrease in hypoglycemia. Longer and larger trials involving different patient populations are ongoing to further advance this important technology.

An artificial pancreas based on simple control algorithms and physiological insight

Abstract We present a simple control algorithm for a single-hormone artificial pancreas (AP). The AP consists of a continuous glucose monitor (CGM) measuring the interstitial glucose concentration, a control algorithm computing the insulin to administer, and an insulin pump dosing the insulin. The control algorithm is based on insights into the underlying dynamics of the glucose-insulin dynamics in people with type 1 diabetes. The main components in this control system are 1) an insulin bolus calculator to compensate for carbohydrates in meals, 2) a run-to-run algorithm for adjusting the basal insulin to long-term metabolic variations, and 3) a micro-bolus correction of the basal insulin to compensate for short-term variations in the endogenous insulin production and insulin sensitivity.

Overnight Glucose Control with Dual- and Single-Hormone Artificial Pancreas in Type 1 Diabetes with Hypoglycemia Unawareness: A Randomized Controlled Trial.

The dual-hormone (insulin and glucagon) artificial pancreas may be justifiable in some, but not all, patients. We sought to compare dual- and single-hormone artificial pancreas systems in patients with hypoglycemia unawareness and documented nocturnal hypoglycemia. We conducted a randomized crossover trial comparing the efficacy of dual- and single-hormone artificial pancreas systems in controlling plasma glucose levels over the course of one night's sleep. We recruited 18 adult participants with hypoglycemia unawareness and 17 participants with hypoglycemia awareness, all of whom had documented nocturnal hypoglycemia during 2 weeks of screening. Outcomes were calculated using plasma glucose. In participants with hypoglycemia unawareness, the median (interquartile range [IQR]) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on dual-hormone artificial pancreas nights and 0% (0-10) on single-hormone artificial pancreas nights (P = 0.20). Additionally, participants with hypoglycemia unawareness experienced two hypoglycemic events (<3.0 mmol/L) on dual-hormone artificial pancreas nights and three hypoglycemic events on single-hormone artificial pancreas nights. In participants with hypoglycemia awareness, the median (IQR) percentage of time that plasma glucose was below 4.0 mmol/L was 0% (0-0) on both dual- and single-hormone artificial pancreas nights. Hypoglycemia awareness participants experienced zero hypoglycemic events on dual-hormone artificial pancreas nights and one event on single-hormone artificial pancreas nights. In this study, dual-hormone and single-hormone systems performed equally well in preventing nocturnal hypoglycemia in participants with hypoglycemia unawareness. Longer studies over the course of multiple days and nights may be needed to explore possible specific benefits in this population. ClinicalTrials.gov No. NCT02282254.

Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials

Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9-10 mmol/L or 3·9-8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854. We identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02-16·16; p<0·0001), from a weighted mean of 58·21% for conventional pump therapy (I2=84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12-23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies (I2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors. None.

Efficacy of single-hormone and dual-hormone artificial pancreas during continuous and interval exercise in adult patients with type 1 diabetes: randomised controlled crossover trial.

The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise. An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6years; HbA1c, 8.0 ± 1.0% [63.9 ± 10.2mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60min) and interval (2min alternating periods at 85% and 50% [Formula: see text] for 40min, with two 10min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30hours until 19:30hours; exercise was started at 18:00hours and announced 20min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal. During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057mg) than during interval exercise (0.093 ± 0.068mg) (p = 0.03), with no reported side-effects in all interventions. The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes. ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.

Overnight Glucose Control with Dual- and Single-Hormone Artificial Pancreas in Type 1 Diabetes with Hypoglycemia Unawareness vs. Hypoglycemia Awareness: Randomized Controlled Trial

Recurrent hypoglycemic events can lead to hypoglycemia unawareness (HU), defined as the failure to sense a significant fall in blood glucose below normal levels. Patients with HU are a sub-population that might benefit the most from the artificial pancreas (AP) technology. In addition, the use of glucagon in the AP might be more useful in this subgroup than in patients without HU. The efficacy of single-hormone AP (SAP) and dual-hormone AP (DAP) has not been assessed in patients with HU, a sub-population at high risk of hypoglycemia. We conducted a randomized crossover trial comparing SAP and DAP over 1 night in 17 adult patients with HU and 14 patients without HU. All patients had documented nocturnal hypoglycemia during 2 weeks of screening. Analysis was performed using plasma glucose. In patients with HU, the time spent below 4 mmol/L was 0% (0 to 10) on SAP nights and 0% (0 to 0) on DAP nights (P=0.28). In patients without HU, the time spent below 4 mmol/L was 0% (0 to 0) on SAP nights and 0% (0 to 0) on DAP nights (P=0.78). In patients with HU, there were 4 hypoglycemic events (<3 mmol/L) on SAP nights and 3 events on DAP nights. In patients without HU, there was 1 event on SAP nights and none on DAP nights. None of the outcomes differed between the 2 patient groups. We conclude that the SAP might be sufficient for hypoglycemia-free overnight control in patients with HU. Day and night studies in this population are needed.

Single- and Dual-Hormone Artificial Pancreas for Overnight Glucose Control in Type 1 Diabetes.

The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. The objective of the study was to compare the efficacy of dual-hormone (insulin and glucagon) artificial pancreas, single-hormone (insulin alone) artificial pancreas, and conventional insulin pump therapy. This study was a three-center, three-arm, open-label, randomized, crossover controlled trial involving three interventions, each applied over a night after a high carbohydrate/high fat meal and a second after exercise to mimic real-life glycemic excursions. The study was conducted in a home setting. Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. The main outcome was a proportion of time in target (4-8 mmol/L) by continuous glucose monitoring from 11:00 PM to 7:00 AM. Analysis was by intention to treat. The median (interquartile range) percentage of time-in-target glucose range was 47% (36%-71%) for conventional therapy, higher on both single-hormone (76% [65%-91%], P < .001) and dual-hormone artificial pancreas (81 [68%-93%], P < .001). The median (interquartile range) time spent below 4 mmol/L was 14% (4%-28%) for conventional therapy, lower on both single-hormone (5% [0%-13%], P = .004) and dual-hormone artificial pancreas (1% [0%-8%], P < .001). There were 14 hypoglycemic events on conventional therapy compared with six incidences on the single-hormone artificial pancreas (P = .059) and three incidences on the dual-hormone artificial pancreas (P = .017). None of these outcomes differed significantly between single- and dual-hormone configurations. Single- and dual-hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out.

Outpatient overnight glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or conventional insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, randomised controlled trial

Additional benefits of the dual-hormone (insulin and glucagon) artificial pancreas compared with the single-hormone (insulin alone) artificial pancreas have not been assessed in young people in outpatient unrestricted conditions. We evaluated the efficacy of three systems for nocturnal glucose control in children and adolescents with type 1 diabetes. We did a randomised, three-way, crossover trial in children aged 9-17 years with type 1 diabetes attending a diabetes camp in Canada. With use of sealed envelopes, children were randomly assigned in a 1:1:1:1:1:1 ratio with blocks of six to different sequences of the three interventions (single-hormone artificial pancreas, dual-hormone artificial pancreas, and conventional continuous subcutaneous insulin pump therapy). Each intervention was applied for 3 consecutive nights. Participants, study staff, and endpoint assessors were not masked. The primary outcome was the percentage of time spent with glucose concentrations lower than 4·0 mmol/L from 2300 h to 0700 h. Analysis was by intention to treat. A p value of less than 0·0167 was regarded as significant. This study is registered with ClinicalTrials.gov, number NCT02189694. Between June 30, 2014, and Aug 9, 2014, we enrolled 33 children of mean age 13·3 years (SD 2·3; range 9-17). The time spent at a glucose concentration lower than 4·0 mmol/L was median 0% (IQR 0·0-2·4) during nights with the dual-hormone artificial pancreas, 3·1% (0·0-6·9) during nights with the single-hormone artificial pancreas (p=0·032), and 3·4% (0-11·0) during nights with conventional pump therapy (p=0·0048 compared with dual-hormone artificial pancreas and p=0·32 compared with single-hormone artificial pancreas). 15 hypoglycaemic events (<3·1 mmol/L for 20 min measured by sensor then confirmed with capillary glucose <4·0 mmol/L) were noted during nights with conventional pump therapy compared with four events with the single-hormone system and no events with the dual-hormone system. None of the assessed outcomes varied with the order in which children and young adults were assigned interventions. The dual-hormone artificial pancreas could improve nocturnal glucose control in children and adolescents with type 1 diabetes. Longer and larger outpatient studies are now needed. Canadian Diabetes Association, Fondation J A De Sève.

A Randomized Crossover Study to Assess Overnight Glucose Control with Single-Hormone and Dual-Hormone Artificial Pancreas Systems in Children with Type 1 Diabetes in a Diabetes Camp

A Randomized Crossover Study to Assess Overnight Glucose Control with Single-Hormone and Dual-Hormone Artificial Pancreas Systems in Children with Type 1 Diabetes in a Diabetes Camp

Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial

The artificial pancreas is an emerging technology for the treatment of type 1 diabetes and two configurations have been proposed: single-hormone (insulin alone) and dual-hormone (insulin and glucagon). We aimed to delineate the usefulness of glucagon in the artificial pancreas system. We did a randomised crossover trial of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy (continuous subcutaneous insulin infusion) in participants aged 12 years or older with type 1 diabetes. Participants were assigned in a 1:1:1:1:1:1 ratio with blocked randomisation to the three interventions and attended a research facility for three 24-h study visits. During visits when the patient used the single-hormone artificial pancreas, insulin was delivered based on glucose sensor readings and a predictive dosing algorithm. During dual-hormone artificial pancreas visits, glucagon was also delivered during low or falling glucose. During conventional insulin pump therapy visits, patients received continuous subcutaneous insulin infusion. The study was not masked. The primary outcome was the time for which plasma glucose concentrations were in the target range (4·0-10·0 mmol/L for 2 h postprandially and 4·0-8·0 mmol/L otherwise). Hypoglycaemic events were defined as plasma glucose concentration of less than 3·3 mmol/L with symptoms or less than 3·0 mmol/L irrespective of symptoms. Analysis was by modified intention to treat, in which we included data for all patients who completed at least two visits. A p value of less than 0·0167 (0·05/3) was regarded as significant. This trial is registered with ClinicalTrials.gov, number NCT01754337. The mean proportion of time spent in the plasma glucose target range over 24 h was 62% (SD 18), 63% (18), and 51% (19) with single-hormone artificial pancreas, dual-hormone artificial pancreas, and conventional insulin pump therapy, respectively. The mean difference in time spent in the target range between single-hormone artificial pancreas and conventional insulin pump therapy was 11% (17; p=0·002) and between dual-hormone artificial pancreas and conventional insulin pump therapy was 12% (21; p=0·00011). There was no difference (15; p=0·75) in the proportion of time spent in the target range between the single-hormone and dual-hormone artificial pancreas systems. There were 52 hypoglycaemic events with conventional insulin pump therapy (12 of which were symptomatic), 13 with the single-hormone artificial pancreas (five of which were symptomatic), and nine with the dual-hormone artificial pancreas (0 of which were symptomatic); the number of nocturnal hypoglycaemic events was 13 (0 symptomatic), 0, and 0, respectively. Single-hormone and dual-hormone artificial pancreas systems both provided better glycaemic control than did conventional insulin pump therapy. The single-hormone artificial pancreas might be sufficient for hypoglycaemia-free overnight glycaemic control. Canadian Diabetes Association; Fondation J A De Sève; Juvenile Diabetes Research Foundation; and Medtronic.

Understanding the Benefits of Glucagon in the Artificial Pancreas: Randomized Crossover Trial

We conducted a randomized crossover comparison between dual-hormone (insulin and glucagon) artificial pancreas (DAP), single-hormone (insulin) artificial pancreas (SAP) and pump therapy (CSII) in 24 patients with type 1 diabetes (adults/pediatrics 18/6, A1c 7.6±0.7%). Patients were studied 3 times in a research facility for 24 hours and ingested meals at 8 AM, 12 PM and 5 PM, conducted activities at 9 AM and 1 PM, exercised at 7:30 PM for 60 min, ingested a snack at 9 PM and stayed in the facility overnight. Over the 24 hours, both SAP and DAP increased the percentage of time spent in target range compared to CSII in a similar fashion (SAP 62%, DAP 64%, CSII 48%; P=NS for DAP vs. SAP; P<0.01 otherwise). SAP decreased the time spent below 4 mmol/L compared to CSII by 5-fold from 16.2% to 3.1% (P<0.001) while DAP reduced it by 20-fold to 0.8% (P<0.001 vs. CSII; P=0.02 vs. SAP). Overnight (11 PM to 8 AM), both SAP and DAP achieved hypoglycemia-free control compared to CSII (time below 4 mmol/L; DAP 0%, SAP 0%, CSII 5%; P=NS for DAP vs. SAP; P<0.05 otherwise). Eight participants (34%) had at least 1 nocturnal hypoglycemic event (<3.0 mmol/L) during CSII visits compared to 0 (0%) on SAP and DAP (P<0.05). We conclude that 1) SAP and DAP are both superior to CSII; 2) DAP provides additional reduction in hypoglycemia compared to SAP and 3) SAP might be sufficient for hypoglycemia-free overnight control. Tabled 1Comparisons between DAP, SAP and CSII (median [IQR] for hypoglycemia endpoints; mean ± SD otherwise) Time plasma glucose is (%) CSII P valueCSII vs. SAP SAP P valueSAP vs. DAP DAP P valueDAP vs. CSII in target‡ 48±17 0.002 62±20 0.9 64±18 0.009 overnight target‡ 42±32 0.004 68±27 0.6 69±31 0.016 <4.0 mmol/L 16 (3.5–21) <0.001 3.1 (0.4–8.0) 0.02 0.8 (0.0–3.0) <0.001 overnight <4.0 mmol/L 4.7 (0–22) 0.014 0.0 (0.0–2.5) 0.27 0.0 (0.0–0.0) 0.005 above target‡ 41±25 0.7 37±21 0.5 40±18 0.8 Above target overnight‡ 44±41 0.14 28±28 0.36 30±30 0.2 ‡Target range 4–10 mmol/L for 2 hours post-prandially and 4–8 mmol/L otherwise Endpoints calculated using plasma glucose Open table in a new tab ‡Target range 4–10 mmol/L for 2 hours post-prandially and 4–8 mmol/L otherwise Endpoints calculated using plasma glucose