Health professionals' views about who would benefit from using a closed-loop system: a qualitative study.

AIM: To explore health professionals' views about who would benefit from using a closed-loop system and who should be prioritized for access to the technology in routine clinical care. METHODS: Health professionals (n = 22) delivering the Closed Loop from Onset in type 1 Diabetes (CLOuD) trial were interviewed after they had ≥ 6 months' experience supporting participants using a closed-loop system. Data were analysed thematically. RESULTS: Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the closed-loop system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefitted from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and, ideally, all individuals should be given the chance to try the technology. However, it was recognized that clinical guidelines will be needed to inform difficult decisions about treatment allocation (and withdrawal), with young children and infants being considered priority groups. CONCLUSIONS: To ensure fair and equitable access to closed-loop systems, prejudicial assumptions held by health professionals may need to be addressed. To support their decision-making, clinical guidelines need to be made available in a timely manner.

Key

Detection of nuclear-decay γ rays provides a sensitive thermometer of nova nucleosynthesis. The most intense γ-ray flux is thought to be annihilation radiation from the ß^{+} decay of ^{18}F, which is destroyed prior to decay by the ^{18}F(p,α)^{15}O reaction. Estimates of ^{18}F production had been uncertain, however, because key near-threshold levels in the compound nucleus, ^{19}Ne, had yet to be identified. We report the first measurement of the ^{19}F(^{3}He,tγ)^{19}Ne reaction, in which the placement of two long-sought 3/2^{+} levels is suggested via triton-γ-γ coincidences. The precise determination of their resonance energies reduces the upper limit of the rate by a factor of 1.5-17 at nova temperatures and reduces the average uncertainty on the nova detection probability by a factor of 2.1.

Molecular memory with downstream logic processing exemplified by switchable and self-indicating guest capture and release.

Molecular-logic based computation (MLBC) has grown by accumulating many examples of combinational logic gates and a few sequential variants. In spite of many inspirations being available in biology, there are virtually no examples of MLBC in chemistry where sequential and combinational operations are integrated. Here we report a simple alcohol-ketone redox interconversion which switches a macrocycle between a large or small cavity, with erect aromatic walls which create a deep hydrophobic space or with collapsed walls respectively. Small aromatic guests can be captured or released in an all or none manner upon chemical command. During capture, the fluorescence of the alcohol macrocycle is quenched via fluorescent photoinduced electron transfer switching, meaning that its occupancy state is self-indicated. This represents a chemically-driven RS Flip-Flop, one of whose outputs is fed into an INHIBIT gate. Processing of outputs from memory stores is seen in the injection of packaged neurotransmitters into synaptic clefts for onward neural signalling. Overall, capture-release phenomena from discrete supermolecules now have a Boolean basis.

Measurement of Transverse Wakefields Induced by a Misaligned Positron Bunch in a Hollow Channel Plasma Accelerator.

Hollow channel plasma wakefield acceleration is a proposed method to provide high acceleration gradients for electrons and positrons alike: a key to future lepton colliders. However, beams which are misaligned from the channel axis induce strong transverse wakefields, deflecting beams and reducing the collider luminosity. This undesirable consequence sets a tight constraint on the alignment accuracy of the beam propagating through the channel. Direct measurements of beam misalignment-induced transverse wakefields are therefore essential for designing mitigation strategies. We present the first quantitative measurements of transverse wakefields in a hollow plasma channel, induced by an off-axis 20 GeV positron bunch, and measured with another 20 GeV lower charge trailing positron probe bunch. The measurements are largely consistent with theory.

Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice.

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota ß-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.

Acceleration of a trailing positron bunch in a plasma wakefield accelerator.

High gradients of energy gain and high energy efficiency are necessary parameters for compact, cost-efficient and high-energy particle colliders. Plasma Wakefield Accelerators (PWFA) offer both, making them attractive candidates for next-generation colliders. In these devices, a charge-density plasma wave is excited by an ultra-relativistic bunch of charged particles (the drive bunch). The energy in the wave can be extracted by a second bunch (the trailing bunch), as this bunch propagates in the wake of the drive bunch. While a trailing electron bunch was accelerated in a plasma with more than a gigaelectronvolt of energy gain, accelerating a trailing positron bunch in a plasma is much more challenging as the plasma response can be asymmetric for positrons and electrons. We report the demonstration of the energy gain by a distinct trailing positron bunch in a plasma wakefield accelerator, spanning nonlinear to quasi-linear regimes, and unveil the beam loading process underlying the accelerator energy efficiency. A positron bunch is used to drive the plasma wake in the experiment, though the quasi-linear wake structure could as easily be formed by an electron bunch or a laser driver. The results thus mark the first acceleration of a distinct positron bunch in plasma-based particle accelerators.

High-field plasma acceleration in a high-ionization-potential gas.

Plasma accelerators driven by particle beams are a very promising future accelerator technology as they can sustain high accelerating fields over long distances with high energy efficiency. They rely on the excitation of a plasma wave in the wake of a drive beam. To generate the plasma, a neutral gas can be field-ionized by the head of the drive beam, in which case the distance of acceleration and energy gain can be strongly limited by head erosion. Here we overcome this limit and demonstrate that electrons in the tail of a drive beam can be accelerated by up to 27 GeV in a high-ionization-potential gas (argon), boosting their initial 20.35 GeV energy by 130%. Particle-in-cell simulations show that the argon plasma is sustaining very high electric fields, of ∼150 GV m(-1), over ∼20 cm. The results open new possibilities for the design of particle beam drivers and plasma sources.

Home Use of an Artificial Beta Cell in Type 1 Diabetes.

BACKGROUND: The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS: In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS: Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS: Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial.

AIMS: To evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D). METHODS: We conducted a randomized crossover study comparing closed-loop therapy with standard prandial insulin boluses versus closed-loop therapy with prandial boluses reduced by 25%. Eight adolescents with T1D [3 males; mean (standard deviation) age 15.9 (1.5) years, glycated haemoglobin 74 (17) mmol/mol; median (interquartile range) total daily dose 0.9 (0.7, 1.1) IU/kg/day] were studied on two 36-h-long visits. In random order, subjects received closed-loop therapy with either standard or reduced insulin boluses administered with main meals (50-80 g carbohydrates) but not with snacks (15-30 g carbohydrates). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd). RESULTS: The median (interquartile range) time spent in target (3.9-10 mmol/l) was similar between the two interventions [74 (66, 84)% vs 80 (65, 96)%; p = 0.87] as was time spent above 10 mmol/l [21.8 (16.3, 33.5)% vs 18.0 (4.1, 34.2)%; p = 0.87] and below 3.9 mmol/l [0 (0, 1.5)% vs 0 (0, 1.8)%; p = 0.88]. Mean plasma glucose was identical during the two interventions [8.4 (0.9) mmol/l; p = 0.98]. Hypoglycaemia occurred once 1.5 h post-meal during closed-loop therapy with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9 (55.2, 75.0) vs 72.5 (63.6, 80.3) IU; p = 0.01] and resulted in lower mean plasma insulin concentration [186 (171, 260) vs 252 (198, 336) pmol/l; p = 0.002]. Lower plasma insulin was also documented overnight [160 (136, 192) vs 191 (133, 252) pmol/l; p = 0.01, pooled nights]. Ra_total was similar [26.3 (21.9, 28.0) vs 25.4 (21.0, 29.2) µmol/kg/min; p = 0.19] during the two interventions as was Rd [25.8 (21.0, 26.9) vs 25.2 (21.2, 28.8) µmol/kg/min; p = 0.46]. CONCLUSIONS: A 25% reduction in prandial boluses during closed-loop therapy maintains similar glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with a 25% reduction in prandial boluses would prevent postprandial hypoglycaemia.

Multi-gigaelectronvolt acceleration of positrons in a self-loaded plasma wakefield.

Electrical breakdown sets a limit on the kinetic energy that particles in a conventional radio-frequency accelerator can reach. New accelerator concepts must be developed to achieve higher energies and to make future particle colliders more compact and affordable. The plasma wakefield accelerator (PWFA) embodies one such concept, in which the electric field of a plasma wake excited by a bunch of charged particles (such as electrons) is used to accelerate a trailing bunch of particles. To apply plasma acceleration to electron-positron colliders, it is imperative that both the electrons and their antimatter counterpart, the positrons, are efficiently accelerated at high fields using plasmas. Although substantial progress has recently been reported on high-field, high-efficiency acceleration of electrons in a PWFA powered by an electron bunch, such an electron-driven wake is unsuitable for the acceleration and focusing of a positron bunch. Here we demonstrate a new regime of PWFAs where particles in the front of a single positron bunch transfer their energy to a substantial number of those in the rear of the same bunch by exciting a wakefield in the plasma. In the process, the accelerating field is altered--'self-loaded'--so that about a billion positrons gain five gigaelectronvolts of energy with a narrow energy spread over a distance of just 1.3 metres. They extract about 30 per cent of the wake's energy and form a spectrally distinct bunch with a root-mean-square energy spread as low as 1.8 per cent. This ability to transfer energy efficiently from the front to the rear within a single positron bunch makes the PWFA scheme very attractive as an energy booster to an electron-positron collider.

Unsupervised home use of an overnight closed-loop system over 3-4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes.

AIMS: To compare overnight closed-loop and sensor-augmented pump therapy in patients with type 1 diabetes by combining data collected during free-living unsupervised randomized crossover home studies. METHODS: A total of 40 participants with type 1 diabetes, of whom 24 were adults [mean ± standard deviation (s.d.) age 43 ± 12 years and glycated haemoglobin (HbA1c) 8.0 ± 0.9%] and 16 were adolescents (mean ± s.d. age 15.6 ± 3.6 years and HbA1c 8.1 ± 0.8%), underwent two periods of sensor-augmented pump therapy in the home setting, in combination with or without an overnight closed-loop insulin delivery system that uses a model predictive control algorithm to direct insulin delivery. The order of the two interventions was random; each period lasted 4 weeks in adults and 3 weeks in adolescents. The primary outcome was time during which sensor glucose readings were in the target range of 3.9-8.0 mmol/l. RESULTS: The proportion of time when sensor glucose was in the target range (3.9-8.0 mmol/l) overnight (between 24:00 and 08:00 hours) was 18.5% greater during closed-loop insulin delivery than during sensor-augmented therapy (p < 0.001). Closed-loop therapy significantly reduced mean overnight glucose levels by 0.9 mmol/l (p < 0.001), with no difference in glycaemic variability, as measured by the standard deviation of sensor glucose. Time spent above the target range was reduced (p = 0.001), as was time spent in hypoglycaemia (<3.9 mmol/l; p = 0.014) during closed-loop therapy. Lower mean overnight glucose levels during closed-loop therapy were brought about by increased overnight insulin delivery (p < 0.001) without changes to the total daily delivery (p = 0.84). CONCLUSION: Overnight closed-loop insulin therapy at home in adults and adolescents with type 1 diabetes is feasible, showing improvements in glucose control and reducing the risk of nocturnal hypoglycaemia.

Safety of closed-loop therapy during reduction or omission of meal boluses in adolescents with type 1 diabetes: a randomized clinical trial.

We evaluated the safety and efficacy of closed-loop therapy with meal announcement during reduction and omission of meal insulin boluses in adolescents with type 1 diabetes (T1D). Twelve adolescents with T1D [six male; mean (s.d.) age 15.9 (1.8) years; mean (s.d.) glycated haemoglobin (HbA1c) 77 (27) mmol/mol] were studied in a randomized crossover study comparing closed-loop therapy with meal announcement with conventional pump therapy over two 24-h stays at a clinical research facility. Identical meals were given on both occasions. The evening meal insulin bolus was calculated to cover half of the carbohydrate content of the meal and no bolus was delivered for lunch. Plasma glucose levels were in the target range of 3.9-10 mmol/l for a median [interquartile range (IQR)] of 74 (55,86)% of the time during closed-loop therapy with meal announcement and for 62 (49,75)% of the time during conventional therapy (p = 0.26). Median (IQR) time spent with plasma glucose levels > 10 mmol/l [23 (13,39) vs. 27 (10,50)%; p = 0.88] or < 3.9 mmol/l [1(0,4) vs. 5 (1,10)%; p = 0.24] and mean [standard deviation (SD)] glucose levels [8.0 (7.6,9.3) vs. 7.7 (6.6,10.1) mmol/l, p = 0.79] were also similar. In conclusion, these results assist home testing of closed-loop delivery with meal announcement in adolescents with poorly controlled T1D who miscalculate or miss meal insulin boluses.

Glucose turnover after replacement of usual therapy by insulin in insulin-naive type 2 diabetes subjects.

CONTEXT: Discontinuation of anti-hyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for inpatients with type 2 diabetes (T2D). The effects on glucose turnover when these agents are acutely withdrawn are poorly understood and may be of importance when insulin therapy is initiated. OBJECTIVE: Our objective was to investigate alterations in glucose turnover after acute withdrawal of noninsulin therapy. DESIGN AND SETTING: This was a randomized crossover study at a clinical research facility. PARTICIPANTS: Participants included 12 insulin-naive subjects with T2D. METHODS: Subjects attended two 24-hour visits. Standard therapy was discontinued and replaced by closed-loop insulin delivery during the intervention visit. Usual anti-hyperglycemic therapy was continued during the control visit. Systemic glucose appearance (Ra) and glucose disposal (Rd) were measured using a tracer dilution technique with iv [6,6-(2)H2]glucose. RESULTS: Plasma glucose profiles during both visits were comparable (P = .48). Glucose Ra increased during the day (21.4 [19.5, 23.5] vs 18.6 [17.0, 21.6) µmol/kg/min, P = .019) and decreased overnight (9.7 [8.5, 11.4] vs 11.6 [10.3, 12.9] µmol/kg/min, P = .004) when the usual therapy was discontinued and replaced with insulin. Increased daytime glucose Rd (21.2 [19.4, 23.9] vs 18.8 [18.3, 21.7] µmol/kg/min, P = .002) and decreased overnight Rd (10.4 [9.1, 12.0] vs 11.8 [10.7, 13.7] µmol/kg/min, P = .005) were observed when the usual therapy was discontinued, whereas daytime peripheral insulin sensitivity was reduced (47.8 [24.8, 66.1] vs 62.5 [34.8, 75.8] nmol/kg/min per pmol/L, P = .034). CONCLUSION: In T2D, acute discontinuation of anti-hyperglycemic therapy and replacement with insulin increases postprandial Ra and reduces peripheral insulin sensitivity. Insulin dose initiation may need to compensate for these alterations.

Modification of fluorescent photoinduced electron transfer (PET) sensors/switches to produce molecular photo-ionic triode action.

The fluorophore-spacer1-receptor1-spacer2-receptor2 system (where receptor2 alone is photoredox-inactive) shows ionically tunable proton-induced fluorescence off-on switching, which is reminiscent of thermionic triode behavior. This also represents a new extension to modular switch systems based on photoinduced electron transfer (PET) towards the emulation of analogue electronic devices.

Absorption patterns of meals containing complex carbohydrates in type 1 diabetes.

AIMS/HYPOTHESIS: Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g). METHODS: On Visit 1, participants consumed an evening meal. On follow-up Visit 2, a variable-target glucose clamp was performed to reproduce glucose and insulin levels from Visit 1. Adopting stable-label tracer dilution methodology, we measured endogenous glucose production on Visit 2 and subtracted it from total glucose appearance measured on Visit 1 to obtain meal-attributable glucose appearance. RESULTS: After the LG meal, 25%, 50% and 75% of cumulative glucose appearance was at 88 ± 21, 175 ± 39 and 270 ± 54 min (mean ± SD), whereas glucose from the HG meal appeared significantly faster at 56 ± 12, 100 ± 25 and 153 ± 39 min (p < 0.001 to 0.003), and resulted in a 50% higher peak appearance (p < 0.001). Higher apparent bioavailability by 15% (p = 0.037) was observed after the LG meal. We documented a 20 min deceleration of dietary mixed carbohydrates compared with dietary glucose for the HG meal and a twofold deceleration for the LG meal. CONCLUSIONS/INTERPRETATION: Absorption patterns may be influenced by glycaemic load and/or meal composition, affecting optimum prandial insulin dosing in type 1 diabetes.

Plasma C-peptide concentration in women with Type 1 diabetes during early and late pregnancy.

AIMS: There are previous suggestions of increased C-peptide concentration in women with Type 1 diabetes during pregnancy. Our aim was to re-evaluate the hypothesis of a pregnancy-induced increase by measuring plasma C-peptide concentration in women with stable blood glucose control under standardized fasting and meal-stimulated conditions. METHODS: Ten women with Type 1 diabetes; median age 31.1 years, median diabetes duration 19 years, median HbA(1c) 52 mmol/mol (6.9%) were admitted to a clinical research facility for two 24-h visits in early (12-16 weeks) and late (28-32 weeks) pregnancy. Women They ate standardized study meals - 80-g carbohydrate dinner, 60-g carbohydrate breakfast, and fasted between meals and overnight. Closed-loop insulin delivery maintained stable and comparable glycaemic conditions. Paired samples for plasma glucose and C-peptide were obtained. RESULTS: Plasma glucose levels were comparable in early (median 6.5 mmol/l; interquartile range 5.6-8.6) and late pregnancy (median 7.0 mmol/l; interquartile range 6.1-7.8; P = 0.72). There was no change in fasting or meal-stimulated plasma C-peptide concentration from early to late pregnancy; mean difference 4.0 pmol/l (95% CI -6.0 to 7.0; P = 0.9). Four women had detectable C-peptide; peak (range) early vs. late pregnancy 48.5 (10-115) vs. 40.0 pmol/l (80-105); P = 0.5, which was weakly associated with plasma glucose; R(2) = 0.15, P < 0.0001. CONCLUSIONS: We found no gestational changes in plasma C-peptide concentration. Previously reported increases may reflect differences in glucose control and/or exogenous insulin doses. This study highlights the importance and challenges of standardizing experimental conditions for accurate plasma C-peptide measurement during Type 1 diabetes pregnancy.

Warming experiments underpredict plant phenological responses to climate change.

Warming experiments are increasingly relied on to estimate plant responses to global climate change. For experiments to provide meaningful predictions of future responses, they should reflect the empirical record of responses to temperature variability and recent warming, including advances in the timing of flowering and leafing. We compared phenology (the timing of recurring life history events) in observational studies and warming experiments spanning four continents and 1,634 plant species using a common measure of temperature sensitivity (change in days per degree Celsius). We show that warming experiments underpredict advances in the timing of flowering and leafing by 8.5-fold and 4.0-fold, respectively, compared with long-term observations. For species that were common to both study types, the experimental results did not match the observational data in sign or magnitude. The observational data also showed that species that flower earliest in the spring have the highest temperature sensitivities, but this trend was not reflected in the experimental data. These significant mismatches seem to be unrelated to the study length or to the degree of manipulated warming in experiments. The discrepancy between experiments and observations, however, could arise from complex interactions among multiple drivers in the observational data, or it could arise from remediable artefacts in the experiments that result in lower irradiance and drier soils, thus dampening the phenological responses to manipulated warming. Our results introduce uncertainty into ecosystem models that are informed solely by experiments and suggest that responses to climate change that are predicted using such models should be re-evaluated.

Validity of triple- and dual-tracer techniques to estimate glucose appearance.

The triple-tracer (TT) dilution technique has been proposed to be the gold standard method to measure postprandial glucose appearance. However, validation against an independent standard has been missing. We addressed this issue and also validated the simpler dual-tracer (DT) technique. Sixteen young subjects with type 1 diabetes (age 19.5 ± 3.8 yr, BMI 23.4 ± 1.5 kg/m(2), HbA(1c) 8.7 ± 1.7%, diabetes duration 9.0 ± 6.9 yr, total daily insulin 0.9 ± 0.2 U·kg(-1)·day(-1), mean ± SD) received a variable intravenous 20% dextrose infusion enriched with [U-(13)C]glucose over 8 h to achieve postprandial-resembling glucose excursions while intravenous insulin was administered to achieve postprandial-resembling levels of plasma insulin. Primed [6,6-(2)H(2)]glucose was infused in a manner that mimicked the expected endogenous glucose production and [U-(13)C; 1,2,3,4,5,6,6-(2)H(7)]glucose was infused in a manner that mimicked the expected glucose appearance from a standard meal. Plasma glucose enrichment was measured by gas chromatography-mass spectrometry. The intravenous dextrose infusion served as an independent standard and was reconstructed using the TT and DT techniques with the two-compartment Radziuk/Mari model and an advanced stochastic computational method. The difference between the infused and reconstructed dextrose profile was similar for the two methods (root mean square error 6.6 ± 1.9 vs. 8.0 ± 3.5 µmol·kg(-1)·min(-1), TT vs. DT, P = NS, paired t-test). The TT technique was more accurate in recovering the overall dextrose infusion (100 ± 9 and 92 ± 12%; P = 0.02). The root mean square error associated with the mean dextrose infusion profile was 2.5 and 3.3 µmol·kg(-1)·min(-1) for the TT and DT techniques, respectively. We conclude that the TT and DT techniques combined with the advanced computational method can measure accurately exogenous glucose appearance. The TT technique tends to outperform slightly the DT technique, but the latter benefits from reduced experimental and computational complexity.

Pathophysiology of postprandial hyperglycaemia in women with type 1 diabetes during pregnancy.

AIMS/HYPOTHESIS: Although maternal hyperglycaemia is associated with increased risk of adverse pregnancy outcome, the mechanisms of postprandial hyperglycaemia during pregnancy are poorly understood. We aimed to describe glucose turnover in pregnant women with type 1 diabetes, according to stage of gestation (early vs late gestation). METHODS: The rates of systemic glucose appearance (R(a)) and glucose disposal (R(d)) were measured in ten pregnant women with type 1 diabetes during early (12-16 weeks) and late (28-32 weeks) gestation. Women ate standardised meals--a starch-rich 80 g carbohydrate dinner and a sugar-rich 60 g carbohydrate breakfast--and fasted between meals and overnight. Stable-label isotope tracers ([6,6-(2)H(2)]glucose and [U-(13)C]glucose) were used to determine R(a), R(d) and glucose bioavailability. Closed-loop insulin delivery maintained stable glycaemic conditions. RESULTS: There were no changes in fasting R(a) (10 ± 2 vs 11 ± 2 µmol kg(-1) min(-1); p = 0.32) or fasting R(d) (11 ± 2 vs 11 ± 1 µmol kg(-1) min(-1); p = 0.77) in early vs late gestation. There was increased hepatic insulin resistance (381 ± 237 vs 540 ± 242 µmol kg(-1) min(-1) × pmol/l; p = 0.04) and decreased peripheral insulin sensitivity (0.09 ± 0.04 vs 0.05 ± 0.02 µmol kg(-1) min(-1) per pmol/l dinner, 0.11 ± 0.05 vs 0.07 ± 0.03 µmol kg(-1) min(-1) per pmol/l breakfast; p = 0.002) in late gestation. It also took longer for insulin levels to reach maximal concentrations (49 [37-55] vs 71 [52-108] min; p = 0.004) with significantly delayed glucose disposal (108 [87-125] vs 135 [110-158] min; p = 0.005) in late gestation. CONCLUSIONS/INTERPRETATION: Postprandial glucose control is impaired by significantly slower glucose disposal in late gestation. Early prandial insulin dosing may help to accelerate glucose disposal and potentially ameliorate postprandial hyperglycaemia in late pregnancy. TRIAL REGISTRATION: ISRCTN 62568875 FUNDING: Diabetes UK Project Grant BDA 07/003551. H.R. Murphy is funded by a National Institute for Health Research (NIHR) research fellowship (PDF/08/01/036). Supported also by the Juvenile Diabetes Research Foundation (JDRF), Abbott Diabetes Care (Freestyle Navigator CGM and sensors free of charge), Medical Research Council Centre for Obesity and Related Metabolic Diseases and NIHR Cambridge Biomedical Research Centre.