OBJECTIVE
We evaluated the safety and efficacy of fully closed-loop with ultrarapid insulin lispro in adults with type 1 diabetes and suboptimal glycemic control compared with insulin pump therapy ...with continuous glucose monitoring (CGM).
RESEARCH DESIGN AND METHODS
This single-center, randomized, crossover study enrolled 26 adults with type 1 diabetes using insulin pump therapy with suboptimal glycemic control (mean ± SD, age 41 ± 12 years, HbA1c 9.2 ± 1.1% 77 ± 12 mmol/mol). Participants underwent two 8-week periods of unrestricted living to compare fully closed-loop with ultrarapid insulin lispro (CamAPS HX system) with insulin pump therapy with CGM in random order.
RESULTS
In an intention-to-treat analysis, the proportion of time glucose was in range (primary end point 3.9–10.0 mmol/L) was higher during closed-loop than during pump with CGM (mean ± SD 50.0 ± 9.6% vs. 36.2 ± 12.2%, mean difference 13.2 percentage points 95% CI 9.5, 16.9, P < 0.001). Time with glucose >10.0 mmol/L and mean glucose were lower during closed-loop than during pump with CGM (mean ± SD time >10.0 mmol/L: 49.0 ± 9.9 vs. 62.9 ± 12.6%, mean difference −13.3 percentage points 95% CI −17.2, −9.5, P < 0.001; mean ± SD glucose 10.7 ± 1.1 vs. 12.0 ± 1.6 mmol/L, mean difference −1.2 mmol/L 95% CI −1.8, −0.7, P < 0.001). The proportion of time with glucose <3.9 mmol/L was similar between periods (median interquartile range (IQR) closed-loop 0.88% 0.51–1.55 vs. pump with CGM 0.64% 0.28–1.10, P = 0.102). Total daily insulin requirements did not differ (median IQR closed-loop 51.9 units/day 35.7–91.2 vs. pump with CGM 50.7 units/day 34.0–70.0, P = 0.704). No severe hypoglycemia or ketoacidosis occurred.
CONCLUSIONS
Fully closed-loop insulin delivery with CamAPS HX improved glucose control compared with insulin pump therapy with CGM in adults with type 1 diabetes and suboptimal glycemic control.
Aims/hypothesis
Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of ...chemically induced (streptozotocin STZ) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms.
Methods
The hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and
Nrf2
−/−
mice (lacking
Nrf2
also known as
Nfe2l2
). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways.
Results
Evidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of
Nrf2
and the
Nrf2
transcriptional targets
Sod2
and
Hmox-1
. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis.
Conclusions/interpretation
There is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus.
Data availability
The datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 (
www.proteomexchange.org
). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request.
Graphical abstract
We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by ...genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism.
One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later.
As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower.
This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
We explored changes in finger forces and in an index of unintentional finger force production (enslaving) under a variety of visual feedback conditions and positional finger perturbations. In ...particular, we tested a hypothesis that enslaving would show a consistent increase with time at characteristic times of about 1–2 s. Young healthy subjects performed accurate force production tasks under visual feedback on the total force of the instructed fingers (index and ring) or enslaved fingers (middle and little). Finger feedback was covertly alternated between master and enslaved fingers in a random fashion. The feedback could be presented over the first 5 s of the trial only or over the whole trial duration (21 s). After 5 s, the fingers were lifted by 1 cm, and after 15 s, the fingers were lowered to the initial position. The force of the instructed fingers drifted toward lower magnitudes in all conditions except the one with continuous feedback on that force. The force of enslaved fingers showed variable behavior across conditions. In all conditions, the index of enslaving showed a consistent increase with the time constant varying between 1 and 3 s. We interpret the results as pointing at the spread of excitation to enslaved fingers (possibly, in the cortical M1 areas). The relatively fast changes in enslaving under positional finger perturbations suggest that quick changes of the input into M1 from pre-M1 areas can accelerate the hypothesized spread of cortical excitation.
Aim
To evaluate the efficacy and safety of fast‐acting insulin aspart (faster aspart) vs insulin aspart (IAsp) used in continuous subcutaneous insulin infusion (CSII) in participants with type 1 ...diabetes (T1D).
Materials and Methods
This was a double‐blind, treat‐to‐target, randomized, 16‐week trial investigating CSII treatment with faster aspart (n = 236) or IAsp (n = 236). All available information, regardless of treatment discontinuation, was used for the evaluation of effect.
Results
Faster aspart was non‐inferior to IAsp regarding the change from baseline in glycated haemoglobin (HbA1c; primary endpoint). The mean HbA1c changed from 58.4 mmol/mol (7.5%) at baseline to 57.8 mmol/mol (7.4%) with faster aspart and to 56.8 mmol/mol (7.4%) with IAsp after 16 weeks' treatment, with an estimated treatment difference (ETD) of 1.0 mmol/mol (95% confidence interval CI 0.14; 1.87) or 0.09% (95% CI 0.01; 0.17; P < 0.001) for non‐inferiority (0.4% margin; P < 0.02 for statistical significance in favour of IAsp). Faster aspart was superior to IAsp in change from baseline in 1‐hour postprandial glucose (PPG) increment after a meal test (ETD −0.91 mmol/L 95% CI −1.43; −0.39 or −16.4 mg/dL 95% CI −25.7; −7.0; P = 0.001), with statistically significant reductions also at 30 minutes and 2 hours. The improvement in PPG was reflected in the change from baseline in 1‐hour interstitial glucose increment after all meals (ETD −0.21 mmol/L 95% CI −0.31; −0.11 or −3.77 mg/dL 95% CI −5.53; −2.01). There was no statistically significant difference in the overall rate of severe or blood glucose‐confirmed hypoglycaemia (estimated rate ratio 1.00 95% CI 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and 4‐week run‐in periods (4 vs 0).
Conclusions
Faster aspart provides an effective and safe option for CSII treatment in T1D.
Background
Ultrashort echo time (UTE) proton MRI has gained popularity for assessing lung structure and function in pulmonary imaging; however, the development of rapid biomarker extraction and ...regional quantification has lagged behind due to labor‐intensive lung segmentation.
Purpose
To evaluate a deep learning (DL) approach for automated lung segmentation to extract image‐based biomarkers from functional lung imaging using 3D radial UTE oxygen‐enhanced (OE) MRI.
Study Type
Retrospective study aimed to evaluate a technical development.
Population
Forty‐five human subjects, including 16 healthy volunteers, 5 asthma, and 24 patients with cystic fibrosis.
Field Strength/Sequence
1.5T MRI, 3D radial UTE (TE = 0.08 msec) sequence.
Assessment
Two 3D radial UTE volumes were acquired sequentially under normoxic (21% O2) and hyperoxic (100% O2) conditions. Automated segmentation of the lungs using 2D convolutional encoder‐decoder based DL method, and the subsequent functional quantification via adaptive K‐means were compared with the results obtained from the reference method, supervised region growing.
Statistical Tests
Relative to the reference method, the performance of DL on volumetric quantification was assessed using Dice coefficient with 95% confidence interval (CI) for accuracy, two‐sided Wilcoxon signed‐rank test for computation time, and Bland–Altman analysis on the functional measure derived from the OE images.
Results
The DL method produced strong agreement with supervised region growing for the right (Dice: 0.97; 95% CI = 0.96, 0.97; P < 0.001) and left lungs (Dice: 0.96; 95% CI = 0.96, 0.97; P < 0.001). The DL method averaged 46 seconds to generate the automatic segmentations in contrast to 1.93 hours using the reference method (P < 0.001). Bland–Altman analysis showed nonsignificant intermethod differences of volumetric (P ≥ 0.12) and functional measurements (P ≥ 0.34) in the left and right lungs.
Data Conclusion
DL provides rapid, automated, and robust lung segmentation for quantification of regional lung function using UTE proton MRI.
Level of Evidence: 2
Technical Efficacy: Stage 1
J. Magn. Reson. Imaging 2019;50:1169–1181.
There is an unmet need for an objective biomarker to predict asthma exacerbations.
Our aim was to assess the ventilation defect percent (VDP) on hyperpolarized helium-3 magnetic resonance imaging as ...a predictor of exacerbation frequency following imaging.
Subjects underwent hyperpolarized helium-3 and conventional clinical measurements, including pulmonary function tests, during a period of disease stability, and exacerbations were recorded prospectively over the following 2 years. We used a Poisson regression tree model to estimate an optimal VDP threshold for classifying subjects into high- versus low-exacerbation groups and then used statistical regression to compare this VDP threshold against conventional clinical measures as predictors of exacerbations.
A total of 67 individuals with asthma (27 males and 40 females, 28 with mild-to-moderate asthma and 39 with severe asthma) had a median VDP of 3.75% (1.2% first quartile-7.9% third quartile). An optimal VDP threshold of 4.28% was selected on the basis of the maximum likelihood estimation of the regression tree model. Subjects with a VDP greater than 4.28% (n = 32) had a median of 1.5 exacerbations versus 0.0 for subjects with a VDP less than 4.28% (n = 35). In a stepwise multivariate regression model, a VDP greater than 4.28% was associated with an exacerbation incidence rate ratio of 2.5 (95% CI = 1.3-4.7) versus a VDP less than or equal to 4.28%. However, once individual medical history was included in the model, VDP was no longer significant. Nonetheless, VDP may provide an objective and complementary quantitative marker of individual exacerbation risk that is useful for monitoring individual change in disease status, selecting patients for therapy, and assessing treatment response.
VDP measured with magnetic resonance imaging shows promise as a biomarker of prospective asthma exacerbations.
Display omitted
Aim
Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans.
...Materials and Methods
We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp.
Results
Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p = .047. This was probably explained by a combination of reduced circulating insulin levels iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p = .005, reduced insulin sensitivity M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p = .010 and glucose effectiveness SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p = .027.
Conclusions
5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness.
To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin ...infusion CSII) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG).
A 24-week 2 × 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score).
A total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (≤3.0 mmol/L) decreased (53 ± 63 to 24 ± 56 min/24 h; P = 0.004 t test) without deterioration in HbA1c. Hypoglycemia awareness improved (5.1 ± 1.1 to 4.1 ± 1.6; P = 0.0001 t test) with decreased SH (8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year; P = 0.0001 t test). At 24 weeks, there was no significant difference in awareness comparing CSII with MDI (4.1 ± 1.6 vs. 4.2 ± 1.7; difference 0.1; 95% CI -0.6 to 0.8) and RT with SMBG (4.3 ± 1.6 vs. 4.0 ± 1.7; difference -0.3; 95% CI -1.0 to 0.4). Between-group analyses demonstrated comparable reductions in SH, fear of hypoglycemia, and insulin doses with equivalent HbA1c. Treatment satisfaction was higher with CSII than MDI (32 ± 3 vs. 29 ± 6; P = 0.0003 t test), but comparable with SMBG and RT (30 ± 5 vs. 30 ± 5; P = 0.79 t test).
Hypoglycemia awareness can be improved and recurrent SH prevented in long-standing type 1 diabetes without relaxing HbA1c. Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT, although satisfaction was higher with CSII.
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