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Hybrid closed-loop (HCL) systems remain underexplored within aviation, and as atmospheric pressure changes can independently affect insulin pumps and continuous glucose monitoring readings, this preliminary study assessed the feasibility of HCL safety evaluation, in both fasting and post-prandial states, by using hypobaric chamber to simulate flights. Participants with type 1 diabetes and on HCL were studied: Medtronic Guardian 4-Medtronic 780G-SmartGuard ( n = 4), Dexcom G6-Omnipod DASH-Android APS ( n = 1), and Dexcom G6-Ypsomed Pump-CamAPS ( n = 1). Flight cabin pressures of 550 mmHg and 750 mmHg were simulated in a hypobaric chamber. Seven-hundred-50 glucose measurements were taken, with glucose levels demonstrating a stable decline to 4 mmol/L during fasting. To maintain a tight fasting and post-prandial glucose range across the different pressure settings, the HCL administered insulin as expected. While not demonstrating any apparent issues, repeating flight simulation protocol with other systems, examining longer flights, and undertaking larger, powered randomised controlled trials can confirm their safety in aviation.

Aims/hypothesis: Glycaemic control and clinical outcomes in diabetes are improved by continuous subcutaneous insulin infusion (CSII). Atmospheric pressure changes during flights may affect insulin delivery from pumps and cause unintended metabolic consequences, including hypoglycaemia, in people with type 1 diabetes. The present report evaluates both hypobaric flight simulation and real-world data in pilots using insulin pumps while flying., Methods: In the flight simulation part of this study, an in vitro study of insulin pumps was conducted in a hypobaric chamber, de-pressurised to 550 mmHg to mimic the atmospheric pressure changes in airliner cabins during commercial flights. Insulin delivery rates and bubble formation were recorded for standard flight protocol. Insulin infusion sets, without pumps, were tested in a simulated rapid decompression scenario. The real-world observational study was a 7.5-year retrospective cohort study in which pre- and in-flight self-monitored blood glucose (SMBG) values were monitored in pilots with insulin-treated diabetes. Commercial and private pilots granted a medical certificate to fly within the European Union Aviation Safety Agency approved protocol and receiving insulin either by pump or multiple daily injections (MDI) were included., Results: In the flight simulation study, full cartridges over-delivered 0.60 U of insulin during a 20 min ascent and under-delivered by 0.51 U during descent compared with ground-level performance. During emergency rapid decompression, 5.6 U of excess insulin was delivered. In the real-world study, seven pilots using CSII recorded 4656 SMBG values during 2345 h of flying across 1081 flights. Only 33 (0.7%) values were outside an acceptable safe range (5.0-15.0 mmol/l [90-270 mg/dl]). No clinically significant fall in the median SMBG concentration was observed after aircraft ascent and no in-flight SMBG values were within the hypoglycaemic range (<4.0 mmol/l [<72 mg/dl]). Compared with pilots receiving MDI therapy, pilots using CSII recorded more SMBG values within the acceptable range (99.3% vs 97.5%), fewer values in the low red range (0.02% vs 0.1%), fewer in-flight out-of-range values (0.2% vs 1.3%) and maintained stricter glycaemic control during flight., Conclusions/interpretation: Ambient pressure reduction during simulated flights results in bubble formation and expansion within insulin cartridges. This causes unintended delivery of small insulin doses independent of pre-determined delivery rates and represents the maximum amount of insulin that could be delivered and retracted. However, in vivo, pilots using CSII in-flight did not experience a fall in blood glucose or episodes of hypoglycaemia during these atmospheric pressure changes and the use of insulin pumps can be endorsed in view of their clinical benefits., Competing Interests: Acknowledgements: We thank B. Dick (Tams Group, Australia) for assisting with the design and construction of our equipment setup, and D. Connolly (QinetiQ, Salisbury, UK) and QinetiQ Ltd, MOD Boscombe Down for facilitating our experiments in the hypobaric chamber. We also thank the teams at Insulet, Medtronic and Tandem Diabetes Care for their product support. We are very grateful to the pilots with insulin-treated diabetes who participated in this study. We also thank J. Vening and J. Montague (aeromedical nurses, UK CAA) and D. Coghlan (aeromedical nurse, IAA) for their help with data collection and management. We also thank C. I. Panait and P. N. P. Caetano for their input on this manuscript as technical reviewers for EASA (EASA, Germany). No other individual or agency was involved in the preparation of this manuscript. The hypobaric simulation study was presented as an e-poster discussion at the 7th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2024 conference, 6–9 March. The abstract was titled ‘The effects of atmospheric pressure experienced during routine airline flight on infusion rates of insulin pumps’ and was published in Diabetes Technology & Therapeutics, Volume 26, Issue S2/February, as abstract no. 144 (page A-133). This study has also been accepted at the 60th EASD Annual Meeting under the title of ‘Simulated commercial flights and the effects of atmospheric pressure changes on insulin pump delivery’. The findings of the retrospective observational study were presented as an oral presentation at the 7th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2024 conference on 6–9 March. The abstract was titled ‘The effects of changes in atmospheric pressure on glycaemic control in pilots with insulin-treated diabetes using insulin pumps during commercial flying’ and was published in Diabetes Technology & Therapeutics, Volume 26, Issue S2/February, as abstract no. 659 (page A-58). EASA Consortium members are as follows: Chantal Mathieu (KU Leuven, Leuven, Belgium), David Russell-Jones (University of Surrey, Guildford, UK), E. Marelise W. Eekhoff (Amsterdam University Medical Center, Amsterdam, the Netherlands), Ewan Hutchison (Civil Aviation Authority, Crawley, UK), Fariba Shojaee-Moradie (University of Surrey, Guildford, UK), Felice Strollo (IRCCS San Raffaele Pisana, Rome, Italy), Gerd Köhler (Medical University of Graz, Graz, Austria), Graham Roberts (Irish Aviation Authority, Dublin, Ireland), Julia Mader (Medical University of Graz, Graz, Austria), Monika Cigler (Medical University of Graz, Graz, Austria), Renald Mecani (Medical University of Graz, Graz, Austria), Richard Helsdingen (TUI, Amsterdam, the Netherlands), Stuart Mitchell (University of Surrey, Guildford, UK) and Thomas Pieber (Medical University of Graz, Graz, Austria). Data availability: Authors agree to make data and materials supporting the results or analyses presented in their paper available upon reasonable request. Funding: The hypobaric simulation part of the study was conducted in conjunction with the Safe Use of New technologies in Diabetes in Flight (SUNDIF; NCT06408558) funded by the EASA Horizon Europe Work Programme 2021–2022. Pumps and associated expenses were covered by unrestricted grants and gifts. Insulin pump manufacturers provided product support but were not involved in the study design or carrying out of the study. No additional sources of funding was received for the retrospective observational study. Authors’ relationships and activities: BMF is a member of the UK Civil Aviation (CAA) Advisory Panel for diabetes and flying and is a member of the advisory board of Zucara Pharmaceuticals. GK is contracted as an independent advisor to Austro Control and has received research funding, speaker and advisory board honoraria from Astra Zeneca, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, Novo Nordisk, Roche Diagnostics and Sanofi. CM is the president of EASD and serves or has served on the advisory panel for Novo Nordisk, Sanofi, Eli Lilly, Novartis, Boehringer Ingelheim, Roche, Medtronic, Imcyse, Insulet and Vertex. Financial compensation for these activities has been received by KU Leuven. KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio Therapeutics. CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly, Medtronic and Boehringer Ingelheim. Financial compensation for these activities has been received by KU Leuven. All external support of EASD is to be found on www.easd.org . JKM is a consultant physician for Internal Medicine, Dept of Internal Medicine Medical University of Graz, is a member on the advisory board of Abbott Diabetes Care, Becton-Dickinson, Boehringer Ingelheim, Eli Lilly, Embecta, Medtronic, Novo Nordisk A/S, Pharmasens AG, Roche Diabetes Care, Viatris and Sanofi-Aventis and received speaker honoraria from Abbott Diabetes Care, A. Menarini Diagnostics, AstraZeneca, Boehringer Ingelheim, Becton-Dickinson, Dexcom, Eli Lilly, Medtrust AG, MSD, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis, Servier, Viatris and Ypsomed. She is a shareholder of decide Clinical Software GmbH and elyte Diagnostics and serves as CMO of elyte Diagnostics. SRH has served as a member of an expert panel of the UK CAA and provides consultancy for Novo Nordisk, Eli Lilly, and Zealand Pharma, for which his institution receives remuneration, and serves on speaker panels for Novo Nordisk and AstraZeneca, for which he receives personal remuneration. GAR is contracted as an independent advisor to the Irish Aviation Authority (IAA) and has received research funding and advisory board honoraria from Novo Nordisk, Mundipharma and Sanofi. KMS has served as a contracted medical consultant (clinical assessments) and an independent advisor to the UK Civil Aviation Authority (CAA). He has previously served on specialist advisory boards for Abbott, GSK, Merk, Novo Nordisk, Novartis, Pfizer, Sanofi and Servier. DLR-J is a Professor of Diabetes and Endocrinology at Royal Surrey County Hospital and at Nutritional Sciences, FHMS, University of Surrey, Guildford, Surrey, UK. He is also contracted as an independent advisor to the UK Civil Aviation Authority (CAA). He has received research funding and advisory board honoraria from Abbott Diabetes Care, AstraZeneca, Dexcom, Eli Lilly, Medtronic, Novartis, Novo Nordisk and Sanofi. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: The conception and design of the studies were developed by GLG, MP, FSM, BRK, DLRJ, KSF, AM, VE, VL, GK, CM, MBI, EJH, DM, SJM, BMF, KMS, SRH, GAR and JKM. Data acquisition was executed by GLG, KSF, MP, FSM, AM, VE, VL, BRK and DRJ. The subsequent analysis and interpretation of the data was performed by GLG, KSF, MBI, MP, FSM, BRK and DRJ. The drafting of the manuscript was undertaken by GLG, KSF, MP, FSM, AM, VE, VL, GK, CM, JKM, BRK, MBI, EJH, DM, SJM, BMF, KMS, SRH, GAR and DRJ. Critical revision of the manuscript was carried out by GLG, KSF, MP, FSM, AM, VE, VL, GK, CM, JKM, BRK, MBI, EJH, DM, GK, SJM, BMF, KMS, SRH, GAR and DLRJ. All authors approved the final version of the manuscript. BRK and DRJ are the guarantors of the hypobaric simulation study and DLRJ is the guarantor for the retrospective observational study. As such, BRK and DLRJ had full access to the respective data in the studies and take responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s).)

Background and Aims: A preliminary study compared the use of continuous glucose monitoring (CGM) with the use of self-monitored blood glucose (SMBG) by aircraft pilots with insulin-treated diabetes in the United Kingdom, Ireland, and Austria, certified to fly commercial aircraft within the European Aviation Safety Agency ARA.MED.330 protocol. Methods: SMBG and simultaneous interstitial glucose measurements using CGM (Dexcom G6 ® ) were recorded during pre- and in-flight periods. Results: Eight male pilots (seven with type 1 diabetes and one with type 3c diabetes), median age of 48.5 years and median diabetes duration of 11.5 years, participated. The correlation coefficient ( R ) between 874 contemporaneously recorded SMBG and CGM values was 0.843, P  < 0.001. The mean glucose concentration was 8.78 mmol/L (standard deviation [SD] 0.67) using SMBG compared with 8.71 mmol/L (SD 0.85) recorded using CGM. The mean absolute relative difference was 9.39% (SD 3.12). Conclusions: CGM using Dexcom G6 systems is a credible alternative to SMBG for monitoring glucose levels when insulin-treated pilots fly commercial aircraft. The study was registered with Clinical Trials.gov NCT04395378.

Objective: To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes., Research Design and Methods: A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose R a , R d , and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L., Results: At baseline, glucose R a was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose R d area under the curve (AUC) 0-180 min and β-hydroxybutyrate (BOHB) AUC 0-180 min were significantly higher. There was a small but significantly higher glycerol R a (measure of lipolysis) AUC 0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m 2 , basal glucose R a , BOHB, and glycerol R a AUC 0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo., Conclusions: During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role., (© 2020 by the American Diabetes Association.)

Objective: Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure., Research Design and Methods: A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured., Results: After 16 weeks, weight change was -0.69±1.85 kg with insulin detemir and +1.7±2.46 kg with NPH insulin (P<0.001). Total energy intake was significantly less with insulin detemir (2,016±501 kcal/day) than with NPH insulin (2,181±559 kcal/day) (P=0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P=0.039, P=0.047). After the meal, ghrelin and pancreatic polypeptide levels (P=0.002, P=0.001) were higher with insulin detemir., Conclusions: The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety.

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1alpha and -1beta, HNF-1beta mutation carriers have hyperinsulinemia, whereas HNF-1alpha mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1beta mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU . kg(-1) . min(-1)) and high-dose (1.5 mU . kg(-1) . min(-1)) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-(2)H(2)]glucose, in six subjects with HNF-1alpha mutations, six subjects with HNF-1beta mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1beta subjects but was suppressed by 89% in HNF-1alpha subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1beta mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1beta in the liver and possibly the kidney. This may be mediated through regulation by HNF-1beta of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.

Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependent on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NaB1-L-thyroxyl-insulin, NaB1-3,3',5'-triiodothyronine-insulin, NaB1-D-thyroxyl-insulin and NaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependent manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.

Aim: People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. Methods: BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic–euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Results: Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. Conclusion: These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties. [ABSTRACT FROM AUTHOR]

Aim: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. Methods: Twenty‐three BA and twenty‐three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic‐euglycaemic clamp with stable glucose isotope infusion to measure whole‐body and hepatic‐specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). Results: BA men had higher glucose‐stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L−1 × min, P =.017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m−2 body surface area min −1, P <.001) compared with WE men. There were no ethnic differences in beta‐cell insulin secretion or beta‐cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole‐body insulin sensitivity (r = 0.691, P =.001) and inversely correlated with IHL (r = −0.674, P =.001). These associations were not found in BA men. Conclusions: While normally glucose‐tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin. [ABSTRACT FROM AUTHOR]

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg ⋅ kg-1 ⋅ day-1) was given subcutaneously at 6:00 P.M. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU ⋅ kg-1 ⋅ min-1) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/ IGFBP-3 dose-dependently reduced endogenous glucose production rate (Ra) (P = 0.004), while peripheral glucose uptake (Rd) was not different from placebo. The increase in glucose Rd during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol Ra, a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake. Diabetes 55:2365-2370, 2006 [ABSTRACT FROM AUTHOR]

Presents a study which estimated the effect of insulin on glucose distribution/transport, glucose disposal and endogenous production during an intravenous glucose tolerance test (IVGTT). Results of the stable-label two-compartment model; Parameter estimates of the minimal model during an IVGTT; Ways in which insulin temporal action can be represented.

Insulin detemir (IDet) is a novel long acting insulin analogue. Previous studies have shown a reduced frequency of hypoglycaemia and less weight gain with IDet compared with NPH insulin (NPH). To investigate symptoms, counterregulatory hormone response, cognitive function and metabolism during hypoglycaemia with IDet and NPH, 23 patients with type 1 diabetes were enrolled in a double blind, randomised, cross-over trial. Following an overnight fast either IDet or NPH were injected subcutaneously (first 5 subjects: 0.4 U/Kg, subsequent 18 subjects: 0.5 U/Kg) and blood glucose was allowed to decline from a baseline level of 7 mmol/l to a minimum of 2.4 mmol/l. Symptoms of hypoglycaemia (based on the Edinburgh Hypoglycaemia Scale), cognitive function (finger tapping test and four choice reaction time test) and autonomic response (heart rate and blood pressure) were recorded at regular intervals. Blood was frequently sampled for measurement of IDet, human insulin, nonesterified fatty acids and counter-regulatory hormones (glucagon, adrenaline, noradrenaline, growth hormone, cortisol and insulin-like growth factor binding protein 1). The blood glucose profiles following IDet/NPH administration were similar and the expected physiological response to hypoglycaemia was observed with no difference between IDet and NPH in symptoms of hypoglycaemia, cognitive function, autonomic response or counter-regulatory hormone responses. These results are reassuring and important as thousands of patients worldwide are now being treated with insulin detemir. [ABSTRACT FROM AUTHOR]