Continuous Glucose Monitoring by Insulin-Treated Pilots Flying Commercial Aircraft Within the ARA.MED.330 Diabetes Protocol: A Preliminary Feasibility Study.

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.

Blood glucose monitoring by insulin-treated pilots of commercial and private aircraft: An analysis of out-of-range values.

AIM: To examine blood glucose measurements recorded as part of the diabetes protocol operated by the UK, Ireland and Austria, which allows commercial airline pilots with insulin-treated diabetes to fly. METHODS: An observational study was conducted in pilots with insulin-treated diabetes, granted medical certification to fly commercial or noncommercial aircraft, who recorded pre-flight and hourly in-flight blood glucose measurements. These values were correlated to a traffic light system (green 5.0 to 15.0 mmol/L; amber 4.0 to 4.9 mmol/L and 15.1 to 20.0 mmol/L; and red <4.0 mmol/L or >20.0 mmol/L) and studied for trends in glucose concentrations, time course within flight and any consequences. Pilot demographics were also analysed. RESULTS: Forty-four pilots (90%) recorded one or more blood glucose value outside the green range during the 7 years of the study. Pilot age, diabetes type and duration, and follow-up period were comparable among subgroups, and mean glycated haemoglobin did not differ before and after certification in a way which would indicate poorer glycaemic control in any subgroup. A total of 892 blood glucose values (2.31%) were outside the green range, with half reported in-flight at various time intervals. There were 48 (0.12%) low red range values recorded, 14 (0.04%) of which occurred in-flight; all but four were restored to within the green range by the time of the next measurement. Appropriate corrective action was taken for all out-of-range values, with no reports of pilot incapacitation from any cause. CONCLUSIONS: The traffic light system appears effective in identifying and reducing the frequency and severity of out-of-range values.

An Evaluation of the Safety of Pilots With Insulin-Treated Diabetes in Europe Flying Commercial and Noncommercial Aircraft.

OBJECTIVE: The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain "safety-critical" occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially. RESEARCH DESIGN AND METHODS: This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5-15 mmol/L), amber (low, 4-4.9 mmol/L; high, 15.1-20 mmol/L), and red (low, <4 mmol/L; high, >20 mmol/L). RESULTS: A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA1c was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification (P = 0.97). Blood glucose values (n = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate. CONCLUSIONS: The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a "safety-critical" occupation, which may be relevant when estimating risk in other safety-critical occupations.

Pre-Exercise Blood Glucose Levels Determine the Amount of Orally Administered Carbohydrates during Physical Exercise in Individuals with Type 1 Diabetes-A Randomized Cross-Over Trial.

The aim of the study was to assess the amount of orally administered carbohydrates needed to maintain euglycemia during moderate-intensity exercise in individuals with type 1 diabetes. Nine participants with type 1 diabetes (four women, age 32.1 ± 9.0 years, BMI 25.5 ± 3.9 kg/m2, HbA1c 55 ± 7 mmol/mol (7.2 ± 0.6%)) on insulin Degludec were randomized to cycle for 55 min at moderate intensity (63 ± 7% VO2peak) for five consecutive days on either 75% or 100% of their regular basal insulin dose. The impact of pre-exercise blood glucose concentration on the carbohydrate requirement was analyzed by one-way ANOVA stratified for pre-exercise blood glucose quartiles. The effect of the basal insulin dose on the amount of orally administered carbohydrates was evaluated by Wilcoxon matched-pairs signed-rank test. The amount of orally administered carbohydrates during the continuous exercise sessions was similar for both trial arms (75% or 100% basal insulin) with median [IQR] of 36 g (9-62 g) and 36 g (9-66 g) (p = 0.78). The amount of orally administered carbohydrates was determined by pre-exercise blood glucose concentration for both trial arms (p = 0.03). Our study elucidated the importance of pre-exercise glucose concentration related orally administered carbohydrates to maintain euglycemia during exercise in individuals with type 1 diabetes.

Reduction in insulin degludec dosing for multiple exercise sessions improves time spent in euglycaemia in people with type 1 diabetes: A randomized crossover trial.

AIMS: To compare the time spent in specified glycaemic ranges in people with type 1 diabetes (T1D) during 5 consecutive days of moderate-intensity exercise while on either 100% or 75% of their usual insulin degludec (IDeg) dose. MATERIALS AND METHODS: Nine participants with T1D (four women, mean age 32.1 ± 9.0 years, body mass index 25.5 ± 3.8 kg/m2 , glycated haemoglobin 55 ± 7 mmol/mol (7.2% ± 0.6%) on IDeg were enrolled in the trial. Three days before the first exercise period, participants were randomized to either 100% or 75% of their usual IDeg dose. Participants exercised on a cycle ergometer for 55 minutes at a moderate intensity for 5 consecutive days. After a 4-week wash-out period, participants performed the last exercise period for 5 consecutive days with the alternate IDeg dose. Time spent in specified glycaemic ranges, area under the curve and numbers of hypoglycaemic events were compared for the 5 days on each treatment allocation using a paired Students' t test, Wilcoxon matched-pairs signed-rank test and two-way ANOVA. RESULTS: Time spent in euglycaemia over 5 days was greater for the 75% IDeg dose versus the 100% IDeg dose (4008 ± 938 minutes vs. 3566 ± 856 minutes; P = 0.04). Numbers of hypoglycaemic events (P = 0.91) and time spent in hypoglycaemia (P = 0.07) or hyperglycaemia (P = 0.38) was similar for both dosing schemes. CONCLUSIONS: A 25% reduction in usual IDeg dose around regular exercise led to more time spent in euglycaemia, with small effects on time spent in hypo- and hyperglycaemia.

Different Heart Rate Patterns During Cardio-Pulmonary Exercise (CPX) Testing in Individuals With Type 1 Diabetes.

To investigate the heart rate during cardio-pulmonary exercise (CPX) testing in individuals with type 1 diabetes (T1D) compared to healthy (CON) individuals. Fourteen people (seven individuals with T1D and seven CON individuals) performed a CPX test until volitional exhaustion to determine the first and second lactate turn points (LTP1 and LTP2), ventilatory thresholds (VT1 and VT2), and the heart rate turn point. For these thresholds cardio-respiratory variables and percentages of maximum heart rate, heart rate reserve, maximum oxygen uptake and oxygen uptake reserve, and maximum power output were compared between groups. Additionally, the degree and direction of the deflection of the heart rate to performance curve (kHR) were compared between groups. Individuals with T1D had similar heart rate at LTP1 (mean difference) -11, [(95% confidence interval) -27 to 4 b.min-1], at VT1 (-12, -8 to 33 b.min-1) and at LTP2 (-7, -13 to 26 b.min-1), at VT2 (-7, -13 to 28 b.min-1), and at the heart rate turn point (-5, -14 to 24 b.min-1) (p = 0.22). Heart rate expressed as percentage of maximum heart rate at LTP1, VT1, LTP2, VT2 and the heart rate turn point as well as expressed as percentages of heart rate reserve at LTP2, VT2 and the heart rate turn point was lower in individuals with T1D (p < 0.05). kHR was lower in T1D compared to CON individuals (0.11 ± 0.25 vs. 0.51 ± 0.32, p = 0.02). Our findings demonstrate that there are clear differences in the heart rate response during CPX testing in individuals with T1D compared to CON individuals. We suggest using submaximal markers to prescribe exercise intensity in people with T1D, as the heart rate at thresholds is influenced by kHR. Clinical Trial Identifier: NCT02075567 (https://clinicaltrials.gov/ct2/show/NCT02075567).

Atypical blood glucose response to continuous and interval exercise in a person with type 1 diabetes: a case report.

BACKGROUND: Therapy must be adapted for people with type 1 diabetes to avoid exercise-induced hypoglycemia caused by increased exercise-related glucose uptake into muscles. Therefore, to avoid hypoglycemia, the preexercise short-acting insulin dose must be reduced for safety reasons. We report a case of a man with long-lasting type 1 diabetes in whom no blood glucose decrease during different types of exercise with varying exercise intensities and modes was found, despite physiological hormone responses. CASE PRESENTATION: A Caucasian man diagnosed with type 1 diabetes for 24 years performed three different continuous high-intensity interval cycle ergometer exercises as part of a clinical trial (ClinicalTrials.gov identifier NCT02075567). Intensities for both modes of exercises were set at 5% below and 5% above the first lactate turn point and 5% below the second lactate turn point. Short-acting insulin doses were reduced by 25%, 50%, and 75%, respectively. Measurements taken included blood glucose, blood lactate, gas exchange, heart rate, adrenaline, noradrenaline, cortisol, glucagon, and insulin-like growth factor-1. Unexpectedly, no significant blood glucose decreases were observed during all exercise sessions (start versus end, 12.97 ± 2.12 versus 12.61 ± 2.66 mmol L-1, p = 0.259). All hormones showed the expected response, dependent on the different intensities and modes of exercises. CONCLUSIONS: People with type 1 diabetes typically experience a decrease in blood glucose levels, particularly during low- and moderate-intensity exercises. In our patient, we clearly found no decline in blood glucose, despite a normal hormone response and no history of any insulin insensitivity. This report indicates that there might be patients for whom the recommended preexercise therapy adaptation to avoid exercise-induced hypoglycemia needs to be questioned because this could increase the risk of severe hyperglycemia and ketosis.

Accuracy of Continuous Glucose Monitoring (CGM) during Continuous and High-Intensity Interval Exercise in Patients with Type 1 Diabetes Mellitus.

Continuous exercise (CON) and high-intensity interval exercise (HIIE) can be safely performed with type 1 diabetes mellitus (T1DM). Additionally, continuous glucose monitoring (CGM) systems may serve as a tool to reduce the risk of exercise-induced hypoglycemia. It is unclear if CGM is accurate during CON and HIIE at different mean workloads. Seven T1DM patients performed CON and HIIE at 5% below (L) and above (M) the first lactate turn point (LTP1), and 5% below the second lactate turn point (LTP2) (H) on a cycle ergometer. Glucose was measured via CGM and in capillary blood (BG). Differences were found in comparison of CGM vs. BG in three out of the six tests (p < 0.05). In CON, bias and levels of agreement for L, M, and H were found at: 0.85 (-3.44, 5.15) mmol·L(-1), -0.45 (-3.95, 3.05) mmol·L(-1), -0.31 (-8.83, 8.20) mmol·L(-1) and at 1.17 (-2.06, 4.40) mmol·L(-1), 0.11 (-5.79, 6.01) mmol·L(-1), 1.48 (-2.60, 5.57) mmol·L(-1) in HIIE for the same intensities. Clinically-acceptable results (except for CON H) were found. CGM estimated BG to be clinically acceptable, except for CON H. Additionally, using CGM may increase avoidance of exercise-induced hypoglycemia, but usual BG control should be performed during intense exercise.

Effects of High-Intensity Interval Exercise versus Moderate Continuous Exercise on Glucose Homeostasis and Hormone Response in Patients with Type 1 Diabetes Mellitus Using Novel Ultra-Long-Acting Insulin.

INTRODUCTION: We investigated blood glucose (BG) and hormone response to aerobic high-intensity interval exercise (HIIE) and moderate continuous exercise (CON) matched for mean load and duration in type 1 diabetes mellitus (T1DM). MATERIAL AND METHODS: Seven trained male subjects with T1DM performed a maximal incremental exercise test and HIIE and CON at 3 different mean intensities below (A) and above (B) the first lactate turn point and below the second lactate turn point (C) on a cycle ergometer. Subjects were adjusted to ultra-long-acting insulin Degludec (Tresiba/ Novo Nordisk, Denmark). Before exercise, standardized meals were administered, and short-acting insulin dose was reduced by 25% (A), 50% (B), and 75% (C) dependent on mean exercise intensity. During exercise, BG, adrenaline, noradrenaline, dopamine, cortisol, glucagon, and insulin-like growth factor-1, blood lactate, heart rate, and gas exchange variables were measured. For 24 h after exercise, interstitial glucose was measured by continuous glucose monitoring system. RESULTS: BG decrease during HIIE was significantly smaller for B (p = 0.024) and tended to be smaller for A and C compared to CON. No differences were found for post-exercise interstitial glucose, acute hormone response, and carbohydrate utilization between HIIE and CON for A, B, and C. In HIIE, blood lactate for A (p = 0.006) and B (p = 0.004) and respiratory exchange ratio for A (p = 0.003) and B (p = 0.003) were significantly higher compared to CON but not for C. CONCLUSION: Hypoglycemia did not occur during or after HIIE and CON when using ultra-long-acting insulin and applying our methodological approach for exercise prescription. HIIE led to a smaller BG decrease compared to CON, although both exercises modes were matched for mean load and duration, even despite markedly higher peak workloads applied in HIIE. Therefore, HIIE and CON could be safely performed in T1DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT02075567 http://www.clinicaltrials.gov/ct2/show/NCT02075567.

Insulin degludec is not associated with a delayed or diminished response to hypoglycaemia compared with insulin glargine in type 1 diabetes: a double-blind randomised crossover study.

AIMS/HYPOTHESIS: Insulin degludec (Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared. METHODS: Twenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 ± 12 years, HbA1c = 7.8 ± 0.6% [62.8 ± 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7-9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter-regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l). RESULTS: The full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI -1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar. CONCLUSIONS/INTERPRETATION: IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins. TRIAL REGISTRATION: ClinicalTrials.gov NCT01002768. FUNDING: Novo Nordisk.

A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec.

BACKGROUND AND OBJECTIVE: Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which IDeg monomers are slowly and continuously absorbed to provide an ultra-long action profile. This double-blind, crossover, randomized study compared the pharmacokinetic and pharmacodynamic properties between IDeg 100 U/mL (U100) and IDeg 200 U/mL (U200) under steady-state (SS) conditions in subjects with type 1 diabetes mellitus. METHODS: Participants (n = 33 adults) underwent 8-day treatment periods with 0.4 U/kg IDeg U100 and IDeg U200 given once daily with insulin aspart at mealtimes. On day 8, a 26-h euglycaemic glucose clamp (5.5 mmol/L) was performed. RESULTS: The concentration-time profiles of IDeg U100 and IDeg U200 were similar, and a post-hoc analysis showed bioequivalence between these formulations, as the 90 % confidence intervals (CIs) of the U200/U100 ratios for area under the steady-state serum IDeg concentration-time curve during a dosing interval (τ; 0-24 h) (AUCτ,SS,IDeg) (0.99 [0.91-1.07]) and maximum steady-state IDeg concentration during a dosing interval (τ) (C max,SS,IDeg) (0.93 [0.84-1.02]) were within the interval 0.80-1.25. Comparable glucose infusion rates (GIR) were observed for IDeg U100 and IDeg U200 (AUCτ,SS,GIR [mg/kg]: 2,255 vs. 2,123) and the mean ratio (95 % CI) of IDeg U200/U100 for the primary endpoint (AUCτ,SS,GIR) was 0.94 [0.86-1.03]. For both formulations, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h post-dosing (U100: AUC12,SS,GIR/AUC24,SS,GIR = 48 %; U200: AUC12,SS,GIR/AUC24,SS,GIR = 46 %). Both formulations were well tolerated, and no safety events of significance were identified. CONCLUSION: IDeg U100 and U200 formulations are bioequivalent and have similar pharmacodynamic profiles at SS, implying that they can be used interchangeably in clinical practice.

Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans.

An imbalance between pro- and anti-inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low-grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18-gauge open-flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid-heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) levels increased during the study period but were not affected by lipid-heparin infusion. In contrast, the level of IL-10, an anti-inflammatory cytokine, was significantly reduced during the final hour of lipid-heparin infusion (saline: 449.2 ± 105.9 vs. lipid-heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.