Gerd Koehler

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

Pharmacodynamics of the long‐acting insulin analogues detemir and glargine following single‐doses and under steady‐state conditions in patients with type 1 diabetes

The pharmacodynamic characteristics of the basal insulin analogues insulin detemir (IDet) and insulin glargine (IGlar) have been examined extensively via euglycaemic clamp studies. However, differences in clamp methodology and in the analysis of clamp data between trials have led to confusion over the duration of action of these two insulins. The aim of this study was to address these ambiguities in the literature by assessing the pharmacodynamic properties of IDet and IGlar over 30 h under single‐dose and steady‐state conditions using the definitions and procedures previously standardized by Heise and Pieber in 2007.

Ultra-Long Pharmacokinetic Properties of Insulin Degludec are Comparable in Elderly Subjects and Younger Adults with Type 1 Diabetes Mellitus

AbstractBackgroundManagement of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.ObjectiveThe aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.MethodsThis trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18–35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUCIDeg,τ,SS) (τ = 0–24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (Cmax,IDeg,SS). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUCGIR,τ,SS), and the maximum GIR at steady state (GIRmax,IDeg,SS).ResultsTotal exposure (AUCIDeg,τ,SS) and maximum concentration (Cmax,IDeg,SS) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUCIDeg,τ,SS and Cmax,IDeg,SS and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73–1.47) and 1.02 (95 % CI 0.74–1.39), respectively. Mean AUCIDeg,0–12h,SS/AUCIDeg,τ,SS was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUCGIR,τ,SS (the primary endpoint of this study) and GIRmax,IDeg,SS. Estimated mean age group ratios (elderly/younger adult) for AUCGIR,τ,SS and GIRmax,IDeg,SS and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47–1.31) and 0.80 (95 % CI 0.54–1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. ConclusionsThe exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes.Clinical trials.gov number: NCT00964418

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.

A direct comparison of the pharmacodynamic properties of insulin detemir and neutral protamine lispro insulin in patients with type 1 diabetes.

To compare the pharmacodynamic properties of insulin detemir (detemir) and neutral protamine lispro (NPL) insulin using a euglycaemic glucose clamp.

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.

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).

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

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.

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

BackgroundTherapy 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 presentationA 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.ConclusionsPeople 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.

Rapid Reversible Coma with Intravenous Gamma-Hydroxybutyrate in a Moxifloxacin-Treated Patient

An adverse reaction rate of 5.0–37.0% has been term sedation anaesthesia. It is also used as an antidepressant, an anxiolytic and for the treatment of reported with moxifloxacin.[1-3] The most common alcohol and opiate withdrawal syndromes.[6] adverse effects are gastrointestinal reactions (nausea 8%, diarrhoea 6%, vomiting 2% and taste perversion We report on a haemodialysis patient with Child 1%); next most common are symptoms of the cenPugh A alcoholic cirrhosis of the liver and coma that tral nervous system (CNS) [mostly headache 2% developed 8 days after commencement of oral moxifloxacin 400 mg/day. After intravenous treatment and dizziness 3%]; less frequent are restlessness, with GHB 15 mg/kg/h for 24 hours, the patient was insomnia, sleep disorders, agitation and vision conscious, orientated and neurologically unremarkchanges. More rare adverse effects of moxifloxacin able. include QTc prolongations, dermatological reactions, liver changes, tendon ruptures and arthroCase Report pathy.