Effect of a phase advance and phase delay of the 24-h cycle on energy metabolism, appetite, and related hormones.
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BACKGROUND: The disruption of the circadian system has been associated with the development of obesity. OBJECTIVE: We examined the effects of circadian misalignment on sleep, energy expenditure, substrate oxidation, appetite, and related hormones. DESIGN: Thirteen subjects [aged 24.3 +/- 2.5 (mean +/- SD) y; BMI (in kg/m(2)): 23.6 +/- 1.7 (mean +/- SD)] completed a randomized crossover study. For each condition, subjects stayed time blinded in the respiration chamber during 3 light-entrained circadian cycles that resulted in a phase advance (3 x 21 h) and a phase delay (3 x 27 h) compared with during a 24-h cycle. Sleep, energy expenditure, substrate oxidation, and appetite were quantified. Blood and saliva samples were taken to determine melatonin, glucose, insulin, ghrelin, leptin, glucagon-like peptide 1 (GLP-1), and cortisol concentrations. RESULTS: Circadian misalignment, either phase advanced or phase delayed, did not result in any changes in appetite or energy expenditure, whereas meal-related blood variables (glucose, insulin, ghrelin, leptin, and GLP-1) followed the new meal patterns. However, phase-advanced misalignment caused flattening of the cortisol-secretion pattern (P < 0.001), increased insulin concentrations (P = 0.04), and increased carbohydrate oxidation (P = 0.03) and decreased protein oxidation (P = 0.001). Phase-delayed misalignment increased rapid eye movement sleep (P < 0.001) and the sleeping metabolic rate (P = 0.02), increased glucose (P = 0.02) and decreased GLP-1 (P = 0.02) concentrations, and increased carbohydrate oxidation (P = 0.01) and decreased protein oxidation (P = 0.003). CONCLUSIONS: The main effect of circadian misalignment, either phase advanced or phase delayed, is a concomitant disturbance of the glucose-insulin metabolism and substrate oxidation, whereas the energy balance or sleep is not largely affected. Chronically eating and sleeping at unusual circadian times may create a health risk through a metabolic disturbance. This trial was registered at the International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) as NTR2926. (+info)
Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion.
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BACKGROUND: Intradermal (ID) delivery has been shown to accelerate insulin pharmacokinetics (PK). We compared the PK and pharmacodynamic (PD) effects of insulin lispro administered before two daily standardized solid mixed meals (breakfast and lunch), using microneedle-based ID or traditional subcutaneous (SC) delivery. METHOD: The study included 22 subjects with type 1 diabetes in an eight-arm full crossover block design. One arm established each subject's optimal meal dose. In six additional arms, the optimal, higher, and lower doses (+30%, -30%) were each given ID and SC delivery, in random order. The final arm assessed earlier timing for the ID optimal dose (-12 versus -2 min). The PK/PD data were collected for 6 h following meals. Intravenous basal regular insulin was given throughout, and premeal blood glucose (BG) adjusted to 115 mg/dl. RESULTS: The primary end point, postprandial time in range (70-180 mg/dl), showed no route-based differences with a high level of overall BG control for both SC and ID delivery. Secondary insulin PK end points showed more rapid ID availability versus SC across doses and meals (Tmax -16 min, T50rising -7 min, T50falling -30 min, all p < .05). Both intrasubject and intersubject variability for ID Tmax were significantly lower. Intradermal delivery showed modest, statistically significant secondary PD differences across doses and meals, generally within 90-120 min postprandially (12 mg/dl BG at 90 min, 7 mg/dl BGmax, 7 mg/dl mean BG 0-2 h, all p < .05). CONCLUSIONS: This study indicates that ID insulin delivery is superior to SC delivery in speed of systemic availability and PK consistency and may improve postprandial glucose control. (+info)
Feasibility of overnight closed-loop control based on hourly blood glucose measurements.
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INTRODUCTION: Safe and effective closed-loop control (artificial pancreas) is the ultimate goal of insulin delivery. In this study, we examined the performance of a closed-loop control algorithm used for the overnight time period to safely achieve a narrow target range of blood glucose (BG) concentrations prior to breakfast. The primary goal was to compare the quality of algorithm control during repeated overnight experiments. MATERIALS AND METHODS: Twenty-three subjects with type 1 diabetes performed 2 overnight experiments on each of three visits at the study site, resulting in 138 overnight experiments. On the first evening, the subject's insulin therapy was applied; on the second, the insulin was delivered by an algorithm based on subcutaneous continuous glucose measurements (including meal control) until midnight. Overnight closed-loop control was applied between midnight and 6 a.m. based on hourly venous BG measurements during the first and second nights. RESULTS: The number of BG values within the target range (90-150 mg/dl) increased from 52.9% (219 out of 414 measurements) during the first nights to 72.2% (299 out of 414 measurements) during the second nights (p < .001, chi(2)-test). The occurrence of hypoglycemia interventions was reduced from 14 oral glucose interventions, the latest occurring at 2:36 a.m. during the first nights, to 1 intervention occurring at 1:02 a.m. during the second nights (p < .001, chi(2)-test). CONCLUSIONS: Overnight controller performance improved when optimized initial control was given; this was suggested by the better metabolic control during the second night. Adequate controller run-in time seems to be important for achieving good overnight control. In addition, the findings demonstrate that hourly BG data are sufficient for the closed-loop control algorithm tested to achieve appropriate glycemic control. (+info)
Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial.
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