Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial.

AIMS: To evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D). METHODS: We conducted a randomized crossover study comparing closed-loop therapy with standard prandial insulin boluses versus closed-loop therapy with prandial boluses reduced by 25%. Eight adolescents with T1D [3 males; mean (standard deviation) age 15.9 (1.5) years, glycated haemoglobin 74 (17) mmol/mol; median (interquartile range) total daily dose 0.9 (0.7, 1.1) IU/kg/day] were studied on two 36-h-long visits. In random order, subjects received closed-loop therapy with either standard or reduced insulin boluses administered with main meals (50-80 g carbohydrates) but not with snacks (15-30 g carbohydrates). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd). RESULTS: The median (interquartile range) time spent in target (3.9-10 mmol/l) was similar between the two interventions [74 (66, 84)% vs 80 (65, 96)%; p = 0.87] as was time spent above 10 mmol/l [21.8 (16.3, 33.5)% vs 18.0 (4.1, 34.2)%; p = 0.87] and below 3.9 mmol/l [0 (0, 1.5)% vs 0 (0, 1.8)%; p = 0.88]. Mean plasma glucose was identical during the two interventions [8.4 (0.9) mmol/l; p = 0.98]. Hypoglycaemia occurred once 1.5 h post-meal during closed-loop therapy with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9 (55.2, 75.0) vs 72.5 (63.6, 80.3) IU; p = 0.01] and resulted in lower mean plasma insulin concentration [186 (171, 260) vs 252 (198, 336) pmol/l; p = 0.002]. Lower plasma insulin was also documented overnight [160 (136, 192) vs 191 (133, 252) pmol/l; p = 0.01, pooled nights]. Ra_total was similar [26.3 (21.9, 28.0) vs 25.4 (21.0, 29.2) µmol/kg/min; p = 0.19] during the two interventions as was Rd [25.8 (21.0, 26.9) vs 25.2 (21.2, 28.8) µmol/kg/min; p = 0.46]. CONCLUSIONS: A 25% reduction in prandial boluses during closed-loop therapy maintains similar glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with a 25% reduction in prandial boluses would prevent postprandial hypoglycaemia.

Safety of closed-loop therapy during reduction or omission of meal boluses in adolescents with type 1 diabetes: a randomized clinical trial.

We evaluated the safety and efficacy of closed-loop therapy with meal announcement during reduction and omission of meal insulin boluses in adolescents with type 1 diabetes (T1D). Twelve adolescents with T1D [six male; mean (s.d.) age 15.9 (1.8) years; mean (s.d.) glycated haemoglobin (HbA1c) 77 (27) mmol/mol] were studied in a randomized crossover study comparing closed-loop therapy with meal announcement with conventional pump therapy over two 24-h stays at a clinical research facility. Identical meals were given on both occasions. The evening meal insulin bolus was calculated to cover half of the carbohydrate content of the meal and no bolus was delivered for lunch. Plasma glucose levels were in the target range of 3.9-10 mmol/l for a median [interquartile range (IQR)] of 74 (55,86)% of the time during closed-loop therapy with meal announcement and for 62 (49,75)% of the time during conventional therapy (p = 0.26). Median (IQR) time spent with plasma glucose levels > 10 mmol/l [23 (13,39) vs. 27 (10,50)%; p = 0.88] or < 3.9 mmol/l [1(0,4) vs. 5 (1,10)%; p = 0.24] and mean [standard deviation (SD)] glucose levels [8.0 (7.6,9.3) vs. 7.7 (6.6,10.1) mmol/l, p = 0.79] were also similar. In conclusion, these results assist home testing of closed-loop delivery with meal announcement in adolescents with poorly controlled T1D who miscalculate or miss meal insulin boluses.

Glucose turnover after replacement of usual therapy by insulin in insulin-naive type 2 diabetes subjects.

CONTEXT: Discontinuation of anti-hyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for inpatients with type 2 diabetes (T2D). The effects on glucose turnover when these agents are acutely withdrawn are poorly understood and may be of importance when insulin therapy is initiated. OBJECTIVE: Our objective was to investigate alterations in glucose turnover after acute withdrawal of noninsulin therapy. DESIGN AND SETTING: This was a randomized crossover study at a clinical research facility. PARTICIPANTS: Participants included 12 insulin-naive subjects with T2D. METHODS: Subjects attended two 24-hour visits. Standard therapy was discontinued and replaced by closed-loop insulin delivery during the intervention visit. Usual anti-hyperglycemic therapy was continued during the control visit. Systemic glucose appearance (Ra) and glucose disposal (Rd) were measured using a tracer dilution technique with iv [6,6-(2)H2]glucose. RESULTS: Plasma glucose profiles during both visits were comparable (P = .48). Glucose Ra increased during the day (21.4 [19.5, 23.5] vs 18.6 [17.0, 21.6) µmol/kg/min, P = .019) and decreased overnight (9.7 [8.5, 11.4] vs 11.6 [10.3, 12.9] µmol/kg/min, P = .004) when the usual therapy was discontinued and replaced with insulin. Increased daytime glucose Rd (21.2 [19.4, 23.9] vs 18.8 [18.3, 21.7] µmol/kg/min, P = .002) and decreased overnight Rd (10.4 [9.1, 12.0] vs 11.8 [10.7, 13.7] µmol/kg/min, P = .005) were observed when the usual therapy was discontinued, whereas daytime peripheral insulin sensitivity was reduced (47.8 [24.8, 66.1] vs 62.5 [34.8, 75.8] nmol/kg/min per pmol/L, P = .034). CONCLUSION: In T2D, acute discontinuation of anti-hyperglycemic therapy and replacement with insulin increases postprandial Ra and reduces peripheral insulin sensitivity. Insulin dose initiation may need to compensate for these alterations.

Absorption patterns of meals containing complex carbohydrates in type 1 diabetes.

AIMS/HYPOTHESIS: Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g). METHODS: On Visit 1, participants consumed an evening meal. On follow-up Visit 2, a variable-target glucose clamp was performed to reproduce glucose and insulin levels from Visit 1. Adopting stable-label tracer dilution methodology, we measured endogenous glucose production on Visit 2 and subtracted it from total glucose appearance measured on Visit 1 to obtain meal-attributable glucose appearance. RESULTS: After the LG meal, 25%, 50% and 75% of cumulative glucose appearance was at 88 ± 21, 175 ± 39 and 270 ± 54 min (mean ± SD), whereas glucose from the HG meal appeared significantly faster at 56 ± 12, 100 ± 25 and 153 ± 39 min (p < 0.001 to 0.003), and resulted in a 50% higher peak appearance (p < 0.001). Higher apparent bioavailability by 15% (p = 0.037) was observed after the LG meal. We documented a 20 min deceleration of dietary mixed carbohydrates compared with dietary glucose for the HG meal and a twofold deceleration for the LG meal. CONCLUSIONS/INTERPRETATION: Absorption patterns may be influenced by glycaemic load and/or meal composition, affecting optimum prandial insulin dosing in type 1 diabetes.

Validity of triple- and dual-tracer techniques to estimate glucose appearance.

The triple-tracer (TT) dilution technique has been proposed to be the gold standard method to measure postprandial glucose appearance. However, validation against an independent standard has been missing. We addressed this issue and also validated the simpler dual-tracer (DT) technique. Sixteen young subjects with type 1 diabetes (age 19.5 ± 3.8 yr, BMI 23.4 ± 1.5 kg/m(2), HbA(1c) 8.7 ± 1.7%, diabetes duration 9.0 ± 6.9 yr, total daily insulin 0.9 ± 0.2 U·kg(-1)·day(-1), mean ± SD) received a variable intravenous 20% dextrose infusion enriched with [U-(13)C]glucose over 8 h to achieve postprandial-resembling glucose excursions while intravenous insulin was administered to achieve postprandial-resembling levels of plasma insulin. Primed [6,6-(2)H(2)]glucose was infused in a manner that mimicked the expected endogenous glucose production and [U-(13)C; 1,2,3,4,5,6,6-(2)H(7)]glucose was infused in a manner that mimicked the expected glucose appearance from a standard meal. Plasma glucose enrichment was measured by gas chromatography-mass spectrometry. The intravenous dextrose infusion served as an independent standard and was reconstructed using the TT and DT techniques with the two-compartment Radziuk/Mari model and an advanced stochastic computational method. The difference between the infused and reconstructed dextrose profile was similar for the two methods (root mean square error 6.6 ± 1.9 vs. 8.0 ± 3.5 µmol·kg(-1)·min(-1), TT vs. DT, P = NS, paired t-test). The TT technique was more accurate in recovering the overall dextrose infusion (100 ± 9 and 92 ± 12%; P = 0.02). The root mean square error associated with the mean dextrose infusion profile was 2.5 and 3.3 µmol·kg(-1)·min(-1) for the TT and DT techniques, respectively. We conclude that the TT and DT techniques combined with the advanced computational method can measure accurately exogenous glucose appearance. The TT technique tends to outperform slightly the DT technique, but the latter benefits from reduced experimental and computational complexity.

Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS database.

BACKGROUND: The possible role of leukotriene receptor antagonist (LTRA) therapy in the pathogenesis of Churg-Strauss syndrome (CSS) is uncertain. The aim was to examine the association between LTRA therapy and CSS in cases registered in the FDA Adverse Event Reporting System (AERS) database. METHODS: All cases of suspected drug-induced CSS reported to the AERS database between November 1997 and April 2003 were reviewed. Subjects in whom LTRAs were the suspected medication and sufficient documentation existed to confirm the diagnosis of CSS were sequentially categorised into one of the following groups: (A) CSS before treatment initiation; (B) oral or inhaled corticosteroids reduced or stopped within 6 months of CSS onset; (C) possible prodromal phase of CSS at treatment initiation; (D) unstable asthma at treatment initiation; (E) stable asthma at treatment initiation. RESULTS: There were 181 case reports of suspected drug-induced CSS with sufficient documentation to confirm a diagnosis of CSS; in 163 (90%) an LTRA was a suspect medication. In 140 of these 163 cases there was sufficient documentation to sequentially categorize the case into groups, with 13 (9%) in A, 27 (19%) in B, 11 (8%) in C, 28 (20%) in D and 61 (44%) in E. CONCLUSION: LTRA therapy was a suspect medication in most confirmed cases of CSS reported in the AERS database. In the majority of cases treated with an LTRA, CSS could not be explained by either corticosteroid withdrawal or pre-existing CSS. These findings are informative in considering the potential associations between LTRA therapy and CSS.