Model-based closed-loop glucose control in type 1 diabetes: the DiaCon experience.

BACKGROUND: To improve type 1 diabetes mellitus (T1DM) management, we developed a model predictive control (MPC) algorithm for closed-loop (CL) glucose control based on a linear second-order deterministic-stochastic model. The deterministic part of the model is specified by three patient-specific parameters: insulin sensitivity factor, insulin action time, and basal insulin infusion rate. The stochastic part is identical for all patients but identified from data from a single patient. Results of the first clinical feasibility test of the algorithm are presented. METHODS: We conducted two randomized crossover studies. Study 1 compared CL with open-loop (OL) control. Study 2 compared glucose control after CL initiation in the euglycemic (CL-Eu) and hyperglycemic (CL-Hyper) ranges, respectively. Patients were studied from 22:00-07:00 on two separate nights. RESULTS: Each study included six T1DM patients (hemoglobin A1c 7.2% ± 0.4%). In study 1, hypoglycemic events (plasma glucose < 54 mg/dl) occurred on two OL and one CL nights. Average glucose from 22:00-07:00 was 90 mg/dl [74-146 mg/dl; median (interquartile range)] during OL and 108 mg/dl (101-128 mg/dl) during CL (determined by continuous glucose monitoring). However, median time spent in the range 70-144 mg/dl was 67.9% (3.0-73.3%) during OL and 80.8% (70.5-89.7%) during CL. In study 2, there was one episode of hypoglycemia with plasma glucose <54 mg/dl in a CL-Eu night. Mean glucose from 22:00-07:00 and time spent in the range 70-144 mg/dl were 121 mg/dl (117-133 mg/dl) and 69.0% (30.7-77.9%) in CL-Eu and 149 mg/dl (140-193 mg/dl) and 48.2% (34.9-72.5%) in CL-Hyper, respectively. CONCLUSIONS: This study suggests that our novel MPC algorithm can safely and effectively control glucose overnight, also when CL control is initiated during hyperglycemia.

Comparison of the pharmacokinetics of three concentrations of insulin aspart during continuous subcutaneous insulin infusion (CSII) in a pig model.

OBJECTIVES: The aim of the study was to investigate the pharmacokinetic properties of insulin aspart (IAsp) in three different concentrations given as a continuous subcutaneous insulin infusion (CSII). METHODS: A randomized cross-over study was performed in pigs, where IAsp U200, U100 or U20 was given for 8 h with the same total dose. Six pigs were included and blood was sampled during the CSII and 3 h after. KEY FINDINGS: The half-life (t(1/2) ) was 24.3 (range 17.3-41.3), 28.8 (range 19.6-54.3) and 23.6 (range 17.4-36.8) min for U200, U100 and U20, respectively. The area under the curve per dose (AUC/D) was determined to be 51.2 ± 19.5, 52.3 ± 12.5 and 51.6 ± 6.7 pm × min/kg for U200, U100 and U20, respectively. The steady state plasma concentration (C(ss) ) was 57.5 ± 27.1, 54.3 ± 10.3 and 55.1 ± 8.0 pm (mean ± SD) for U200, U100 and U20, respectively. Time to steady state (T(ss) ) was 110 ± 36, 98 ± 48 and 90 ± 27 min for U200, U100 and U20, respectively. CONCLUSIONS: In conclusion, no significant difference was found in t(1/2) , AUC/D, C(ss) or T(ss) between the three IAsp concentrations when given at a basal rate in CSII.

Explorative study of pharmacokinetics and pharmacodynamics after change in basal insulin infusion rate.

BACKGROUND: The use of insulin pumps is rapidly increasing and new, technologically more advanced pumps are continuously being developed. It is of interest to assess the clinical relevance of the many technical features of these pumps, e.g., the effect on pharmacokinetics and pharmacodynamics with change in infusion rate. METHOD: The aim of this study was to explore the sequence of pharmacokinetic and pharmacodynamic changes after dose doubling of the basal insulin infusion rate with subcutaneous bolus insulin injections once an hour, continuous subcutaneous insulin infusion, and continuous intravenous insulin infusion. Ten type 1 diabetes mellitus patients were included. The insulin doses were calculated based on the habitual insulin doses. The study was designed as an open-labeled, single-center, randomized, crossover exploratory trial. RESULTS: Dose doubling of the basal insulin infusion rate with the three different administration protocols did not result in any clinically relevant differences in the time courses of the pharmacokinetic and pharmacodynamic parameters. With all three administration protocols, we observed a time interval of more than 6 hours before a new steady state of insulin was achieved. CONCLUSIONS: Our results indicate that frequent changes in basal subcutaneous insulin infusion rates are not of significant clinical relevance on a 24-hour basis. Regarding technological features of subcutaneous insulin pumps, no discernable advantages of increasing pump stroke frequency were found. This indicates that pump stroke frequency sophistication might not be of clinical relevance in pumps used for basal subcutaneous insulin infusion.

Comparison of a luminescent oxygen channeling immunoassay and an ELISA for detecting insulin aspart in human serum.

The study was a comparison between a Luminescent Oxygen Channeling Immunoassay (LOCI) and an enzyme-linked immunosorbent assay (ELISA) for quantification of Insulin Aspart (IAsp) in human serum. The advantage of LOCI compared to ELISA is reduced workload and higher throughput. The ELISA assay was performed as published (Andersen et al., 2000 [5]). The LOCI followed a 2-step reaction. First, the sample was incubated for 1h with a mixture of biotinylated antibody specific for IAsp and beads coated with insulin-detecting antibody. This step was followed by a 30-min incubation with beads covalently coated with streptavidin. When the beads were brought in proximity through binding of IAsp, light was generated from a chemiluminescent reaction in the beads. This light was measured and quantified. Spiked samples with different concentrations of IAsp were prepared in human serum to compare ELISA and LOCI. Human serum samples (n=510) from a pilot study with healthy subjects receiving IAsp were also analysed and compared in the two assays. Higher precision, improved accuracy and a wider analytical range were found using LOCI compared to ELISA. However, sample haemolysis interfered more when using LOCI than ELISA. The IAsp concentrations determined in the human serum samples from the pilot study gave a good correlation between the two assays. In conclusion, LOCI can determine IAsp in human serum just as well as ELISA. Using LOCI reduces the workload, which is particularly useful when handling large sample sizes.

Changes in intracellular cAMP reported by a Redistribution assay using a cAMP-dependent protein kinase-green fluorescent protein chimera.

We report on a novel method to monitor changes in intracellular cAMP concentration ([cAMP]i) within intact living cells using a chimeric fusion of the catalytic subunit of cAMP-dependent protein kinase to green fluorescent protein (PKAcat-GFP). In stably transfected unstimulated fibroblasts, fusion protein fluorescence is highly concentrated in aggregates throughout the cytoplasm and absent in the nucleus. Elevation of [cAMP]i disperses GFP fluorescence from the cytoplasmic aggregates within minutes. Spot-photobleach measurements show that the rate of exchange of GFP-labeled catalytic subunits at these aggregates increases in proportion to [cAMP]i. For any given stimulus, the response curve for dispersal of GFP fluorescence from aggregates agrees closely with the increase in total [cAMP]i as measured by standard in vitro methods (SPA). The redistribution of fluorescence is completely reversible: reduction of [cAMP]i results in return of fluorescence to the cytoplasmic aggregates. Consistent behaviour of PKAcat-GFP is seen in different cell backgrounds. We demonstrate that PKA Redistribution assays are suitable for measurement of changes in [cAMP]i brought about by both Gs- and Gi-protein-coupled receptor stimulation as well as by inhibition of cAMP phosphodiesterases.