Biomarkers Associated With Future Severe Liver Disease in Children With Alpha-1-Antitrypsin Deficiency.

Background and Aims: Children with alpha-1-antitrypsin deficiency (AATD) exhibit a wide range of liver disease outcomes from portal hypertension and transplant to asymptomatic without fibrosis. Individual outcomes cannot be predicted. Liver injury in AATD is caused by the accumulation in hepatocytes of the mutant Z alpha-1-antitrypsin (AAT) protein, especially the toxic, intracellular polymerized conformation. AATD patients have trace Z polymer detectable in serum with unknown significance. Methods: The Childhood Liver Disease Research Network is an NIH consortium for the study of pediatric liver diseases, including AATD. We obtained data and samples with the aim of identifying biomarkers predictive of severe AATD liver disease. Results: We analyzed prospective AATD Childhood Liver Disease Research Network data and serum samples in 251 subjects from 2007 to 2015 for outcomes and Z polymer levels. Fifty-eight of 251 had clinically evident portal hypertension (CEPH) at enrollment, and 10 developed CEPH during follow-up. Higher Z AAT polymer levels were associated with existing CEPH (P = .01). In infants without CEPH, higher polymer levels were associated with future CEPH later in childhood, but total AAT was not predictive. Higher gamma-glutamyl transferase (GGT) in the first few months of life was also significantly associated with future CEPH, and risk-threshold GGT levels can be identified. A model was constructed to identify subjects at high risk of future CEPH by combining clinical GGT and polymer levels (area under the curve of 0.83; 95% confidence interval: 0.656-1.00, P = .019). Conclusion: High circulating Z polymer levels and high GGT early in life are associated with future CEPH in AATD, and the use of predictive cutoffs may assist in future clinical trial design.

Evaluation of Intradermal and Subcutaneous Infusion Set Performance Under 24-Hour Basal and Bolus Conditions.

BACKGROUND: This study sought to assess the function and delivery reliability of intradermal (ID) infusion sets used with commercial insulin pumps. METHOD: Healthy subjects (n = 43) were randomized to either ID or subcutaneous (SC) arms, and received basal/bolus placebo delivery for 24 hours. Subjects received 4 of 8 infusion set combinations (ID: microneedle design A or B, with 2 pump brands [Animas or MiniMed]; SC: Teflon Quickset or steel Rapid-D, Animas pump only, with or without overtaping) and were evaluated for pump occlusion alarms, fluid leakage, pain, and tissue tolerability. A novel algorithm was developed to determine flow consistency based on fluid pressure, and the duration and occurrence rate for periods of unalarmed but interrupted flow ("silent occlusions'") were compared. RESULTS: ID delivery was successfully maintained over the 24-hour infusion period. The number of silent occlusions was lower for ID microneedle cannula design B than A (P < .01) and lower for Rapid-D SC device compared to Quick-set (P = .03). There was no significant difference in the number of occlusion alarms between the ID and SC devices with the Animas pump. However, the pumps tested with ID devices had significantly different alarm rates (MiniMed 29.5%, Animas 0%, P < .001). Leakage and tissue tolerability were comparable across devices. CONCLUSION: The ID infusion set reliably delivered diluent for an extended 24-hour period in healthy subjects and was well tolerated. Silent occlusion flow interruptions could be detected in both ID and SC infusion sets using a proprietary algorithm. This algorithm is a promising method for quantitatively evaluating infusion set flow performance.

Characterizing normal-use temperature conditions of pumped insulin.

In this study, the temperature profiles of insulin pump reservoirs during normal wear conditions across multiple seasons were characterized. Thermocouples secured in reservoirs filled with insulin diluent were loaded in infusion pumps worn by volunteers. Reservoir and ambient environmental temperature data and activity levels were logged during the course of normal daily activities in February (winter), April (spring), and August (summer). Each seasonal data set comprised 7 to 14 days of wear from 3 to 5 volunteers. Reservoir temperature profiles were generally higher than ambient temperatures, likely due to heat transfer from the wearer when the pump was placed close to the body. Temperature conditions inside pump reservoirs fluctuated between 25°C and 37°C regardless of seasonal variations. The average reservoir temperature remained close to 30°C across all seasons, notably lower than used in previously published compatibility and stability protocols (37°C). Results from this study could be utilized to develop more accurate stability and compatibility testing procedures for new insulin formulations and/or delivery devices.

Multi-day pre-clinical demonstration of glucose/galactose binding protein-based fiber optic sensor.

We report here the first pre-clinical demonstration of continuous glucose tracking by fluorophore-labeled and genetically engineered glucose/galactose binding protein (GGBP). Acrylodan-labeled GGBP was immobilized in a hydrogel matrix at the tip of a small diameter optical fiber contained in a stainless steel needle. The fiber optic biosensors were inserted subcutaneously into Yucatan and Yorkshire swine, and the sensor response to changing glucose levels was monitored at intervals over a 7-day period. Sensor mean percent error on day 7 was 16.4±5.0% using a single daily reference blood glucose value to calibrate the sensor. The GGBP sensor's susceptibility to common interferents was tested in a well-plate system using human sera. No significant interference was observed from the tested interferents except for tetracycline at the drug's maximum plasma concentration. The robust performance of the GGBP-based fiber optic sensor in swine models and resistance to interferents indicates the potential of this technology for continuous glucose monitoring in humans.

Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection.

BACKGROUND: This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions. METHODS: Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5). RESULTS: Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites. CONCLUSIONS: Microneedle ID insulin lispro delivery enables more rapid onset and offset of metabolic effect than SC therapy and is safe and well tolerated; further study for insulin therapy is warranted.

Continuous glucose monitoring using a novel glucose/galactose binding protein: results of a 12-hour feasibility study with the becton dickinson glucose/galactose binding protein sensor.

AIM: This study evaluated the performance characteristics of a prototype Becton Dickinson (BD) (Franklin Lakes, NJ) glucose/galactose binding protein (GGBP) sensor placed intradermally (BD-ID) or subcutaneously (BD-SC) for continuous glucose monitoring. MATERIALS AND METHODS: The performance characteristics of the prototype BD GGBP sensor after intradermal or subcutaneous placement were assessed, and its accuracy was compared with that of a glucose oxidase (GOx)-based sensor and a standard laboratory method (YSI STAT2300 analyzer, Yellow Springs Instrument, Yellow Springs, OH) under glucose clamp conditions and during an off-clamp meal challenge in 40 patients with type 1 or 2 diabetes in a 12-h feasibility study. RESULTS: BD-ID and BD-SC sensors performed as well as or better than the GOx-based sensor (differences in median absolute percentage error 2-4 points in hyperglycemic and euglycemic regions, ≥ 10 points in the hypoglycemic region). For glucose values ≤ 100 mg/dL, the percentage of measurement values in consensus error plot Zone A was substantially higher with the GGBP sensors than the GOx-based sensor. CONCLUSIONS: The BD prototype sensor demonstrated competitive accuracy relative to a GOx-based sensor and a YSI blood standard with a single calibration and minimal warm-up. Current development work is focused on the design and manufacture of a commercially feasible device that will include marked enhancements to device robustness and longevity.