Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo-controlled, double-blind, crossover trial.

AIMS: To investigate the effect of glucagon-like peptide 1 receptor agonist liraglutide on the counter-regulatory hormone response to hypoglycaemia in type 1 diabetes. METHODS: We conducted a randomized, double-blind, placebo-controlled, single-centre trial, in which a total of 45 adults with type 1 diabetes [mean ± standard deviation age 34.5 ± 11.2 years, BMI 23.9 ± 2.4 kg/m(2) , glycated haemoglobin (HbA1c) 7.6 ± 0.8%, diabetes duration 16.6 ± 9.4 years] underwent a hypoglycaemic clamp after 4 weeks' crossover treatment with once-daily liraglutide/placebo added to insulin in one of three liraglutide dose groups: 0.6 mg (n = 15); 1.2 mg (n = 14); and 1.8 mg (n = 16). The main outcome measure was glucagon concentration at nadir plasma glucose (2.5 mmol/l). Clinical outcomes were also evaluated. Five participants were withdrawn from the trial; three because of adverse events. All participants were included in the analysis. RESULTS: Glucagon concentration at nadir plasma glucose was modest, trending towards lower concentrations at increasing liraglutide dose versus placebo: 34.7 versus 38.1 pg/ml, p = 0.555 (0.6 mg); 28.8 versus 37.2 pg/ml, p = 0.126 (1.2 mg); and 28.4 versus 37.5 pg/ml, p = 0.092 (1.8 mg). There was no difference, however, between liraglutide and placebo in incremental change in glucagon during hypoglycaemia. Other counter-regulatory hormone levels increased during hypoglycaemia with no systematic differences between groups. Glucose infusion rates were significantly lower with liraglutide versus placebo during the clamp. After 4 weeks' treatment, HbA1c remained unchanged in the liraglutide and placebo groups. Greater reductions in insulin dose and body weight were seen with liraglutide versus placebo. CONCLUSIONS: Liraglutide did not compromise hypoglycaemic responses in type 1 diabetes after 4 weeks' treatment.

Ultra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus.

BACKGROUND: Management 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. OBJECTIVE: The 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. METHODS: This 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 (AUC(IDeg,τ,SS)) (τ = 0-24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (C(max,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 (AUC(GIR,τ,SS)), and the maximum GIR at steady state (GIR(max,IDeg,SS)). RESULTS: Total exposure (AUC(IDeg,τ,SS)) and maximum concentration (C(max,IDeg,SS)) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUC(IDeg,τ,SS) and C(max,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 AUC(IDeg,0-12h,SS)/AUC(IDeg,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 AUC(GIR,τ,SS) (the primary endpoint of this study) and GIR(max,IDeg,SS). Estimated mean age group ratios (elderly/younger adult) for AUC(GIR,τ,SS) and GIR(max,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. CONCLUSIONS: The 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.

Flavin-dependent quinone reductases.

Quinones are abundant cyclic organic compounds present in the environment as well as in pro- and eukaryotic cells. Several species have been shown to possess enzymes that afford the two-electron reduction to the hydroquinone form in an attempt to avoid the generation of one-electron reduced semiquinone known to cause oxidative stress. These enzymes utilize a flavin cofactor, either FMN or FAD, to transfer a hydride from an electron donor, such as NAD(P)H, to a quinone substrate. This family of flavin-dependent quinone reductases shares a flavodoxin-like structure and reaction mechanism pointing towards a common evolutionary origin. Recent studies of their physiological functions in eukaryotes suggest a role beyond detoxication of quinones and involvement in the oxygen stress response. Accordingly, mammalian quinone reductases emerge as central molecular switches that control the lifespan of transcription factors, such as p53, and hence participate in the development of apoptosis and cell transformation.

The significance of sunlight for the elimination of indicator bacteria in small-scale bathing ponds in central Europe.

In order to determine the impact of sunlight on the reduction rate of indicator bacteria, bathing waters of different turbidity were artificially contaminated with indicator bacteria and exposed to sunlight. The reduction rates determined for the indicator bacteria showed a significant correlation with radiation intensity and, thus, also the time of day as well as the turbidity of the water. Under conditions of strong radiation intensity and low water turbidity (< 5 FTU), indicator bacteria were eliminated within 1-2 h of contamination with an initial concentration of 10(5) CFU/mL. Moreover, differences between different indicator bacteria were found. Enterococcus faecalis proved to be significantly more resistant to sunlight than the other indicator bacteria tested (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus). The results of the present study, namely the complete elimination of indicator bacteria within a few hours, showed that sunlight, given an appropriate intensity and good water transparency, was the most important factor in the reduction of hygienically-relevant microorganisms in surface waters and, thus, also in small-scale bathing ponds.

The economic and fiscal impact of aging retirees on a small rural region.

The literature on the economic and fiscal impacts of in-migrating retirees on rural communities tends to concentrate on the younger, more affluent newly retired. This article addresses an issue not systematically addressed: the impacts on communities as these retirees age. Households that vary by age have different income levels and expenditure patterns. A county-level, conjoined input-output/econometrics simulation model is used to assess the impacts of an aging rural population. As hypothesized, the magnitude and nature of impacts is in direct proportion to relative household size and income level. The increased local government expenditures are covered by the increased revenues, even as retirees age.