Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, L-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products

Impact of diabetic nephropathy on pharmacodynamic and pharmacokinetic properties of insulin in type 1 diabetic patients

WSTĘP. Celem pracy jest ilościowa ocena parametrów farmakodynamicznych i farmakokinetycznych krótkodziałającej insuliny ludzkiej i insuliny lispro u chorych na cukrzycę typu 1 z i/lub bez jawnej nefropatii cukrzycowej. MATERIAŁ I METODY. Badanie przeprowadzone metodą podwójnie ślepej próby miało charakter krzyżowy. Stosując technikę klamry euglikemicznej (5 mmol/l), oceniano odpowiedź metaboliczną na podskórne wstrzyknięcia insuliny krótkodziałającej i lispro (0,2 j./kg) u 12 chorych z cukrzycą typu 1 i jawną nefropatią cukrzycową (białkomocz > 500 mg/24 h i/lub stężenie kreatyniny w surowicy > 1,5 mg/dl, grupa NP) oraz u 12 chorych na cukrzycę typu 1 z prawidłową funkcją nerek, stanowiących grupę kontrolną (grupa DC). WYNIKI. Szczytowe stężenie wolnej insuliny w osoczu w przypadku lispro (359 [NP] vs. 254 pmol/l [DC]) było wyższe, a czas do osiągnięcia maksymalnego stężenia insuliny (85 [NP] vs. 99 min [DC]) był krótszy niż w przypadku ludzkiej insuliny krótkodziałającej (213 [NP] vs. 144 pmol/l [DC]; 118 [NP] vs. 153 min [DC]) w obu grupach chorych. Podsumowując, stężenia ludzkiej insuliny krótkodziałającej i lispro były wyższe u chorych z jawną nefropatią niż w grupie kontrolnej. Czas do uzyskania maksymalnego efektu metabolicznego był krótszy w przypadku insuliny lispro niż w przypadku insuliny ludzkiej w obu grupach chorych (102 vs. 191 min [NP]; 105 vs. 172 min [DC]). Całkowity efekt metaboliczny insuliny krótkodziałającej w przeciwieństwie do insuliny lispro był mniejszy u chorych z nefropatią cukrzycową niż z grupie kontrolnej (odpowiednio 967 vs. 1510 mg/kg). WNIOSKI. Chociaż stwierdzono wyższe stężenia insuliny u chorych z nefropatią cukrzycową, odpowiedź metaboliczna na ludzką insulinę krótkodziałającą pozostaje zmniejszona. Insulina lispro zachowuje swoją charakterystyczną farkmakokinetykę i farmakodynamikę u chorych z jawną nefropatią cukrzycową.INTRODUCTION. To quantify pharmacokinetic and pharmacodynamic properties of regular insulin and insulin lispro in type 1 diabetic patients with and without overt diabetic nephropathy. MATERIAL AND METHODS. In this double-blind, two- -way cross-over, euglycemic (5 mmol/l) glucose clamp study, we investigated the metabolic response to subcutaneous injections of regular insulin and insulin lispro (0.2 U/kg) in 12 type 1 diabetic patients with overt diabetic nephropathy (proteinuria > 500 mg/24 h and/or serum creatinine > 1.5 mg/dl; NP group) and in a control group of 12 type 1 diabetic patients with normal renal function (DC group). RESULTS. Peak plasma free insulin levels with insulin lispro (359 [NP] vs. 254 pmol/l [DC]) were higher and time to maximal insulin concentrations (85 [NP] vs. 99 min [DC]) shorter than with regular insulin (213 [NP] vs. 144 pmol/l [DC]; 118 [NP] vs. 153 min [DC]) in both patient groups. Overall insulin levels for regular insulin and for insulin lispro were higher in patients with overt diabetic nephropathy compared with control patients. Time to maximal metabolic effect was shorter with insulin lispro than with regular insulin in both patient groups (102 vs. 191 min [NP]; 105 vs. 172 min [DC]). The overall metabolic effect of regular insulin but not of insulin lispro was lower in patients with diabetic nephropathy than in diabetic control patients (967 vs. 1,510 mg/kg, respectively). CONCLUSIONS. Although insulin levels are higher in patients with overt diabetic nephropathy, the metabolic response to regular insulin is reduced. Insulin lispro maintains its characteristic pharmacokinetic and pharmacodynamic properties in patients with overt diabetic nephropathy

Prompt Optical Observations of Gamma-ray Bursts

The Robotic Optical Transient Search Experiment (ROTSE) seeks to measure simultaneous and early afterglow optical emission from gamma-ray bursts (GRBs). A search for optical counterparts to six GRBs with localization errors of 1 square degree or better produced no detections. The earliest limiting sensitivity is m(ROTSE) > 13.1 at 10.85 seconds (5 second exposure) after the gamma-ray rise, and the best limit is m(ROTSE) > 16.0 at 62 minutes (897 second exposure). These are the most stringent limits obtained for GRB optical counterpart brightness in the first hour after the burst. Consideration of the gamma-ray fluence and peak flux for these bursts and for GRB990123 indicates that there is not a strong positive correlation between optical flux and gamma-ray emission.Comment: 4 pages, 3 figures, submitted to ApJ Letter

Heart rate dynamics during cardio-pulmonary exercise testing are associated with glycemic control in individuals with type 1 diabetes

IntroductionThis study investigated the degree and direction (kHR) of the heart rate to performance curve (HRPC) during cardio-pulmonary exercise (CPX) testing and explored the relationship with diabetes markers, anthropometry and exercise physiological markers in type 1 diabetes (T1DM).Material and methodsSixty-four people with T1DM (13 females; age: 34 ± 8 years; HbA1c: 7.8 ± 1% (62 ± 13 mmol.mol-1) performed a CPX test until maximum exhaustion. kHR was calculated by a second-degree polynomial representation between post-warm up and maximum power output. Adjusted stepwise linear regression analysis was performed to investigate kHR and its associations. Receiver operating characteristic (ROC) curve was performed based on kHR for groups kHR 0.20 in relation to HbA1c.ResultsWe found significant relationships between kHR and HbA1c (β = -0.70, P < 0.0001), age (β = -0.23, P = 0.03) and duration of diabetes (β = 0.20, P = 0.04). Stepwise linear regression resulted in an overall adjusted R2 of 0.57 (R = 0.79, P < 0.0001). Our data revealed also significant associations between kHR and percentage of heart rate at heart rate turn point from maximum heart rate (β = 0.43, P < 0.0001) and maximum power output relativized to bodyweight (β = 0.44, P = 0.001) (overall adjusted R2 of 0.44 (R = 0.53, P < 0.0001)). ROC curve analysis based on kHR resulted in a HbA1c threshold of 7.9% (62 mmol.mol-1).ConclusionOur data demonstrate atypical HRPC during CPX testing that were mainly related to glycemic control in people with T1DM

Improved Preservation of Residual Beta Cell Function by Atorvastatin in Patients with Recent Onset Type 1 Diabetes and High CRP Levels (DIATOR Trial)

A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin.The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin.Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators.ClinicalTrials.gov NCT00974740

A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage.

Glycine and cysteine are non-essential amino acids that are required to generate glutathione, an intracellular tripeptide that neutralizes reactive oxygen species and prevents tissue damage. During aging glutathione demand is thought to increase, but whether additional dietary intake of glycine and cysteine contributes towards the generation of glutathione in healthy older adults is not well understood. We investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers. Despite representing a cohort of healthy older adults (age mean = 65 years), we found significantly higher baseline levels of markers of oxidative stress, including that of malondialdehyde (MDA, 0.158 vs. 0.136 µmol/L, p < 0.0001), total cysteine (Cysteine-T, 314.8 vs. 276 µM, p < 0.0001), oxidized glutathione (GSSG, 174.5 vs. 132.3 µmol/L, p < 0.0001), and a lower ratio of reduced to oxidized glutathione (GSH-F:GSSG) (11.78 vs. 15.26, p = 0.0018) compared to a young reference group (age mean = 31.7 years, n = 20). GlyNAC supplementation was safe and well tolerated by the subjects, but did not increase levels of GSH-F:GSSG (end of study, placebo = 12.49 vs. 7.2 g = 12.65, p-value = 0.739) or that of total glutathione (GSH-T) (end of study, placebo = 903.5 vs. 7.2 g = 959.6 mg/L, p-value = 0.278), the primary endpoint of the study. Post-hoc analyses revealed that a subset of subjects characterized by high oxidative stress (above the median for MDA) and low baseline GSH-T status (below the median), who received the medium and high doses of GlyNAC, presented increased glutathione generation (end of study, placebo = 819.7 vs. 4.8g/7.2 g = 905.4 mg/L, p-value = 0.016). In summary GlyNAC supplementation is safe, well tolerated, and may increase glutathione levels in older adults with high glutathione demand. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05041179, NCT05041179

A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice

No single animal model for severe acute respiratory syndrome (SARS) reproduces all aspects of the human disease. Young inbred mice support SARS-coronavirus (SARS-CoV) replication in the respiratory tract and are available in sufficient numbers for statistical evaluation. They are relatively inexpensive and easily accessible, but their use in SARS research is limited because they do not develop illness following infection. Older (12- to 14-mo-old) BALB/c mice develop clinical illness and pneumonitis, but they can be hard to procure, and immune senescence complicates pathogenesis studies. We adapted the SARS-CoV (Urbani strain) by serial passage in the respiratory tract of young BALB/c mice. Fifteen passages resulted in a virus (MA15) that is lethal for mice following intranasal inoculation. Lethality is preceded by rapid and high titer viral replication in lungs, viremia, and dissemination of virus to extrapulmonary sites accompanied by lymphopenia, neutrophilia, and pathological changes in the lungs. Abundant viral antigen is extensively distributed in bronchial epithelial cells and alveolar pneumocytes, and necrotic cellular debris is present in airways and alveoli, with only mild and focal pneumonitis. These observations suggest that mice infected with MA15 die from an overwhelming viral infection with extensive, virally mediated destruction of pneumocytes and ciliated epithelial cells. The MA15 virus has six coding mutations associated with adaptation and increased virulence; when introduced into a recombinant SARS-CoV, these mutations result in a highly virulent and lethal virus (rMA15), duplicating the phenotype of the biologically derived MA15 virus. Intranasal inoculation with MA15 reproduces many aspects of disease seen in severe human cases of SARS. The availability of the MA15 virus will enhance the use of the mouse model for SARS because infection with MA15 causes morbidity, mortality, and pulmonary pathology. This virus will be of value as a stringent challenge in evaluation of the efficacy of vaccines and antivirals