Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. METHODS: Subjects (18-64 years; body mass index 20.0-28.0 kg/m(2); glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. RESULTS: The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. CONCLUSIONS: Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

We obtained evidence from a large study in Dutch twins (N = 8387) and siblings (N = 2295) that variation in loneliness has a genetic component. The heritability estimate for loneliness, which was assessed as an ordinal trait, was 40% and did not differ between males and females. There were 682 sibling pairs with genotypic (around 400 microsatellite markers) data. We combined phenotypic and genotypic data to carry out a genome scan to localize QTLs for loneliness. One region on chromosome 12q23.3-24.3, showed near suggestive linkage. Genetic association tests within this region revealed significant association (p-value 0.009) with one of the alleles of marker D12S79 and with one of the alleles of neighbouring marker D12S395 (p-value 0.043). We review evidence for linkage in this region for psychiatric disorders and discuss our findings within this context. © 2006 Springer Science+Business Media, Inc

T cell receptor sequence clustering and antigen specificity

There has been increasing interest in the role of T cells and their involvement in cancer, autoimmune and infectious diseases. However, the nature of T cell receptor (TCR) epitope recognition at a repertoire level is not yet fully understood. Due to technological advances a plethora of TCR sequences from a variety of disease and treatment settings has become readily available. Current efforts in TCR specificity analysis focus on identifying characteristics in immune repertoires which can explain or predict disease outcome or progression, or can be used to monitor the efficacy of disease therapy. In this context, clustering of TCRs by sequence to reflect biological similarity, and especially to reflect antigen specificity have become of paramount importance. We review the main TCR sequence clustering methods and the different similarity measures they use, and discuss their performance and possible improvement. We aim to provide guidance for non-specialists who wish to use TCR repertoire sequencing for disease tracking, patient stratification or therapy prediction, and to provide a starting point for those aiming to develop novel techniques for TCR annotation through clustering

Effects of several types of biomass fuels on the yield, nanostructure and reactivity of soot from fast pyrolysis at high temperatures

peer-reviewedThis study presents the effect of biomass origin on the yield, nanostructure and reactivity of soot. Soot was produced from wood and herbaceous biomass pyrolysis at high heating rates and at temperatures of 1250 and 1400° C in a drop tube furnace. The structure of solid residues was characterized by electron microscopy techniques, X-ray diffraction and N2 adsorption. The reactivity of soot was investigated by thermogravimetric analysis. Results showed that soot generated at 1400° C was more reactive than soot generated at 1250° C for all biomass types. Pinewood, beechwood and wheat straw soot demonstrated differences in alkali content, particle size and nanostructure. Potassium was incorporated in the soot matrix and significantly influenced soot reactivity. Pinewood soot particles produced at 1250° C had a broader particle size range (27.2–263 nm) compared to beechwood soot (33.2–102 nm) and wheat straw soot (11.5–165.3 nm), and contained mainly multi-core structures

One week's treatment with the long-acting glucagon-like peptide 1 derivate liraglutide (NN2211) markedly improves 24-h glycemia and α- and β-cell function and reduces endogenous glucose release in patients with type 2 diabetes

Glukagonopodobny peptyd 1 (GLP-1, glucagon-like peptide 1) może być bardzo skuteczny w leczeniu cukrzycy typu 2. Autorzy badali wpływ krótkiego (1 tydzień) stosowania pochodnej GLP-1, liraglutydu (NN2211), na 24-godzinny profil glikemii i stężenia krążących wolnych kwasów tłuszczowych, wydzielanie hormonów przez komórki wysp trzustkowych oraz na opróżnianie żołądka podczas posiłków (z użyciem acetaminofenu). Ponadto, oceniali endogenne uwalnianie glukozy na czczo oraz glukoneogenezę (odpowiednio wlew 3-3H-glukozy i wypicie 2H2O), a następnie zbadali funkcję komórek wysp trzustkowych, stosując homeostatyczny model oceny oraz 1. i 2. fazę wydzielania insuliny z użyciem klamry hiperglikemicznej (stężenie glukozy w osoczu wynosiło ok. 16 mmol/l). Na szczycie hiperglikemii wykonano test stymulacji argininą. W badaniu przeprowadzonym jako podwójnie ślepa próba w układzie naprzemiennym z grupą kontrolną placebo wzięło udział 13 chorych na cukrzycę typu 2. Liraglutyd podawano podskórnie raz na dobę (6 &micro;g/kg). Stosowanie leku spowodowało istotne zmniejszenie 24-godzinnego pola pod krzywą dla glukozy (p = 0,01) i glukagonu (p = 0,04), natomiast pole pod krzywą dla krążących wolnych kwasów tłuszczowych nie uległo zmianie. Dobowe wydzielanie insuliny oceniane na podstawie dekonwolucji stężeń C-peptydu w osoczu nie zmieniło się, co wskazuje na jego względny wzrost. Liraglutyd w zastosowanej dawce nie wpłynął na opróżnianie żołądka. Uwalnianie endogennej glukozy na czczo zmniejszyło się (p = 0,04) na skutek zahamowania glikogenolizy (p = 0,01), natomiast nasilenie glukoneogenezy nie uległo zmianie. Pierwsza faza wydzielania insuliny oraz reakcja na argininę w warunkach hiperglikemii wyraźnie się nasiliły (p < 0,001), a współczynnik proinsulina/insulina się zmniejszył (p = 0,001). Wskaźnik podatności (disposition index) (maksymalne stężenie insuliny po dożylnym podaniu bolusa glukozy pomnożone przez insulinowrażliwość obliczoną za pomocą modelu homeostatycznego) niemal podwoił się w czasie leczenia liraglutydem (p < 0,01). W okresie stosowania leku zaobserwowano również zmniejszone wydzielanie glukagonu, zarówno pod wpływem samej hiperglikemii, jak i po podaniu argininy (p < 0,01; p = 0,01). Stosowanie liraglutydu raz na dobę przez 1 tydzień u chorych na cukrzycę typu 2 poprawia 24-godzinną kontrolę glikemii (również po posiłkach i w nocy). Lek ten działa na zasadzie kilku różnych mechanizmów, między innymi poprawia czynność komórek wysp trzustkowych. W badaniu zwrócono uwagę na GLP-1 i jego pochodne jako nowe i obiecujące leki w terapii cukrzycy typu 2.Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-3Hglucose infusion and 2H2O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first- and second-phase insulin response during a hyperglycemic clamp (plasma glucose ~16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 &#956;g/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P = 0.01) and glucagon (P = 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P = 0.04) as a result of a reduced glycogenolysis (P = 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P = 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P = 0.01). Thus, 1 week&#8217;s treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This study further emphasizes GLP-1 and its derivatives as a promising novel concept for treatment of type 2 diabetes

Reaction mechanism of dimethyl ether carbonylation to methyl acetate over mordenite: a combined DFT/experimental study

Dimethyl ether carbonylation to methyl acetate over mordenite was studied theoretically with density functional theory calculations and experimentally in a fixed bed flow reactor. A new reaction path to methyl acetate entirely in the 8 membered ring was discovered.</p