Novel hepatoselective insulin analog

Cel pracy. Zbadanie, czy tyroksylowy analog insuliny z ograniczonym dostępem do receptora w tkankach obwodowych wykazuje względnie wybiórcze powinowactwo do wątroby u ludzi. MATERIAŁ i metody. Pięć zdrowych osób otrzymywało podskórnie Na B1L-thyroksyl-insulinę (B1-T4-Ins) lub insulinę NPH w przypadkowej kolejności. Posługując się metodą klamry euglikemicznej i rozcieńczania znacznika izotopowego([D-6,6-2H2] glukozy), badano kinetykę insuliny oraz jej względny wpływ na wątrobową produkcję i obwodowy wychwyt glukozy. Pobierano próbki krwi w celu oznaczenia całkowitego stężenia insuliny immunoreaktywnej (bądź jej analogu) oraz w celu określenia stopnia wiązania analogu insuliny z białkami krwi, który badano metodą chromatografii cieczowej. Wyniki. Po podskórnym podaniu B1-T4-Ins była dobrze tolerowana i szybko wchłaniana. Analog cechował się długim czasem półtrwania w surowicy oraz wysokim stopniem wiązania (ok. 86%) z białkami. Jego czas działania, mierzony czasem wlewu glukozy niezbędnym do utrzymania euglikemii, był podobny do czasu działania insuliny NPH. Wpływ analogu na wątrobową produkcję glukozy był podobny do wpływu insuliny NPH, co wskazuje na podobny stopień oddziaływania. Analog w mniejszym stopniu działał na obwodowy wychwyt insuliny w porównaniu z insuliną NPH (p = 0,025), nie wpływał na szybkość przemian metabolicznych glukozy oraz wykazywał zmniejszoną zdolność do hamowania lipolizy (p < 0,05). Wnioski. U osób zdrowych B1-T4-Ins po podaniu podskórnym jest dobrze tolerowana, szybko się wchłania i ma wysoki stopień związania z białkami krwi, co odpowiada za długi czas połowicznego zaniku w surowicy. Analog ten wydaje się bardziej wybiórczy w oddziaływaniu na komórki wątroby, a zatem potencjalnie ma bardziej fizjologiczny profil działania w porównaniu z dotychczas stosowanymi preparatami insuliny.OBJECTIVE. To test whether a thyroxyl-insulin analog with restricted access to receptor sites in peripheral tissues displays relative hepatoselectivity in humans. RESEARCH DESIGN AND METHODS. Five normal human subjects received a subcutaneous bolus injection of either N B1 L-thyroxyl-insulin (B1-T4-Ins) or NPH insulin in random order. Insulin kinetics, relative effects on hepatic glucose production, and peripheral glucose uptake were studied using euglycemic clamp and stable isotope [D-6,6-2H2]glucose) dilution techniques. Blood samples were taken for the determination of total immunoreactive insulin/analog concentrations and for liquid chromatography to assess the protein binding of the analog in the circulation. RESULTS. After subcutaneous administration, B1-T4-Ins was well tolerated and rapidly absorbed. The analog had a long serum half-life and was highly protein bound (~86%). Its duration of action, as judged by the duration of infusion of exogenous glucose to maintain euglycemia, was similar to that of NPH insulin. The effect of the analogs on hepatic glucose production was similar to that of NPH insulin, indicating equivalent hepatic potency. The analog demonstrated less effect on peripheral glucose uptake than NPH insulin (P = 0,025), had no effect on metabolic clearance rate of glucose, and exhibited a reduced capacity to inhibit lipolysis (P < 0,05). CONCLUSIONS. When injected subcutaneously into normal human subjects, B1-T4-Ins is well tolerated, quickly absorbed, and highly protein bound, resulting in a long plasma half-life. This analog appears to have a hepatoselective action, and, therefore, has the potential to provide more physiological insulin action than the insulin preparations currently used

Cross-realm assessment of climate change impacts on species' abundance trends

Climate change, land-use change, pollution and exploitation are among the main drivers of species' population trends; however, their relative importance is much debated. We used a unique collection of over 1,000 local population time series in 22 communities across terrestrial, freshwater and marine realms within central Europe to compare the impacts of long-term temperature change and other environmental drivers from 1980 onwards. To disentangle different drivers, we related species' population trends to species- and driver-specific attributes, such as temperature and habitat preference or pollution tolerance. We found a consistent impact of temperature change on the local abundances of terrestrial species. Populations of warm-dwelling species increased more than those of cold-dwelling species. In contrast, impacts of temperature change on aquatic species' abundances were variable. Effects of temperature preference were more consistent in terrestrial communities than effects of habitat preference, suggesting that the impacts of temperature change have become widespread for recent changes in abundance within many terrestrial communities of central Europe.Additionally, we appreciate the open access marine data provided by the International Council for the Exploration of the Sea. We thank the following scientists for taxonomic or technical advice: C. Brendel, T. Caprano, R. Claus, K. Desender, A. Flakus, P. R. Flakus, S. Fritz, E.-M. Gerstner, J.-P. Maelfait, E.-L. Neuschulz, S. Pauls, C. Printzen, I. Schmitt and H. Turin, and I. Bartomeus for comments on a previous version of the manuscript. R.A. was supported by the EUproject LIMNOTIP funded under the seventh European Commission Framework Programme (FP7) ERA-Net Scheme (Biodiversa, 01LC1207A) and the long-term ecological research program at the Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB). R.W.B. was supported by the Scottish Government Rural and Environment Science and Analytical Services Division (RESAS) through Theme 3 of their Strategic Research Programme. S.D. acknowledges support of the German Research Foundation DFG (grant DO 1880/1-1). S.S. acknowledges the support from the FP7 project EU BON (grant no. 308454). S.K., I.Kü. and O.S. acknowledge funding thorough the Helmholtz Association’s Programme Oriented Funding, Topic ‘Land use, biodiversity, and ecosystem services: Sustaining human livelihoods’. O.S. also acknowledges the support from FP7 via the Integrated Project STEP (grant no. 244090). D.E.B. was funded by a Landes–Offensive zur Entwicklung Wissenschaftlich–ökonomischer Exzellenz (LOEWE) excellence initiative of the Hessian Ministry for Science and the Arts and the German Research Foundation (DFG: Grant no. BO 1221/23-1).Peer Reviewe