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

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s=7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb(-1) of root s = 7 TeV proton-proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s=7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb-1 of sqrt(s) = 7 TeV proton-proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results