OBJECTIVEChemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo.RESEARCH DESIGN AND METHODSWe used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet.RESULTSExpression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5′AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue.CONCLUSIONSChemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.
BackgroundGLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study.MethodsGLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain.ResultsGLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 – 6.08; p = 0.03).ConclusionCirculating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.
ABSTRACT:Progestins are widely used as oral contraceptives and hormone replacement therapy. Recently it has been demonstrated that many progestins are inhibitors of P-glycoprotein, possibly explaining gender differences in drug actions. In vitro evidence suggested that at least norgestimate might also inhibit other transporters like the multidrug resistance-associated protein 2 (MRP2). We therefore investigated whether norgestimate, desogestrel, medroxyprogesterone acetate, norethisterone, progesterone, cyproterone acetate, chlormadinone acetate, and levonorgestrel inhibit MRP2 in vitro using confocal laser scanning microscopy and 5-chloromethylfluorescein diacetate as a prodrug of the fluorescent 5-chloromethylfluorescein (CMF), which is actively transported by MRP2 as glutathione conjugate. Of the progestins tested, only norgestimate (50 M) and progesterone (100 M) significantly increased intracellular CMF fluorescence by 62% and 53%, respectively. In conclusion, the progestins norgestimate and progesterone significantly inhibit the transport activity of MRP2 in vitro.Multidrug resistance-associated proteins (MRPs) are a subfamily of the ATP-binding cassette transport protein family involved in drug resistance (Schinkel and Jonker, 2003). MRP2 is a key member of this group and was identified in the canalicular membrane of hepatocytes as a transporter for organic anions extruding a wide range of glutathione, glucuronate, and sulfate conjugates into the bile (Ishikawa 1993;Ito et al., 1997;Paulusma and Oude Elferink, 1997). It was also detected in renal brush-border membranes, the intestine (Schaub et al., 1997), placenta (St.-Pierre et al., 2000;Gerk and Vore, 2002), and brain (Török et al., 2003). In human carcinoma, MRP2 may confer resistance to chemotherapy (Norris et al., 1996;Nies et al., 2001;Young et al., 2001;Schinkel and Jonker, 2003), and it appears also to play a role in drug-drug interactions (Fromm et al., 2000;Bramow et al., 2001;Bode et al., 2002;Huisman et al., 2002;Giessmann et al., 2004).In recent years it has been suggested that gender could alter the activity of drug transporters like P-glycoprotein (P-gp) (Cummins et al., 2002). Hence in a previous study we have investigated whether P-gp is inhibited by progestins used in oral contraceptives and hormone replacement therapy. All progestins tested had P-gp inhibitor properties, with some of them being as potent as the well known P-gp inhibitor quinidine (Fröhlich et al., 2004). Interestingly, one of the tested progestins (norgestimate) revealed an inhibitory effect on the transport of calcein-acetoxymethylester (calcein-AM) not only in the P-gp-overexpressing cell line L-MDR1, but also in the parental cell line LLC-PK1, which only expresses low amounts of P-gp (Decorti et al., 2001;Weiss et al., 2003;Fröhlich et al., 2004), indicating that this effect was not selective. Because LLC-PK1 expresses MRP2 (Evers et al., 1996;Decorti et al., 2001) and MRP2 can transport calcein-AM (Evers et al., 2000), these data may suggest that norgestimate also...
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