| 1. |
- Grunddal, K. V., et al.
(författare)
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Opposing roles of the entero-pancreatic hormone urocortin-3 in glucose metabolism in rats
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65, s. 1018-1031
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Tidskriftsartikel (refereegranskat)abstract
- Aim/hypothesis Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic islets. The aim of this study was to clarify the acute effects of UCN3 on glucose regulation following an oral glucose challenge and to investigate the mechanisms involved. Methods We studied the effect of UCN3 on blood glucose, gastric emptying, glucose absorption and secretion of gut and pancreatic hormones in male rats. To supplement these physiological studies, we mapped the expression of UCN3 and the UCN3-sensitive receptor, type 2 corticotropin-releasing factor receptor (CRHR2), by means of fluorescence in situ hybridisation and by gene expression analysis. Results In rats, s.c. administration of UCN3 strongly inhibited gastric emptying and glucose absorption after oral administration of glucose. Direct inhibition of gastrointestinal motility may be responsible because UCN3's cognate receptor, CRHR2, was detected in gastric submucosal plexus and in interstitial cells of Cajal. Despite inhibited glucose absorption, post-challenge blood glucose levels matched those of rats given vehicle in the low-dose UCN3 group, because UCN3 concomitantly inhibited insulin secretion. Higher UCN3 doses did not further inhibit gastric emptying, but the insulin inhibition progressed resulting in elevated post-challenge glucose and lipolysis. Incretin hormones and somatostatin (SST) secretion from isolated perfused rat small intestine was unaffected by UCN3 infusion; however, UCN3 infusion stimulated secretion of somatostatin from delta cells in the isolated perfused rat pancreas which, unlike alpha cells and beta cells, expressed Crhr2. Conversely, acute antagonism of CRHR2 signalling increased insulin secretion by reducing SST signalling. Consistent with these observations, acute drug-induced inhibition of CRHR2 signalling improved glucose tolerance in rats to a similar degree as administration of glucagon-like peptide-1. UCN3 also powerfully inhibited glucagon secretion from isolated perfused rat pancreas (perfused with 3.5 mmol/l glucose) in a SST-dependent manner, suggesting that UCN3 may be involved in glucose-induced inhibition of glucagon secretion. Conclusions/interpretation Our combined data indicate that UCN3 is an important glucoregulatory hormone that acts through regulation of gastrointestinal and pancreatic functions.
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| 2. |
- Bronden, A., et al.
(författare)
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Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer
- 2018
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 20:7, s. 1623-1631
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Tidskriftsartikel (refereegranskat)abstract
- Aims Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. Materials and Methods In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. Results Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. Conclusions Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.
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| 3. |
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| 4. |
- Sommer, Martha E., et al.
(författare)
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The European Research Network on Signal Transduction (ERNEST) : Toward a Multidimensional Holistic Understanding of G Protein-Coupled Receptor Signaling
- 2020
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Ingår i: ACS Pharmacology & Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 3:2, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are intensively studied due to their therapeutic potential as drug targets. Members of this large family of transmembrane receptor proteins mediate signal transduction in diverse cell types and play key roles in human physiology and health. In 2013 the research consortium GLISTEN (COST Action CM1207) was founded with the goal of harnessing the substantial growth in knowledge of GPCR structure and dynamics to push forward the development of molecular modulators of GPCR function. The success of GLISTEN, coupled with new findings and paradigm shifts in the field, led in 2019 to the creation of a related consortium called ERNEST (COST Action CA18133). ERNEST broadens focus to entire signaling cascades, based on emerging ideas of how complexity and specificity in signal transduction are not determined by receptor-ligand interactions alone. A holistic approach that unites the diverse data and perspectives of the research community into a single multidimensional map holds great promise for improved drug design and therapeutic targeting.
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| 5. |
- Gerlach, L O, et al.
(författare)
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Metal ion enhanced binding of amd3100 to asp-262 in the cxcr4 receptor.
- 2003
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 42:3, s. 710-717
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Tidskriftsartikel (refereegranskat)abstract
- The affinity of AMD3100, a symmetrical nonpeptide antagonist composed of two 1,4,8,11-tetraazacyclotetradecane (cyclam) rings connected through a 1,4-dimethylene(phenylene) linker to the CXCR4 chemokine receptor was increased 7, 36, and 50-fold, respectively, by incorporation of the following: Cu2+, Zn2+, or Ni2+ into the cyclam rings of the compound. The rank order of the transition metal ions correlated with the calculated binding energy between free acetate and the metal ions coordinated in a cyclam ring. Construction of AMD3100 substituted with only a single Cu2+ or Ni2+ ion demonstrated that the increase in binding affinity of the metal ion substituted bicyclam is achieved through an enhanced interaction of just one of the ring systems. Mutational analysis of potential metal ion binding residues in the main ligand binding crevice of the CXCR4 receptor showed that although binding of the bicyclam is dependent on both Asp171 and Asp262, the enhancing effect of the metal ion was selectively eliminated by substitution of Asp262 located at the extracellular end of TM-VI. It is concluded that the increased binding affinity of the metal ion substituted AMD3100 is obtained through enhanced interaction of one of the cyclam ring systems with the carboxylate group of Asp262. It is suggested that this occurs through a strong concomitant interaction of one of the oxygen's directly with the metal ion and the other oxygen to one of the nitrogens of the cyclam ring through a hydrogen bond.
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| 6. |
- Lindqvist, Andreas, et al.
(författare)
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GPR162 is a beta cell CART receptor
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:12
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine and amphetamine-regulated transcript (CART) is expressed in pancreatic islet cells and neuronal elements. We have previously established insulinotropic actions of CART in human and rodent islets. The receptor for CART in the pancreatic beta cells is unidentified. We used RNA sequencing of Cartpt knockdown (KD) INS-1 832/13 cells and identified GPR162 as the most Cartpt-regulated receptor. We therefore tested if GPR162 mediates the effects of CART in beta cells. Binding of CART to GPR162 was established using proximity ligation assay, radioactive binding, and co-immunoprecipitation, and KD of Gpr162 mRNA caused reduced binding. Gpr162 KD cells had blunted CARTp-induced exocytosis, and reduced CARTp-induced insulin secretion. Furthermore, we identified a hitherto undescribed GPR162-dependent role of CART as a regulator of cytoskeletal arrangement. Thus, our findings provide mechanistic insight into the effect of CART on insulin secretion and show that GPR162 is the CART receptor in beta cells.
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| 7. |
- Nordström, Birgitta, et al.
(författare)
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The Geneva-Copenhagen Survey of the Solar Neighbourhood
- 2004
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Ingår i: Publications Astronomical Society of Australia. - 1448-6083. ; 21:2, s. 129-133
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Tidskriftsartikel (refereegranskat)abstract
- We report on a new survey of metallicities, ages, and Galactic orbitsfor a complete, magnitude-limited, and kinematically unbiased all-skysample of 16682 nearby F- and G-dwarfs. Our~63000 new, accurate radialvelocities for nearly 13500 of the stars, combined with Hipparcosparallaxes and Tycho-2 proper motions, complete the kinematic data for14139 stars and allow us to identify most of the binary stars in thesample. Isochrone ages have been determined whenever reliable resultsare possible, with particular attention to realistic error estimates.Among the basic properties of the Galactic disk that can bereinvestigated from our data are the metallicity distribution ofG-dwarfs and the age-metallicity and age-velocity relations of the solarneighbourhood. We confirm the lack of metal-poor G-dwarfs relative toclassical model predictions (the `G-dwarf problem'), the near-constancyof the mean metallicity since the formation of the thin disk, and theappearance of the kinematic signature of the thick disk ~ 10Gyr ago.
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| 8. |
- Nordström, Birgitta, et al.
(författare)
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The Geneva-Copenhagen survey of the Solar neighbourhood. Ages, metallicities, and kinematic properties of ∼14 000 F and G dwarfs
- 2004
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 418:3, s. 989-1019
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Forskningsöversikt (refereegranskat)abstract
- We present and discuss new determinations of metallicity, rotation, age,kinematics, and Galactic orbits for a complete, magnitude-limited, andkinematically unbiased sample of 16 682 nearby F and G dwarf stars. Our∼63 000 new, accurate radial-velocity observations for nearly 13 500stars allow identification of most of the binary stars in the sampleand, together with published uvbyβ photometry, Hipparcosparallaxes, Tycho-2 proper motions, and a few earlier radial velocities,complete the kinematic information for 14 139 stars. These high-qualityvelocity data are supplemented by effective temperatures andmetallicities newly derived from recent and/or revised calibrations. Theremaining stars either lack Hipparcos data or have fast rotation. Amajor effort has been devoted to the determination of new isochrone agesfor all stars for which this is possible. Particular attention has beengiven to a realistic treatment of statistical biases and errorestimates, as standard techniques tend to underestimate these effectsand introduce spurious features in the age distributions. Our ages agreewell with those by Edvardsson et al. (cite{edv93}), despite severalastrophysical and computational improvements since then. We demonstrate,however, how strong observational and theoretical biases cause thedistribution of the observed ages to be very different from that of thetrue age distribution of the sample. Among the many basic relations ofthe Galactic disk that can be reinvestigated from the data presentedhere, we revisit the metallicity distribution of the G dwarfs and theage-metallicity, age-velocity, and metallicity-velocity relations of theSolar neighbourhood. Our first results confirm the lack of metal-poor Gdwarfs relative to closed-box model predictions (the ``G dwarfproblem''), the existence of radial metallicity gradients in the disk,the small change in mean metallicity of the thin disk since itsformation and the substantial scatter in metallicity at all ages, andthe continuing kinematic heating of the thin disk with an efficiencyconsistent with that expected for a combination of spiral arms and giantmolecular clouds. Distinct features in the distribution of the Vcomponent of the space motion are extended in age and metallicity,corresponding to the effects of stochastic spiral waves rather thanclassical moving groups, and may complicate the identification ofthick-disk stars from kinematic criteria. More advanced analyses of thisrich material will require careful simulations of the selection criteriafor the sample and the distribution of observational errors.Based on observations made with the Danish 1.5-m telescope at ESO, LaSilla, Chile, and with the Swiss 1-m telescope at Observatoire deHaute-Provence, France.Complete Tables 1 and 2 are only available in electronic form at the CDSvia anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or viahttp://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/418/989
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