125,031 research outputs found
Building the Glucagon-Like Peptide-1 Receptor Brick by Brick: Revisiting a 1993 Diabetes Classic by Thorens et al
No full textThe glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor involved in the regulation of blood glucose levels and food intake. Stabilized agonists targeting GLP-1R are used in the treatment of type 2 diabetes and have recently become a breakthrough obesity therapy. Here, we revisit a classic article in Diabetes by Thorens et al. that described the cloning, sequencing, and functional expression of the human GLP-1R. The article also demonstrated that exendin4(1-39) was a full agonist of the human GLP-1R whereas exendin4(9-39) was a full antagonist. We discuss how the knowledge imparted by these studies has gone on to inform multiple strands of GLP-1R biology over the past three decades, including pharmacology, signaling, human genetics, structural biology, and chemical biology
Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells
No full text Pages C279–C294: B. Thorens, Z.-Q. Cheng, D. Brown, and H. F. Lodish. “Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells.” B. Thorens, H. F. Lodish, and D. Brown. “Differential localization of two glucose transporter isoforms in rat kidney.” Because of the disappointing reproduction of the halftones, these articles are reprinted at the end of the December issue. </jats:p
Type 2 Diabetes, SGLT2 Inhibitors, and Glucose Secretion
No full textFrom New England Journal of Medicine, Hattersley, A. T., & Thorens, B. (2015). Type 2 Diabetes, SGLT2 Inhibitors, and Glucose Secretion. 373(10), 974-976. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission.No abstrac
Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells
No full text Pages C279–C294: B. Thorens, Z.-Q. Cheng, D. Brown, and H. F. Lodish. “Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells.” B. Thorens, H. F. Lodish, and D. Brown. “Differential localization of two glucose transporter isoforms in rat kidney.” Because of the disappointing reproduction of the halftones, these articles are reprinted at the end of the December issue. </jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Normal kinetics of intestinal glucose absorption in the absence of GLUT2: Evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum
No full textGlucose is absorbed through the intestine by a transepithelial transport system initiated at the apical membrane by the cotransporter SGLT-1; intracellular glucose is then assumed to diffuse across the basolateral membrane through GLUT2. Here, we evaluated the impact of GLUT2 gene inactivation on this transepithelial transport process. We report that the kinetics of transepithelial glucose transport, as assessed in oral glucose tolerance tests, was identical in the presence or absence of GLUT2; that the transport was transcellular because it could be inhibited by the SGLT-1 inhibitor phlorizin, and that it could not be explained by overexpression of another known glucose transporter. By using an isolated intestine perfusion system, we demonstrated that the rate of transepithelial transport was similar in control and GLUT2(-/-) intestine and that it was increased to the same extent by cAMP in both situations. However, in the absence, but not in the presence, of GLUT2, the transport was inhibited dose-dependently by the glucose-6-phosphate translocase inhibitor S4048. Furthermore, whereas transport of [C-14]glucose proceeded with the same kinetics in control and GLUT2(-/-) intestine, [C-14]3-O-methylglucose was transported in intestine of control but not of mutant mice. Together our data demonstrate the existence of a transepithelial glucose transport system in GLUT2(-/-) intestine that requires glucose phosphorylation and transfer of glucose-6-phosphate into the endoplasmic reticulum. Glucose may then be released out of the cells by a membrane traffic-based pathway similar to the one we previously described in GLUT2-null hepatocytes
Autocrine secretion of IGF2 regulates adult ß cell functional plasticity
No full textIn the pathogenesis of type 2 diabetes, hyperglycemia appears when ß cell mass and insulin secretory capacity are no longer sufficient to compensate for insulin resistance. The reduction in ß cell mass results from increased apoptosis. Therefore, finding strategies to preserve ß cell mass and function may be useful for the treatment or prevention of diabetes. Glucagon-like peptide-1 (GLP-1) protects ß cells against apoptosis, increases their glucose competence, and induces their proliferation. Previous studies in the lab of Prof. Bernard Thorens showed that the GLP-1 anti- apoptotic effect was mediated by robust up-regulation of IGF-1R expression, and this was paralleled with an increase in Akt phosphorylation. This effect was dependent not only on increased IGF-1R expression but also on the autocrine secretion of insulin-like growth factor 2 (IGF2). They also demonstrated that GLP-1 up-regulated IGF-1R expression by a protein a kinase A-dependent translational control mechanism.
The main aim of this PhD work has been to further investigate the role of the IGF2/IGF-1 Receptor autocrine loop in ß cell function and to determine the physiological role of IGF2 in ß cell plasticity and its regulation by nutrients. This PhD thesis is divided in 3 chapters. The first chapter describes the role of IGF2/IGF-1R autocrine loop in ß cell glucose competence and proliferation. Here using MIN6 cells and primary mouse islets as an experimental model we demonstrated that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF2 secretion. Furthermore, we showed that GLP-1-induced primary ß cell proliferation was significantly reduced by Igf-lr gene inactivation and by IGF2 immunoneutralization or knockdown.
In the second chapter we examined the role of this IGF2/IGF-1R autocrine loop on the ß cell functional plasticity during ageing, pregnancy, and in response to acute induction of insulin resistance using mice with ß cell-specific inactivation of ig/2. Here we showed a gender-dependent role of ß cell IGF2 in ageing and high fat diet-induced metabolic stress; we demonstrated that the autocrine secretion of IGF2 is essential for ß cell mass adaptation during pregnancy. Further we also showed that this autocrine
loop plays an important role in ß cell expansion in response to acute induction of insulin resistance.
The aim of the third chapter was to investigate whether we can modulate the expression and secretion of IGF2 by nutrients in order to increase the activity of autocrine loop. Here we showed that glutamine induces IGF2 biosynthesis and its fast secretion through the regulated pathway, a mechanism enhanced in the presence of glucose. Furthermore, we demonstrated that glutamine-mediated Akt phosphorylation is dependent on IGF2 secretion, indicating that glutamine controls the activity of the IGF2/IGF1R autocrine loop through IGF2 up-regulation.
In summary, this PhD work highlights that autocrine secretion of IGF2 is required for compensatory ß cell adaptation to ageing, pregnancy, and insulin resistance. Moreover IGF2/IGF1R autocrine loop is regulated by two feeding-related cues, GLP-1 to increase IGF-1R expression and glutamine to control IGF2 biosynthesis and secretion.
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Dans le diabète de type 2, lorsque la sécrétion d'insuline des cellules Beta du pancréas n'est plus suffisante pour compenser la résistance à l'insuline, une hyperglycémie est observée. Cette baisse de sécrétion d'insuline est Causée par la diminution de la masse de cellules Beta suite à l'augmentation du phénomène de mort cellulaire ou « apoptose ». En diabétologie, une des stratégies médicales concerne la préservation des cellules Beta du pancréas. Une des protéines intervenant dans cette fonction est GLP-1 (Glucagon-like peptide-1). GLP-1 est capable de protéger les cellules Beta contre la mort cellulaire et d'induire leur prolifération. Des études précédemment menées dans le laboratoire du Professeur Bernard Thorens ont montrées que l'activité « anti-apoptotique » de GLP-1 est le résultat l'une augmentation de l'expression du gène IGF-1R sous la dépendance de la sécrétion autocrine d'IGF2 (Insulin-Like Growth Factor).
Le but de mon travail de thèse aura été d'étudier le mécanisme de la régulation de GLP-1 par IGF2 et plus précisément de déterminer le rôle physiologique d'IGF2 dans la plasticité des cellules ß ainsi que sa régulation par les nutriments. Ce manuscrit est ainsi divisé en trois chapitres : Le premier chapitre décrit la fonction d'IGF2/IGF- R1 dans la réponse des cellules Beta au glucose ainsi que dans leur capacité à proliférer. Dans ce chapitre nous avons montré l'importance du niveau d'expression d'IGFR-1 et de la sécrétion d'IGF2 dans la régulation du métabolisme du glucose.
Dans un deuxième chapitre, nous étudions la boucle de régulation IGF2/IGF-R1 sur la plasticité des cellules Beta lors du vieillissement, de la grossesse ainsi que dans un modèle de souris résistantes à l'insuline. Cette étude met en évidence un dimorphisme sexuel dans le rôle d'IGF2 lors du vieillissement et lors d'un stress métabolique. Nous montrons également l'importance d'IGF2 pour l'adaptation des cellules Beta tout au long de la grossesse ou lors du phénomène de résistance à l'insuline.
Dans un troisième chapitre, nous mettons en évidence la possibilité de moduler l'expression et la sécrétion d'IGF2 par les nutriments.
En conclusion, ce travail de thèse aura permis de mettre en évidence l'importance d'IGF2 dans la plasticité des cellules ß, une plasticité indispensable lors du vieillissement, de la grossesse ou encore dans le cas d'une résistance à l'insuline
Ephippiger terrestris subsp. bormansi von Wattenwyl 1882
No full textEphippiger terrestris bormansi von Wattenwyl, 1882 Südalpen-Sattelschrecke VU B 2b(iii,iv) GrünlandartPublished as part of Monnerat C., Thorens P., Walter T. & Gonseth Y., 2007, Rote Liste der Heuschrecken der Schweiz, pp. 1-62 in Umwelt-Vollzug 7 (19) on page 34, DOI: 10.5281/zenodo.27023
Pragmatic Case Studies as a Source of Unity in Applied Psychology
No full textTo unify or not to unify applied psychology: that is the question. In this article we review pendulum swings in the historical efforts to answer this question—from a comprehensive, positivist, “top-down,” deductive yes between the 1930s and the early 60s, to a postmodern no since then. A rationale and proposal for a limited, “bottom-up,” inductive yes in applied psychology is then presented, employing a case-based paradigm that integrates both positivist and postmodern themes and components. This paradigm is labeled “pragmatic psychology” and, its specific use of case studies, the “Pragmatic Case Study Method” (“PCS Method”). We call for the creation of peer-reviewed journal-databases of pragmatic case studies as a foundational source of unifying applied knowledge in our discipline. As one example, the potential of the PCS Method for unifying different angles of theoretical regard is illustrated in an area of applied psychology, psychotherapy, via the case of Mrs. B. The article then turns to the broader historical and epistemological arguments for the unifying nature of the PCS Method in both applied and basic psychology.Peer reviewe
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