26 research outputs found

    GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

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    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.This is the final version of the article. It was first available from the American Society for Clinical Investigation via http://dx.doi.org/10.1172/JCI8197

    Monolithic Perovskite Tandem Solar Cells A Review of the Present Status and Advanced Characterization Methods Toward 30 Efficiency

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    Tandem solar cells are the next step in the photovoltaic PV evolution due to their higher power conversion efficiency PCE potential than currently dominating, but inherently limited, single junction solar cells. With the emergence of metal halide perovskite absorber materials, the fabrication of highly efficient tandem solar cells, at a reasonable cost, can significantly impact the future PV landscape. The perovskite based tandem solar cells have already shown that they can convert light more efficiently than their standalone sub cells. However, to reach PCEs over 30 , several challenges have to be overcome and the understanding of this fascinating technology has to be broadened. In this review, the main scientific and engineering challenges in the field are presented, alongside a discussion of the current status of three main perovskite tandem technologies perovskite silicon, perovskite CIGS, and perovskite perovskite tandem solar cells. A summary of the advanced structural, electrical, optical, radiative, and electronic characterization methods as well as simulations being utilized for perovskite based tandem solar cells is presented. The main findings are summarized and the strength of the techniques to overcome the challenges and gain deeper knowledge for further performance improvement is assessed. Finally, the PCE potential in different experimental and theoretical limits is compared with an aim to shed light on the path towards overcoming the 30 efficiency threshold for all of the three herein reviewed tandem technologie

    Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1

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    Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express α-gustducin. Ingestion of glucose by α-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from α-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses α-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for α-gustducin. We conclude that L cells of the gut “taste” glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut “taste cells” may provide an important treatment for obesity, diabetes and abnormal gut motility
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