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Müller, G.

Assays for insulin and Insulin-like regulation of energy metabolism.

In: Drug Discovery and Evaluation: Pharmacological Assays. Cham, Switzerland: Springer, 2016. 2871-2893
DOI
Accumulating experimental evidence indicates that dysregulation of energy metabolism is a fundamental process that is associated with the phenotype of metabolic disorders, in particular type II diabetes and obesity. Many current antidiabetic drugs (metformin, glitazones) target the pathways that control glucose metabolism. Very recently, technologies (Bionas Inc., Germany; Seahorse Bioscience Inc., USA) have been developed that manage to rapidly profile the bioenergetic pathways in a variety of cell types. These include alterations caused by drugs that target the specific metabolic pathways the cell uses to ensure its energy demands, normal metabolic functions, and survival. These technologies allow a more detailed analysis of the link between glucose/lipid metabolism and energy metabolism, including interference of one or the other by compounds/drug candidates, as well as the screening for or characterization of drug candidates affecting or leaving unaffected those pathways. For this, both the oxygen consumption rate (OCR), which primarily reflects mitochondrial respiration, and the extracellular acidification rate (ECAR), which primarily reflects lactic acid production (glycolysis), are measured using the Bionas or Seahorse technology. Furthermore, the OCR and ECAR readings allow to profile the metabolic sensitivities and degree of inhibition/stimulation of a number of cell lines relevant for the study of glucose and lipid metabolism and its regulation toward modulators of anaerobic and aerobic energy metabolism (e.g., phloretin, 2-deoxyglucose, dinitrophenol). Analysis of the sensitivities of the cell lines to these modulators provides insights into their bioenergetic preferences/dependencies and their global physiological responses to the modulation. This characterization may be useful for the selection of cell lines appropriate for use in screening for compounds with antiproliferative activity (ECAR for anaerobic energy metabolism; Boros et al. 2002) as well as insulin-like metabolic activity (OCR for aerobic energy metabolism; Wolf et al. 1997), with regard to sensitivity and responsiveness of their energy metabolism and the relevant bioenergetic pathways (Ehret et al. 2001). During the last decade, multiparametric cellular microelectronic interdigitated biosensor chips for microphysiological and screening applications with living cells have been developed (Ehret et al. 2001; Lehmann et al. 2000).
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Publikationstyp Artikel: Sammelbandbeitrag/Buchkapitel
Herausgeber Hock, F.J.*
Korrespondenzautor
e-ISSN 978-3-319-05392-9
ISBN 978-3-319-05391-2
Bandtitel Drug Discovery and Evaluation: Pharmacological Assays
Quellenangaben Band: , Heft: , Seiten: 2871-2893 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Cham, Switzerland
Nichtpatentliteratur Publikationen
Institut(e) Institute of Diabetes and Obesity (IDO)