{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:10:43Z","timestamp":1791144643174,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin\u2010sensitizing effect of topiramate both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Male <jats:styled-content style=\"fixed-case\">C57Bl\/6J<\/jats:styled-content> mice were fed a run\u2010in high\u2010fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high\u2010fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic\u2010euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed <jats:italic>in vivo<\/jats:italic> and in cultured muscle cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>In hyperinsulinaemic\u2010euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (\u223c4\u2009\u03bcg\u00b7mL<jats:sup>\u22121<\/jats:sup>) improved insulin sensitivity (glucose infusion rate + 58%). Using 2\u2010deoxy\u2010<jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>\u2010[<jats:sup>3<\/jats:sup><jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>]glucose, we established that topiramate improved the insulin\u2010mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin\u2010sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither <jats:italic>in vivo<\/jats:italic> nor in cultured muscle cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>In conclusion, topiramate stimulates insulin\u2010mediated glucose uptake <jats:italic>in vivo<\/jats:italic> through the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12338","type":"journal-article","created":{"date-parts":[[2013,8,20]],"date-time":"2013-08-20T02:04:45Z","timestamp":1376964285000},"page":"908-918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The insulin sensitizing effect of topiramate involves <scp>K<sub>ATP<\/sub><\/scp> channel activation in the central nervous system"],"prefix":"10.1111","volume":"170","author":[{"given":"C P","family":"Coomans","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolic Disorders Leiden University Medical Center  Leiden The Netherlands"},{"name":"Department of Molecular Cell Biology Leiden University Medical Center  Leiden The 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