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The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system

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Author: Coomans, C.P. · Geerling, J.J. · Berg, S.A.A. van den · Diepen, H.C. van · Garcia-Tardõn, N. · Thomas, A. · Schröder-Van Der Elst, J.P. · Ouwens, D.M. · Pijl, H. · Rensen, P.C.N. · Havekes, L.M. · Guigas, B. · Romijn, J.A.
Type:article
Date:2013
Source:British Journal of Pharmacology, 4, 170, 908-918
Identifier: 481447
doi: doi:10.1111/bph.12338
Keywords: Health · Brain · Insulin · KATP-channels · Tolbutamide · Type 2 diabetes mellitus · Healthy for Life · Healthy Living · Life · MHR - Metabolic Health Research · EELS - Earth, Environmental and Life Sciences

Abstract

Background and Purpose 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-sensitizing effect of topiramate both in vivo and in vitro. Experimental Approach Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells. Key results In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL-1) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[ 3H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells. Conclusion and Implications In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS. © 2013 The British Pharmacological Society.