title: The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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-[(3) H]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.
  
  
  CONCLUSIONS
  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.
authors: Department of Endocrinology and Metabolic Disorders, Leiden University Medical Center, Leiden, The Netherlands; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors: C P
authors: CP
authors: Coomans
authors: J J
authors: JJ
authors: Geerling
authors: S A A
authors: SA
authors: van den Berg
authors: H C
authors: HC
authors: van Diepen
authors: N
authors: N
authors: Garcia-Tardón
authors: A
authors: A
authors: Thomas
authors: J P
authors: JP
authors: Schröder-van der Elst
authors: D M
authors: DM
authors: Ouwens
authors: H
authors: H
authors: Pijl
authors: P C N
authors: PC
authors: Rensen
authors: L M
authors: LM
authors: Havekes
authors: B
authors: B
authors: Guigas
authors: J A
authors: JA
authors: Romijn
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D057967:Infusions, Intraventricular; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels; D026902:Potassium Channel Blockers; D000077236:Topiramate; D005632:Fructose
keywords: KATP-channels; brain; insulin; tolbutamide; type 2 diabetes mellitus
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