title: Cerebrovascular Safety of Sulfonylureas: The Role of KATP Channels in Neuroprotection and the Risk of Stroke in Patients With Type 2 Diabetes.
abstract: Sulfonylureas are ATP-sensitive potassium (KATP) channel blockers commonly used in the treatment of type 2 diabetes mellitus (T2DM). Activation of KATP channels plays a neuroprotective role in ischemia; thus, whether sulfonylureas affect the outcomes of stroke in patients with T2DM needs to be further studied. In our study, streptozotocin (STZ)-induced diabetic mice subjected to transient middle cerebral artery occlusion (MCAO) showed larger areas of brain damage and poorer behavioral outcomes. Blocking the KATP channel by tolbutamide increased neuronal injury induced by oxygen-glucose deprivation (OGD) in vitro and permanent MCAO (pMCAO) in vivo. Activating the KATP channel by diazoxide reduced the effects of both the OGD and pMCAO. Western blot analysis in STZ mouse brains indicated an early increase in protein levels of N-methyl-d-aspartate receptor 2B and postsynaptic density protein-95, followed by a decrease in phosphorylation of glycogen synthase kinase 3β. Our systematic meta-analysis indicated that patients with T2DM treated with sulfonylureas had a higher odds ratio for stroke morbidity than those who received comparator drugs. Taken together, these results suggest that sulfonylurea treatment in patients with T2DM may inhibit the neuroprotective effects of KATP channels and increase the risk of stroke.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Turlova
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Dong
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher L F
authors.initials: CL
authors.lastname: Sun
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yangqingqin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hanhui
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ranran
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Barszczyk
authors.affiliation: Department of Obstetrics and Gynecology, Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Dongzi
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
authors.affiliation: Diabetology, Careggi Hospital, University of Florence, Florence, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Mannucci
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada zp.feng@utoronto.ca hss.sun@utoronto.ca.
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada zp.feng@utoronto.ca hss.sun@utoronto.ca.
authors.forename: Hong-Shuo
authors.initials: HS
authors.lastname: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D007150:Immunohistochemistry; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D015201:Meta-Analysis as Topic; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012307:Risk Factors; D020521:Stroke / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D054086:KATP Channels; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013453:Sulfonylurea Compounds; D014044:Tolbutamide; D000071679:Glycogen Synthase Kinase 3 beta; D051528:Guanylate Kinases