title: Glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats.
abstract: OBJECTIVE
  We investigated whether glucose fluctuations aggravate cardiac fibrosis and increase the occurrence of atrial fibrillation (AF) in rats with diabetes mellitus (DM).
  
  
  RESULTS
  Streptozotocin-induced diabetic rats were randomly divided into three groups: uncontrolled DM (U-STZ) group, controlled DM (C-STZ) group, and DM with glucose fluctuations (STZ-GF) group. Glucose fluctuations were induced by fasting for 24 h and additional regular insulin injections (0.5 IU/kg) administered three times per week for three consecutive weeks. C-STZ rats were administered long acting insulin (20 IU/kg) twice a day to control blood glucose levels. Cardiac fibrosis evaluated by Masson trichrome staining and the expressions of collagen type 1, collagen type 3, and α-smooth muscle actin were increased in U-STZ rats compared with C-STZ rats, which were more pronounced in STZ-GF rats. The inducibility of AF was significantly larger in U-STZ rats than C-STZ rats and was greatest in STZ-GF rats. To explore the mechanism of cardiac fibrosis, we investigated the levels of reactive oxygen species (ROS) and apoptosis. The expression of malondialdehyde, an indicator of ROS levels, was significantly upregulated in STZ-GF rats compared with U-STZ rats, along with increased thioredoxin-interacting protein (Txnip) expression in STZ-GF rats. Furthermore, caspase-3 expression and the number of TUNEL-positive cells were significantly increased in STZ-GF rats compared with U-STZ and C-STZ rats.
  
  
  CONCLUSIONS
  Glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis. Increased ROS levels caused by upregulation of Txnip expression may be a mechanism whereby in glucose fluctuations induce fibrosis.
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan teshima@oita-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Teshima
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fukui
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Nishio
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Tetsunori
authors.initials: T
authors.lastname: Saikawa
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000199:Actins / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D017209:Apoptosis; D001281:Atrial Fibrillation / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D049528:Insulin, Long-Acting / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D015398:Signal Transduction; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D000199:Actins; D015415:Biomarkers; D001786:Blood Glucose; D002352:Carrier Proteins; D053148:Caspase 3; D018797:Cell Cycle Proteins; D024042:Collagen Type I; D024061:Collagen Type III; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D008315:Malondialdehyde; D017382:Reactive Oxygen Species; C493796:TXNIP protein, rat; C498862:Acta2 protein, rat; C505410:Casp3 protein, rat
keywords: Atrial fibrillation; Diabetes mellitus; Glucose fluctuation