title: Both stimulation of GLP-1 receptors and inhibition of glycogenolysis additively contribute to a protective effect of oral miglitol against ischaemia-reperfusion injury in rabbits.
abstract: OBJECTIVE
  We previously reported that pre-ischaemic i.v. miglitol reduces myocardial infarct size through the inhibition of glycogenolysis during ischaemia. Oral administration of miglitol has been reported to produce glucagon-like peptide 1 (GLP-1). We hypothesized that p.o. administration of miglitol, an absorbable antidiabetic drug, reduces myocardial infarct size by stimulating GLP-1 receptors and inhibiting glycogenolysis in the myocardium.
  
  
  METHODS
  The effects of p.o. and i.v. administration of miglitol on myocardial infarct size were compared in a rabbit model of ischaemia induced by 30 min of coronary occlusion and 48 h of reperfusion. The levels of phospho(p)-PI3kinase and p-Akt were measured in cardiac tissue by use of Western blot analysis.
  
  
  RESULTS
  Both p.o. and i.v. administration of miglitol reduced the infarct size, and this effect was greater after p.o. than after i.v. administration under similar plasma miglitol concentrations. The reduction in infarct size induced by p.o. miglitol but not that induced by i.v. miglitol was partially inhibited by treatment with exendin(9-39), a GLP-1 receptor blocker. Both p.o. and i.v. miglitol improved ejection fraction and ±dP/dt after myocardial infarction. Miglitol administered p.o. but not i.v. up-regulated the myocardial expression of phospho(p)-PI3kinase and p-Akt following myocardial infarction; an effect that was inhibited by exendin(9-39).
  
  
  CONCLUSIONS
  Administration of miglitol p.o. reduces myocardial infarct size through stimulation of GLP-1 receptors and activation of PI3kinase-Akt pathway in addition to the inhibition of glycogenolysis. These findings may have clinical implications for the p.o. administration of miglitol for the treatment of patients with diabetes mellitus combined with coronary artery disease.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iwasa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuda
authors.forename: Itta
authors.initials: I
authors.lastname: Kawamura
authors.forename: Shohei
authors.initials: S
authors.lastname: Sumi
authors.forename: Takeru
authors.initials: T
authors.lastname: Shiraki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Arihiro
authors.initials: A
authors.lastname: Hattori
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishigaki
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D050261:Glycogenolysis / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C045621:miglitol; D017485:1-Deoxynojirimycin; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt