title: Diabetes mellitus reduces the function and expression of ATP-dependent K⁺ channels in cardiac mitochondria.
abstract: OBJECTIVE
  Our goal was to determine the effects of type I diabetes mellitus on the function and expression of ATP-dependent K(+) channels in cardiac mitochondria (mitoKATP), composed of a pore-forming subunit (Kir6.1) and a diazoxide-sensitive sulphonylurea receptor (SUR1). We tested the hypothesis that diabetes reduces Kir6.1 and SUR1 expression as well as diazoxide-induced depolarization of mitochondrial membrane potential (ΔΨm).
  
  
  METHODS
  Male FVB mice were made diabetic for 5weeks with multiple low dose injections of streptozotocin. Cardiac mitochondria were separated into two populations: subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). mitoKATP expression was determined via Western blot analysis of Kir6.1 and SUR1 proteins. mitoKATP function was determined by measuring ΔΨm with the potentiometric dye rhodamine 123.
  
  
  RESULTS
  Diabetes reduced Kir6.1 and SUR1 expression in IFM by over 40% (p<0.05 for both). Similarly, diabetes reduced Kir6.1 expression in SSM by approximately 40% (p<0.05); however, SUR1 expression was unaffected. Opening mitoKATP with diazoxide (100μM) depolarized control IFM ΔΨm by 80% of the valinomycin maximum; diabetic IFM depolarized only 30% (p<0.05). Diazoxide-induced depolarization was much less in SSM (20-30%) and unaffected by diabetes.
  
  
  CONCLUSIONS
  Our data indicate that diabetes reduces mitoKATP expression and function in IFM. These changes in mitoKATP may provide an opportunity to understand mechanisms leading to diabetic cardiomyopathy and loss of cardioprotective mechanisms in the diabetic heart.
authors.affiliation: Department of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Ibra S
authors.initials: IS
authors.lastname: Fancher
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1; D058065:Diabetic Cardiomyopathies / Q000503:physiopathology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C117780:mitochondrial K(ATP) channel; C092520:uK-ATP-1 potassium channel