title: Openers of ATP-dependent K+-channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes.
abstract: OBJECTIVE
  We tested whether chronic overstimulation by levels of hyperglycaemia commonly found in Type 2 diabetes can irreversibly desensitise beta cells and, if so, whether desensitisation relates to the reduction of insulin content and/or the number of beta cells.
  
  
  METHODS
  We transplanted islets from Wistar-Furth rats under the kidney capsule to neonatally streptozotocinised recipients. Recipients received daily vehicle, diazoxide (100 mg/kg) or the selective activator of beta cell type K(+)-ATP channels 6-chloro -3-(1-methylcyclopropyl) amino-4 H-thienol [3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414) (3 mg/kg) intragastrically for at least 9 weeks. Endpoint measurements were made exactly 7 days after cessation of treatment.
  
  
  RESULTS
  Blood glucose did not differ between groups (mean of total: 13.2+/-1.4 mmol/l). C-peptide levels were significantly depressed in drug- versus vehicle-treated rats 3 to 4 hours after the last gastric tubing event, but not at endpoint. Insulin responses to 27 mmol/l glucose from perifused grafts were not significant after vehicle (median increment 18 x 10(-3) microU.islet(-1).min(-1)) but were significant per se and versus vehicle in the diazoxide and NN414 groups (median 107 and 83 x 10(-3) respectively). Rising second-phase secretion was seen only in the drug-treated groups. Stimulation by 25 mmol/l KCl, together with 0.5 mmol/l 3-isobutyl-1-methylxanthine and 3.3 mmol/l glucose, was enhanced in the drug-treated groups (p<0.05 versus vehicle). Graft insulin content did not differ between groups, nor did percentage of beta cells (between 67 and 68% of endocrine cells).
  
  
  CONCLUSIONS
  Chronic overstimulation by moderate hyperglycaemia damages signalling events including those required for glucose-induced insulin secretion. This signal transduction defect occurs in the absence of any effect on islet macro-morphometry or insulin stores.
authors.affiliation: Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. anneli.bjorklund@molmed.ki.se
authors.forename: A
authors.initials: A
authors.lastname: Björklund
authors.forename: J
authors.initials: J
authors.lastname: Bondo Hansen
authors.forename: S
authors.initials: S
authors.lastname: Falkmer
authors.forename: V
authors.initials: V
authors.lastname: Grill
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008297:Male; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D011920:Rats, Inbred WF; D015398:Signal Transduction / Q000502:physiology*; D014185:Transplantation, Isogeneic
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D015221:Potassium Channels