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 |
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Authors: | A.?Bj?rklund author-information" > author-information__contact u-icon-before" > mailto:anneli.bjorklund@molmed.ki.se" title=" anneli.bjorklund@molmed.ki.se" itemprop=" email" data-track=" click" data-track-action=" Email author" data-track-label=" " >Email author,J.?Bondo Hansen,S.?Falkmer,V.?Grill |
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Affiliation: | (1) Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden;(2) Novo Nordisk Research and Development (JBH), Novo Nordisk Park, Måløv, Denmark;(3) Morphology Unit, Department of Laboratory Medicine, St. Olavs University Hospital, Norwegian University of Science and Technology, Trondheim, Norway;(4) Endocrine Unit, Department of Abdominal Diseases, St. Olavs University Hospital, Norwegian University of Science and Technology, Trondheim, Norway;(5) Endocrine Lab L6B: 01, Karolinska Hospital, 171 76 Stockholm, Sweden |
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Abstract: | Aims/hypothesis 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-4H-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 18×10–3 µU·islet–1·min–1) but were significant per se and versus vehicle in the diazoxide and NN414 groups (median 107 and 83×10–3 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/interpretation 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.Abbreviations IBMX 3-isobutyl-1-methylxanthine - IHC immunohistochemical - K+-ATP channels ATP-sensitive potassium channels - NN414 6-chloro -3-(1-methylcyclopropyl) amino-4H-thienol [3,2-e]-1,2,4-thiadiazine 1,1-dioxide - PP cells pancreatic polypeptide cells |
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Keywords: | Beta cell overstimulation Diazoxide Insulin secretion Islets of Langerhans Transplantation |
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