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

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/1 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.