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

• Published in: Diabetologia Vol. 47; no. 5; pp. 885 - 891
• Main Authors: BJÖRKLUND, A, HANSEN, J. Bondo, FALKMER, S, GRILL, V
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-05-2004; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight; C-Peptide - blood; Diabetes; Diabetes Mellitus, Type 2 - surgery; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Glucose; Hyperglycemia; Insulin; Insulin - metabolism; Insulin Secretion; Ion Channel Gating - physiology; Islets of Langerhans Transplantation - physiology; Male; Medical sciences; Medicin och hälsovetenskap; Potassium; Potassium Channels - physiology; Rats; Rats, Inbred WF; Signal transduction; Signal Transduction - physiology; Transplantation, Isogeneic; Transplants & implants; Type 2 diabetes; Endocrinopathy; Animal model; Pancreatic hormone; Langerhans islet; Ionic channel; Transplantation; Diazoxide; Inorganic element; Insulin; Endocrine secretion; Insulin secretion; Signal transduction; Beta cell overstimulation; Islets of Langerhans; ATP; Potassium; Endocrine pancreas
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-004-1386-7

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.
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.
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).
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.