Glucose- and Interleukin-1 -Induced -Cell Apoptosis Requires Ca2+ Influx and Extracellular Signal-Regulated Kinase (ERK) 1/2 Activation and Is Prevented by a Sulfonylurea Receptor 1/Inwardly Rectifying K+ Channel 6.2 (SUR/Kir6.2) Selective Potassium Channel Opener in Human Islets

K. Maedler, J. Storling, J. Sturis, R. A. Zuellig, G. A. Spinas, P. O.G. Arkhammar, T. Mandrup-Poulsen, M. Y. Donath
2004 Diabetes  
Increasing evidence indicates that a progressive decrease in the functional ␤-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, ␤-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1␤ and/or high-glucose-induced ␤-cell production of IL-1␤. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied
more » ... effect of diazoxide and of the novel potassium channel opener NN414, selective for the ␤-cell potassium channel SUR1/Kir6.2, on glucose-and IL-1␤-induced apoptosis and impaired function in human ␤-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1␤, or 10 and 100 mol/l of the sulfonylurea tolbutamide induced ␤-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1␤ were blocked by 200 mol/l diazoxide as well as by 3 and 30 mol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1␤ were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 mol/l NN414. Similarly, 1 mol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 mol/l of the L-type Ca 2؉ channel blocker nimodipine prevented glucose-and IL-1␤-induced ERK activation, ␤-cell apoptosis, and impaired function. Finally, islet release of From the
doi:10.2337/diabetes.53.7.1706 pmid:15220194 fatcat:r5akfujq4jdjhev25bbsxwhltq