PT  - JOURNAL ARTICLE
AU  - Maedler, Kathrin
AU  - Størling, Joachim
AU  - Sturis, Jeppe
AU  - Zuellig, Richard A.
AU  - Spinas, Giatgen A.
AU  - Arkhammar, Per O.G.
AU  - Mandrup-Poulsen, Thomas
AU  - Donath, Marc Y.
TI  - Glucose- and Interleukin-1β-Induced β-Cell Apoptosis Requires Ca<sup>2+</sup> Influx and Extracellular Signal-Regulated Kinase (ERK) 1/2 Activation and Is Prevented by a Sulfonylurea Receptor 1/Inwardly Rectifying K<sup>+</sup> Channel 6.2 (SUR/Kir6.2) Selective Potassium Channel Opener in Human Islets
AID  - 10.2337/diabetes.53.7.1706
DP  - 2004 Jul 01
TA  - Diabetes
PG  - 1706--1713
VI  - 53
IP  - 7
4099  - http://diabetes.diabetesjournals.org/content/53/7/1706.short
4100  - http://diabetes.diabetesjournals.org/content/53/7/1706.full
SO  - Diabetes2004 Jul 01; 53
AB  - Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the β-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 μmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 μmol/l diazoxide as well as by 3 and 30 μmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 μmol/l NN414. Similarly, 1 μmol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 μmol/l of the l-type Ca2+ channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca2+ influx and ERK dependent and can be prevented by the β-cell selective potassium channel opener NN414.