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Glucose- and Interleukin-1ß-Induced ß-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

¹ Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland
² Steno Diabetes Center, Gentofte, Denmark
³ Novo Nordisk, Måløv, Denmark
⁴ Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden

Increasing evidence indicates that a progressive decrease in the functional ß-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, ß-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1ß and/or high-glucose-induced ß-cell production of IL-1ß. 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 ß-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1ß-induced apoptosis and impaired function in human ß-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1ß, or 10 and 100 µmol/l of the sulfonylurea tolbutamide induced ß-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1ß 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-1ß 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-1ß-induced ERK activation, ß-cell apoptosis, and impaired function. Finally, islet release of IL-1ß in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1ß-induced ß-cell secretory dysfunction and apoptosis are Ca²⁺ influx and ERK dependent and can be prevented by the ß-cell selective potassium channel opener NN414.

Abbreviations: ERK, extracellular signal-regulated kinase; IL, interleukin; K_ATP, ATP-sensitive K⁺; iNOS, inducible nitric oxide synthase; Kir, inwardly rectifying K⁺ channel; MAPK, mitogen-activated protein kinase; SUR, sulfonylurea receptor; TUNEL, transferase-mediated dUTP nick-end labeling

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