PMID: 15220194Jun 29, 2004Paper

Glucose- and interleukin-1beta-induced beta-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

Diabetes
Kathrin MaedlerMarc Donath

Abstract

Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. 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 beta-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that...Continue Reading

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis