Glucose- and interleukin-1β-induced β-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 islet

Kathrin Maedler, Joachim Størling, Jeppe Sturis, Richard A. Zuellig, Giatgen A. Spinas, Per O.G. Arkhammar, Thomas Mandrup-Poulsen, Marc Y. Donath*

*Corresponding author af dette arbejde
144 Citationer (Scopus)

Abstract

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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind53
Udgave nummer7
Sider (fra-til)1706-1713
Antal sider8
ISSN0012-1797
DOI
StatusUdgivet - jul. 2004
Udgivet eksterntJa

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