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.
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 was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective potassium channel opener NN414.
Maedler
Kathrin
K
Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland.
Størling
Joachim
J
Sturis
Jeppe
J
Zuellig
Richard A
RA
Spinas
Giatgen A
GA
Arkhammar
Per O G
PO
Mandrup-Poulsen
Thomas
T
Donath
Marc Y
MY
D018528:ATP-Binding Cassette Transporters; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020746:Calcium Channels, L-Type; D003499:Cyclic S-Oxides; D007375:Interleukin-1; C475618:NN 414; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; D003981:Diazoxide; D002118:Calcium