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 Islets

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 7; pp. 1706 - 1713
• Main Authors: MAEDLER, Kathrin, STØRLING, Joachim, STURIS, Jeppe, ZUELLIG, Richard A, SPINAS, Giatgen A, ARKHAMMAR, Per O. G, MANDRUP-POULSEN, Thomas, DONATH, Marc Y
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-07-2004
• Subjects: Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Fundamental and applied biological sciences. Psychology; Hormones. Régulation; Medical sciences; Vertebrates: endocrinology; Endocrinopathy; Human; Calcium; Extracellular signal-regulated protein kinase; Enzyme; Diabetes mellitus; Cytokine; Interleukin 1β; Ionic channel; Glucose; Inorganic element; Micronutrient; Cell death; Sulfonylureas; β Cell; Endocrine pancreas; Apoptosis; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.7.1706

Glucose- and Interleukin-1β-Induced β-Cell Apoptosis Requires Ca 2+ 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
Kathrin Maedler 1 ,
Joachim Størling 2 ,
Jeppe Sturis 3 ,
Richard A. Zuellig 1 ,
Giatgen A. Spinas 1 ,
Per O.G. Arkhammar 3 ,
Thomas Mandrup-Poulsen 2 4 and
Marc Y. Donath 1
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
Address correspondence and reprint requests to Marc Y. Donath, MD, Division of Endocrinology and Diabetes, Department of Medicine,
University Hospital, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch
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 Ca 2+ 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 Ca 2+ influx and ERK dependent and can be prevented by the β-cell selective potassium channel opener NN414.
ERK, extracellular signal-regulated kinase
IL, interleukin
KATP, 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
Footnotes
J.S., P.O.G.A., and T.M.-P are employed by Novo Nordisk A/S, Bagsværd, Denmark, at Steno Diabetes Center. The clinical activities
of this center are paid by the public health care system, but Novo Nordisk strongly subsidizes the research activities of
the center. Novo Nordisk manufactures and markets pharmaceuticals related to the treatment of diabetes.
Accepted March 25, 2004.
Received November 7, 2003.
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