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Title

Glucose and leptin induce apoptosis in human beta-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases

Authors
Maedler, Kathrin
Schulthess, Fabienne T.
Bielman, Christelle
Bonny, Christophe
Donath, Marc Y.
Roduit, Raphael
Published in FASEB Journal. 2008, vol. 22, no. 6, p. 1905-1913
Abstract c-Jun N-terminal kinases (SAPK/JNKs) are activated by inflammatory cytokines, and JNK signaling is involved in insulin resistance and beta-cell secretory function and survival. Chronic high glucose concentrations and leptin induce interleukin-1beta (IL-1beta) secretion from pancreatic islets, an event that is possibly causal in promoting beta-cell dysfunction and death. The present study provides evidence that chronically elevated concentrations of leptin and glucose induce beta-cell apoptosis through activation of the JNK pathway in human islets and in insulinoma (INS 832/13) cells. JNK inhibition by the dominant inhibitor JNK-binding domain of IB1/JIP-1 (JNKi) reduced JNK activity and apoptosis induced by leptin and glucose. Exposure of human islets to leptin and high glucose concentrations leads to a decrease of glucose-induced insulin secretion, which was partly restored by JNKi. We detected an interplay between the JNK cascade and the caspase 1/IL-1beta-converting enzyme in human islets. The caspase 1 gene, which contains a potential activating protein-1 binding site, was up-regulated in pancreatic sections and in isolated islets from type 2 diabetic patients. Similarly, cultured human islets exposed to high glucose- and leptin-induced caspase 1 and JNK inhibition prevented this up-regulation. Therefore, JNK inhibition may protect beta-cells from the deleterious effects of high glucose and leptin in diabetes.
Keywords Apoptosis/*drug effectsCaspase 1/geneticsCells, CulturedDiabetes Mellitus, Type 2/pathologyGlucose/*pharmacologyHumansInsulin/*secretionInsulin-Secreting Cells/*cytology/*secretionIslets of Langerhans/cytologyJNK Mitogen-Activated Protein Kinases/*metabolismLeptin/*pharmacologyUp-Regulation/drug effects
Identifiers
PMID: 18263705
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Other version: http://www.fasebj.org/content/22/6/1905.full.pdf
Structures
Research group La transplantation d'îlots de Langerhans (623)
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MAEDLER, Kathrin et al. Glucose and leptin induce apoptosis in human beta-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases. In: FASEB Journal, 2008, vol. 22, n° 6, p. 1905-1913. https://archive-ouverte.unige.ch/unige:19100

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Deposited on : 2012-03-27

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