Glucose and leptin induce apoptosis in human beta-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases.
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.
Maedler
Kathrin
K
Larry L. Hillblom Islet Research Center, University of California, Los Angeles, California, USA. kmaedler@uni-bremen.de
Schulthess
Fabienne T
FT
Bielman
Christelle
C
Berney
Thierry
T
Bonny
Christophe
C
Prentki
Marc
M
Donath
Marc Y
MY
Roduit
Raphael
R
D017209:Apoptosis / Q000187:drug effects*; D020170:Caspase 1 / Q000235:genetics; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D007328:Insulin; D020738:Leptin; D048031:JNK Mitogen-Activated Protein Kinases; D020170:Caspase 1; D005947:Glucose