Document Detail

In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas.
MedLine Citation:
PMID:  23349497     Owner:  NLM     Status:  Publisher    
Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated c-Jun N-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic β-cells. Using a transgenic mouse model, here we show that JNK activation in β-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, KIC-, IBMX-, KCl- and tolbutamide-induced insulin secretion. At molecular level, JNK activation in β-cells inhibited insulin-induced Akt phosphorylation, Pdx1 nucleocytoplasmic shuttling and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic β-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit β-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin-sensitizing action directly on pancreatic β-cells.
Jordi Lanuza-Masdeu; M Isabel Arévalo; Cristina Vila; Albert Barberà; Ramon Gomis; Carme Caelles
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-24
Journal Detail:
Title:  Diabetes     Volume:  -     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
University of Barcelona, Biochemistry and Molecular Biology, Barcelona, Spain.
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