Journal
CELL METABOLISM
Volume 16, Issue 5, Pages 625-633Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2012.10.009
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Funding
- NovoNordisk Foundation
- O.E. Johansson Foundation
- Albert Pahlsson Foundation
- Royal Physiographic Society
- Crafoord Foundation
- Wallenberg Foundation
- Sigrid Juselius Foundation
- ISCIII COMBIOMED [RD07/0067/0001]
- MICINN [TIN2011-22826]
- Swedish Research Council through research positions
- Linnaeus grant
- Strategic Research Grant (Exodiab)
- Novo Nordisk Fonden [NNF10OC1013350] Funding Source: researchfish
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A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly over-expressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1 beta. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca2+ channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
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