Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 10, Pages 1906-1915Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr072
Keywords
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Funding
- European Foundation for the Study of Diabetes (EFSD)
- Chinese Diabetes Society (CDS)
- Lilly, the University of Bremen
- French National Research Agency [ANR-06-BLAN-0236]
- German Research Foundation (DFG) [MA4172/1-1]
- ERC [260336]
- JDRF [31-2008-413]
- European Research Council (ERC) [260336] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-06-BLAN-0236] Funding Source: Agence Nationale de la Recherche (ANR)
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Type 2 diabetes manifests when the beta-cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis. The disease progression results from an interplay of environmental factors and genetic predisposition. Polymorphisms in T-cell factor 7-like 2 (TCF7L2) strongly correlate with type 2 diabetes mellitus (T2DM). While TCF7L2 mRNA is upregulated in islets in diabetes, protein levels are down-regulated. The loss of TCF7L2 induces impaired function and apoptosis. By analyzing human isolated islets, we provide three explanations for this opposite regulation and the mechanisms of TCF7L2 on beta-cell function and survival. (i) We found TCF7L2 transcripts in the human beta-cell, which had opposite effects on beta-cell survival, function and Wnt signaling activation. While TCF7L2 clone B1, which lacks exons 13, 14, 15 and 16 induced beta-cell apoptosis, impaired function and inhibited glucagon-like peptide 1 response and downstream targets of Wnt signaling, clones B3 and B7 which both contain exon 13, improved beta-cell survival and function and activated Wnt signaling. (ii) TCF7L2 mRNA is extremely unstable and is rapidly degraded under pro-diabetic conditions and (iii) TCF7L2 depletion in islets induced activation of glycogen synthase kinase 3-beta, but this was independent of endoplasmic reticulum stress. We demonstrated function-specific transcripts of TCF7L2, which possessed distinct physiological and pathophysiological effects on the beta-cell. The presence of deleterious TCF7L2 splice variants may be a mechanism of beta-cell failure in T2DM.
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