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OBJECTIVE- Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature β-cell function and suggest a potential mechanism for its actions.
RESEARCH DESIGN AND METHODS- TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-Cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology.
RESULTS- Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca^sup 2+^ concentration ([Ca^sup 2+^]^sub i^) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca^sup 2+^]^sub i^ and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin IA but decreased Muncl8-1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion.
CONCLUSION- TCF7L2 is involved in maintaining expression of β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles. Diabetes 58: 894-905, 2009
Type 2 diabetes is the most common metabolic disease in industrialized societies (1). The dis- ease has a complex etiology involving interplay between environmental risk factors (obesogenic diet, lack of exercise) and a susceptible genetic back- ground (2). Although the hereditary nature of type 2 diabetes has been acknowledged for many years (3), only recently have candidate gene studies (4-6) and whole genome association approaches (7-10) identified polymorphisms in 12 specific gene loci that increase disease risk. These, and an earlier candidate gene study (11), identified single nucleotide polymorphisms (SNPs), including SNP rs7903146, in the third intron of the gene encoding transcription factor 7-like 2 (TCF7L2; also known as transcription factor 4) as strongly associated with type 2 diabetes in different ethnic backgrounds (9-13). rs7903146 has been estimated to contribute to 10 to 25% of all cases of diabetes in lean individuals (14).
TCF7L2...