TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells.
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 beta-cell function and suggest a potential mechanism for its actions.


METHODS
TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. Beta-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 Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18-1 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.


CONCLUSIONS
TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.
da Silva Xavier
Gabriela
G
Section of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College, London, UK.
Loder
Merewyn K
MK
McDonald
Angela
A
Tarasov
Andrei I
AI
Carzaniga
Raffaella
R
Kronenberger
Katrin
K
Barg
Sebastian
S
Rutter
Guy A
GA
D000818:Animals; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D051381:Rats; D051820:TCF Transcription Factors / Q000235:genetics* / Q000502:physiology; D058118:Transcription Factor 7-Like 2 Protein
D017931:DNA Primers; D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein