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01.09.2009 | Article | Ausgabe 9/2009

Diabetologia 9/2009

WNT/β-catenin increases the production of incretins by entero-endocrine cells

Zeitschrift:
Diabetologia > Ausgabe 9/2009
Autoren:
J. M. García-Martínez, A. Chocarro-Calvo, C. M. Moya, C. García-Jiménez
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-009-1429-1) contains supplementary material, which is available to authorised users.
J. M. García-Martínez and A. Chocarro-Calvo contributed equally to this work.

Abstract

Aims/hypothesis

Glucose-dependent insulinotropic peptide (GIP) plays a pivotal role in the regulation of glucose homeostasis. Rates of diet-induced obesity, insulin resistance and type 2 diabetes are decreased when GIP signalling is disturbed in mice, suggesting that GIP plays a role in the onset of type 2 diabetes. WNT signalling is linked to type 2 diabetes and induces synthesis of the other incretin, glucagon-like peptide 1 (GLP-1). GLP-1 analogues improve treatment of type 2 diabetes patients in whom GLP-1 signalling is intact and have captured clinical attention. GIP levels are altered at the onset of type 2 diabetes and later on, while GIP signalling is impaired. Thus, GIP is not a candidate for treatment but might be an important target from a prevention perspective. Hypothesising that hypersecretion of GIP links altered WNT signalling to the onset of type 2 diabetes, we sought to determine whether WNT signalling induces GIP production by entero-endocrine cells.

Methods

RT-PCR and chromatin immunoprecipitation (ChIP) were used to study Gip gene induction. Gip promoter elements mediating WNT/lithium induction were identified (electrophoretic mobility shift assay, co-transfection of deletion mutants, ChIP).

Results

Lithium or WNT/β-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/β-catenin binding to Gip promoter and diminishes ChIP through T cell factor-4 and histone deacetylase 1.

Conclusions/interpretation

Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.

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Zusatzmaterial
ESM Table 1 Oligonucleotides used (PDF 35 kb)
125_2009_1429_MOESM1_ESM.pdf
ESM Table 2 Primer pairs used for detection of WNT receptors (PDF 17 kb)
125_2009_1429_MOESM2_ESM.pdf
ESM Fig. 1 WNT receptors expressed in entero-endocrine STC-1 cells. RNA from cells treated or not with the indicated lithium concentrations were subjected to RT-PCR using primers indicated in ESM Table  2. A DNA molecular weight marker (Mark) (100 bp ladder) was used, with upper and lower band corresponding to 400 and 100 bp respectively (all seven gels), as indicated. C+, HT-29 cell line from colon used as positive control; C−, negative control. Water was used to show primer and product specificity (TIFF 2522 kb)
ESM Fig. 2 Lithium and WNT increase LEF1 and β-catenin binding to the TCF/LEF binding site (TL)5 in the mouse Gip promoter. Cells were cultured for 24 h with LiCl (50 mmol/l) or recombinant WNT3A (50 ng/ml). Cross-linked chromatin immunoprecipitated with anti-LEF1 or anti-β-catenin antibodies and purified was analysed by PCR using primers specified in ESM Table  1. a Semiquantitative PCR showed that TL5 containing chromatin from cells treated with WNT or lithium binds LEF1 and β-catenin better than chromatin from control cells (compare lanes 8–9 with 7 and lanes 11–12 with 10). C, control cells. Preimm, preimmune serum was used to control the specificity of α-LEF1 and α–β catenin antibodies. GIP Int Control, a sequence lacking TL sites from an intron in the mouse Gip gene is not bound nor immunoprecipitated. b Quantitative PCR (QPCR) on the immunoprecipitated chromatin. Values were normalised (subtraction of preimmune and division by input) and expressed as fold induction over chromatin immunoprecipitated from control (untreated) cells (PDF 670 kb)
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