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Diabetologia. 2009 Sep;52(9):1913-24. doi: 10.1007/s00125-009-1429-1. Epub 2009 Jul 7.

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

Author information

1
Dptal I. Despacho 020, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcon, Madrid, Spain.

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/beta-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/beta-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.

PMID:
19582394
DOI:
10.1007/s00125-009-1429-1
[Indexed for MEDLINE]

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