WNT/beta-catenin increases the production of incretins by entero-endocrine cells.
OBJECTIVE
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
Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.
García-Martínez
J M
JM
Dptal I. Despacho 020, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcon, Madrid, Spain.
Chocarro-Calvo
A
A
Moya
C M
CM
García-Jiménez
C
C
D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D054795:Incretins / Q000096:biosynthesis*; D007414:Intestinal Neoplasms / Q000503:physiopathology; D008094:Lithium / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D002843:Chromatin; D004273:DNA, Neoplasm; D054795:Incretins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051153:Wnt Proteins; D051176:beta Catenin; D005749:Gastric Inhibitory Polypeptide; D008094:Lithium; D008156:Luciferases