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.
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 diabetespatients 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.
Authors: K Miyawaki; Y Yamada; H Yano; H Niwa; N Ban; Y Ihara; A Kubota; S Fujimoto; M Kajikawa; A Kuroe; K Tsuda; H Hashimoto; T Yamashita; T Jomori; F Tashiro; J Miyazaki; Y Seino Journal: Proc Natl Acad Sci U S A Date: 1999-12-21 Impact factor: 11.205
Authors: V Korinek; N Barker; P J Morin; D van Wichen; R de Weger; K W Kinzler; B Vogelstein; H Clevers Journal: Science Date: 1997-03-21 Impact factor: 47.728
Authors: Matthew C Althage; Eric L Ford; Songyan Wang; Patrick Tso; Kenneth S Polonsky; Burton M Wice Journal: J Biol Chem Date: 2008-04-17 Impact factor: 5.157
Authors: A P Gjesing; L L Kjems; M A Vestmar; N Grarup; A Linneberg; C F Deacon; J J Holst; O Pedersen; T Hansen Journal: Diabetologia Date: 2010-10-19 Impact factor: 10.122