The WNT signalling pathway and diabetes mellitus

被引:156
作者
Jin, T. [1 ,2 ,3 ,4 ]
机构
[1] Univ Hlth Network, Toronto Gen Res Inst, Div Cell & Mol Biol, Toronto, ON M5G 1L7, Canada
[2] Univ Toronto, Dept Med, Toronto, ON, Canada
[3] Univ Toronto, Dept Physiol, Toronto, ON, Canada
[4] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
基金
加拿大健康研究院;
关键词
beta-Cat/TCF; FOXO; GLP-1; stress; TCF7L2; WNT;
D O I
10.1007/s00125-008-1084-y
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The WNT signalling pathway is involved in many physiological and pathophysiological activities. WNT ligands bind to Frizzled receptors and co-receptors (LDL receptor-related protein 5/6), triggering a cascade of signalling events. The major effector of the canonical WNT signalling pathway is the bipartite transcription factor beta-catenin/T cell transcription factor (beta-cat/TCF), formed by free beta-cat and one of the four TCFs. The WNT pathway is involved in lipid metabolism and glucose homeostasis, and mutations in LRP5 may lead to the development of diabetes and obesity. beta-Cat/TCF is also involved in the production of the incretin hormone glucagon-like peptide-1 in the intestinal endocrine L cells. More recently, genome-wide association studies have identified TCF7L2 as a diabetes susceptibility gene, and individuals carrying certain TCF7L2 single nucleotide polymorphisms could be more susceptible to the development of type 2 diabetes. Furthermore, beta-cat is able to interact with forkhead box transcription factor subgroup O (FOXO) proteins. Since FOXO and TCF proteins compete for a limited pool of beta-cat, enhanced FOXO activity during ageing and oxidative stress may attenuate WNT-mediated activities. These observations shed new light on the pathogenesis of type 2 diabetes as an age-dependent disease.
引用
收藏
页码:1771 / 1780
页数:10
相关论文
共 92 条
[1]   FoxOs at the crossroads of cellular metabolism, differentiation, and transformation [J].
Accili, D ;
Arden, KC .
CELL, 2004, 117 (04) :421-426
[2]   Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids [J].
Almeida, Maria ;
Han, Li ;
Martin-Millan, Marta ;
Plotkin, Lilian I. ;
Stewart, Scott A. ;
Roberson, Paula K. ;
Kousteni, Stavroula ;
O'Brien, Charles A. ;
Bellido, Teresita ;
Parfitt, A. Michael ;
Weinstein, Robert S. ;
Jilka, Robert L. ;
Manolagas, Stavros C. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (37) :27285-27297
[3]   Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor- to Forkhead box O-mediated transcription [J].
Almeida, Maria ;
Han, Li ;
Martin-Millan, Marta ;
O'Brien, Charles A. ;
Manolagas, Stavros C. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (37) :27298-27305
[4]   Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes [J].
Asghar, Z ;
Yau, D ;
Chan, F ;
LeRoith, D ;
Chan, CB ;
Wheeler, MB .
DIABETOLOGIA, 2006, 49 (01) :90-99
[5]   FoxO proteins in insulin action and metabolism [J].
Barthel, A ;
Schmoll, D ;
Unterman, TG .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2005, 16 (04) :183-189
[6]   TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population [J].
Cauchi, Stephane ;
Meyre, David ;
Choquet, Helene ;
Deghmoun, Samia ;
Durand, Emmanuelle ;
Gaget, Stefan ;
Lecoeur, Cecile ;
Froguel, Philippe ;
Levy-Marchal, Claire .
BMC MEDICAL GENETICS, 2007, 8
[7]   Analysis of novel risk loci for type 2 diabetes in a general French population:: the DESIR study [J].
Cauchi, Stephane ;
Proenca, Christine ;
Choquet, Helene ;
Gaget, Stefan ;
De Graeve, Franck ;
Marre, Michel ;
Balkau, Beverley ;
Tichet, Jean ;
Meyre, David ;
Vaxillaire, Martine ;
Froguel, Philippe .
JOURNAL OF MOLECULAR MEDICINE-JMM, 2008, 86 (03) :341-348
[8]   Effects of TCF7L2 polymorphisms on obesity in European populations [J].
Cauchi, Stephane ;
Choquet, Helesne ;
Gutierrez-Aguilar, Ruth ;
Capel, Frederic ;
Grau, Katrine ;
Proenca, Christine ;
Dina, Christian ;
Duval, Alex ;
Balkau, Beverley ;
Marre, Michel ;
Potoczna, Natascha ;
Langin, Dominique ;
Horber, Fritz ;
Sorensen, Thorkild I. A. ;
Charpentier, Guillaume ;
Meyre, David ;
Froguel, Philippe .
OBESITY, 2008, 16 (02) :476-482
[9]   TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis [J].
Cauchi, Stephane ;
El Achhab, Younes ;
Choquet, Helene ;
Dina, Christian ;
Krempler, Franz ;
Weitgasser, Raimund ;
Nejjari, Chakib ;
Patsch, Wolfgang ;
Chikri, Mohamed ;
Meyre, David ;
Froguel, Philippe .
JOURNAL OF MOLECULAR MEDICINE-JMM, 2007, 85 (07) :777-782
[10]   TCF7L2 variation predicts hyperglycentia incidence in a French general population -: The Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study [J].
Cauchi, Stephane ;
Meyre, David ;
Choquet, Helene ;
Dina, Christian ;
Born, Catherine ;
Marre, Michel ;
Balkau, Beverley ;
Froguel, Philippe .
DIABETES, 2006, 55 (11) :3189-3192