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Diabetologia
Published in: Diabetologia 10/2008

Open Access 01-10-2008 | Review

The WNT signalling pathway and diabetes mellitus

Author: T. Jin

Published in: Diabetologia | Issue 10/2008

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Abstract

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 β-catenin/T cell transcription factor (β-cat/TCF), formed by free β-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. β-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, β-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 β-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.
Literature
1.
Peifer M, Polakis P (2000) Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 287:1606–1609PubMedCrossRef
2.
Moon RT, Brown JD, Torres M (1997) WNTs modulate cell fate and behavior during vertebrate development. Trends Genet 13:157–162PubMedCrossRef
3.
Morin PJ, Sparks AB, Korinek V et al (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790PubMedCrossRef
4.
Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186PubMedCrossRef
5.
Zeng X, Tamai K, Doble B et al (2005) A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438:873–877PubMedCrossRef
6.
Polakis P (2000) Wnt signaling and cancer. Genes Dev 14:1837–1851PubMed
7.
Rulifson IC, Karnik SK, Heiser PW et al (2007) Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci USA 104:6247–6252PubMedCrossRef
8.
Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K (2008) TCF7L2 regulates cell survival and function in human pancreatic islets. Diabetes 57:645–653PubMedCrossRef
9.
Liu Z, Habener JF (2008) Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta-cell proliferation. J Biol Chem 283:8723–8735PubMedCrossRef
10.
Fujino T, Asaba H, Kang MJ et al (2003) Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci USA 100:229–234PubMedCrossRef
11.
Yi F, Brubaker PL, Jin T (2005) TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 280:1457–1464PubMedCrossRef
12.
Ni Z, Anini Y, Fang X, Mills G, Brubaker PL, Jin T (2003) Transcriptional activation of the proglucagon gene by lithium and beta-catenin in intestinal endocrine L cells. J Biol Chem 278:1380–1387PubMedCrossRef
13.
Yi F, Sun J, Lim GE, Fantus IG, Brubaker PL, Jin T (2008) Crosstalk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells. Endocrinology 149:2341–2351PubMedCrossRef
14.
15.
16.
Elbein SC (2007) Evaluation of polymorphisms known to contribute to risk for diabetes in African and African-American populations. Curr Opin Clin Nutr Metab Care 10:415–419PubMedCrossRef
17.
Frayling TM (2007) A new era in finding type 2 diabetes genes—the unusual suspects. Diabet Med 24:696–701PubMedCrossRef
18.
Grarup N, Andersen G (2007) Gene–environment interactions in the pathogenesis of type 2 diabetes and metabolism. Curr Opin Clin Nutr Metab Care 10:420–426PubMedCrossRef
19.
20.
Grant SF, Thorleifsson G, Reynisdottir I et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323PubMedCrossRef
21.
Hey PJ, Twells RC, Phillips MS et al (1998) Cloning of a novel member of the low-density lipoprotein receptor family. Gene 216:103–111PubMedCrossRef
22.
Twells RC, Mein CA, Payne F et al (2003) Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Hum Genet 113:99–105PubMed
23.
Twells RC, Mein CA, Phillips MS et al (2003) Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene. Genome Res 13:845–855PubMedCrossRef
24.
Mani A, Radhakrishnan J, Wang H et al (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282PubMedCrossRef
25.
Kokubu C, Heinzmann U, Kokubu T et al (2004) Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131:5469–5480PubMedCrossRef
26.
Kanazawa A, Tsukada S, Sekine A et al (2004) Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. Am J Hum Genet 75:832–843PubMedCrossRef
27.
Heller RS, Dichmann DS, Jensen J et al (2002) Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation. Dev Dyn 225:260–270PubMedCrossRef
28.
Heller RS, Klein T, Ling Z et al (2003) Expression of Wnt, Frizzled, sFRP, and DKK genes in adult human pancreas. Gene Expr 11:141–147PubMedCrossRef
29.
Lim HW, Lee JE, Shin SJ et al (2002) Identification of differentially expressed mRNA during pancreas regeneration of rat by mRNA differential display. Biochem Biophys Res Commun 299:806–812PubMedCrossRef
30.
Murtaugh LC, Law AC, Dor Y, Melton DA (2005) Beta-catenin is essential for pancreatic acinar but not islet development. Development 132:4663–4674PubMedCrossRef
31.
Papadopoulou S, Edlund H (2005) Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes 54:2844–2851PubMedCrossRef
32.
Heiser PW, Lau J, Taketo MM, Herrera PL, Hebrok M (2006) Stabilization of beta-catenin impacts pancreas growth. Development 133:2023–2032PubMedCrossRef
33.
Schinner S, Ulgen F, Papewalis C et al (2008) Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules. Diabetologia 51:147–154PubMedCrossRef
34.
Tamai K, Semenov M, Kato Y et al (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407:530–535PubMedCrossRef
35.
Wehrli M, Dougan ST, Caldwell K et al (2000) arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407:527–530PubMedCrossRef
36.
Gong Y, Slee RB, Fukai N et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523PubMedCrossRef
37.
Kato M, Patel MS, Levasseur R et al (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314PubMedCrossRef
38.
Guo YF, Xiong DH, Shen H et al (2006) Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet 43:798–803PubMedCrossRef
39.
Figueroa DJ, Hess JF, Ky B et al (2000) Expression of the type I diabetes-associated gene LRP5 in macrophages, vitamin A system cells, and the islets of Langerhans suggests multiple potential roles in diabetes. J Histochem Cytochem 48:1357–1368PubMed
40.
Kim DH, Inagaki Y, Suzuki T et al (1998) A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J Biochem 124:1072–1076PubMed
41.
Mao J, Wang J, Liu B et al (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7:801–809PubMedCrossRef
42.
Kieffer TJ (2004) Gastro-intestinal hormones GIP and GLP-1. Ann Endocrinol (Paris) 65:13–21
43.
44.
45.
Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells. Curr Biol 6:1664–1668PubMedCrossRef
46.
Drucker DJ, Jin T, Asa SL, Young TA, Brubaker PL (1994) Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol 8:1646–1655PubMedCrossRef
47.
Lu F, Jin T, Drucker DJ (1996) Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line. Endocrinology 137:3710–3716PubMedCrossRef
48.
Chen L, Wang P, Andrade CF et al (2005) PKA independent and cell type specific activation of the expression of caudal homeobox gene Cdx-2 by cyclic AMP. FEBS J 272:2746–2759PubMedCrossRef
49.
Lotfi S, Li Z, Sun J et al (2006) Role of the exchange protein directly activated by cyclic adenosine 5′-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells. Endocrinology 147:3727–3736PubMedCrossRef
50.
Drucker DJ, Campos R, Reynolds R, Stobie K, Brubaker PL (1991) The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells. Endocrinology 128:394–400PubMedCrossRef
51.
Gajic D, Drucker DJ (1993) Multiple cis-acting domains mediate basal and adenosine 3′,5′-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line. Endocrinology 132:1055–1062PubMedCrossRef
52.
Wang J, Cao Y, Steiner DF (2003) Regulation of proglucagon transcription by activated transcription factor (ATF) 3 and a novel isoform, ATF3b, through the cAMP-response element/ATF site of the proglucagon gene promoter. J Biol Chem 278:32899–32904PubMedCrossRef
53.
Furstenau U, Schwaninger M, Blume R, Jendrusch EM, Knepel W (1999) Characterization of a novel calcium response element in the glucagon gene. J Biol Chem 274:5851–5860PubMedCrossRef
54.
Philippe J (1989) Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. J Clin Invest 84:672–677PubMedCrossRef
55.
Philippe J (1991) Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element. Proc Natl Acad Sci USA 88:7224–7227PubMedCrossRef
56.
Sun J, Jin T (2008) Both Wnt and mTOR signaling pathways are involved in insulin-stimulated proto-oncogene expression in intestinal cells. Cell Signal 20:219–229PubMed
57.
Zhang Q, Adiseshaiah P, Kalvakolanu DV, Reddy SP (2006) A phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression. J Biol Chem 281:10174–10181PubMedCrossRef
58.
Qiao M, Shapiro P, Kumar R, Passaniti A (2004) Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Akt-independent signaling pathway. J Biol Chem 279:42709–42718PubMedCrossRef
59.
Fernandez AM, Kim JK, Yakar S et al (2001) Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev 15:1926–1934PubMedCrossRef
60.
Asghar Z, Yau D, Chan F, Leroith D, Chan CB, Wheeler MB (2006) Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes. Diabetologia 49:90–99PubMedCrossRef
61.
Freathy RM, Weedon MN, Bennett A et al (2007) Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. Am J Hum Genet 80:1150–1161PubMedCrossRef
62.
Florez JC, Jablonski KA, Bayley N et al (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355:241–250PubMedCrossRef
63.
Lyssenko V, Lupi R, Marchetti P et al (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117:2155–2163PubMedCrossRef
64.
Schafer SA, Tschritter O, Machicao F et al (2007) Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 50:2443–2450PubMedCrossRef
65.
Cauchi S, Choquet H, Gutierrez-Aguilar R et al (2008) Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring) 16:476–482CrossRef
66.
Cauchi S, El Achhab Y, Choquet H et al (2007) TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 85:777–782PubMedCrossRef
67.
Cauchi S, Meyre D, Choquet H et al (2007) TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population. BMC Med Genet 8:37PubMedCrossRef
68.
Cauchi S, Meyre D, Choquet H et al (2006) TCF7L2 variation predicts hyperglycemia incidence in a French general population: the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 55:3189–3192PubMedCrossRef
69.
Cauchi S, Meyre D, Dina C et al (2006) Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes 55:2903–2908PubMedCrossRef
70.
Cauchi S, Proenca C, Choquet H et al (2008) Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study. J Mol Med 86:341–348CrossRef
71.
Duan QL, Dube MP, Frasure-Smith N et al (2007) Additive effects of obesity and TCF7L2 variants on risk for type 2 diabetes among cardiac patients. Diabetes Care 30:1621–1623PubMedCrossRef
72.
Saxena R, Gianniny L, Burtt NP et al (2006) Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55:2890–2895PubMedCrossRef
73.
Helgason A, Palsson S, Thorleifsson G et al (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39:218–225PubMedCrossRef
74.
Goodarzi MO, Rotter JI (2007) Testing the gene or testing a variant? The case of TCF7L2. Diabetes 56:2417–2419PubMedCrossRef
75.
Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S (2007) Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 50:980–984PubMedCrossRef
76.
Horikoshi M, Hara K, Ito C, Nagai R, Froguel P, Kadowaki T (2007) A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia 50:747–751PubMedCrossRef
77.
Chang YC, Chang TJ, Jiang YD, Kuo SS, Lee KC, Chiu KC, Chuang LM (2007) Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 56:2631–2637PubMedCrossRef
78.
Ng MC, Tam CH, Lam VK, So WY, Ma RC, Chan JC (2007) Replication and identification of novel variants at TCF7L2 associated with type 2 diabetes in Hong Kong Chinese. J Clin Endocrinol Metab 92:3733–3737PubMedCrossRef
79.
Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19:379–383PubMedCrossRef
80.
Puig O, Tjian R (2006) Nutrient availability and growth: regulation of insulin signaling by dFOXO/FOXO1. Cell Cycle 5:503–505PubMed
81.
Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425PubMedCrossRef
82.
Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117:421–426PubMedCrossRef
83.
Barthel A, Schmoll D, Unterman TG (2005) FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab 16:183–189PubMedCrossRef
84.
Essers MA, Weijzen S, de Vries-Smits AM et al (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812PubMedCrossRef
85.
Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184PubMedCrossRef
86.
Eisenmann DM, Maloof JN, Simske JS, Kenyon C, Kim SK (1998) The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. Development 125:3667–3680PubMed
87.
88.
Almeida M, Han L, Martin-Millan M et al (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282:27285–27297PubMedCrossRef
89.
Almeida M, Han L, Martin-Millan M, O’Brien CA, Manolagas SC (2007) Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem 282:27298–27305PubMedCrossRef
90.
Hoogeboom D, Essers MA, Polderman PE, Voets E, Smits LM, Burgering BM (2008) Interaction of FOXO with beta-catenin inhibits beta-catenin/TCF activity. J Biol Chem 283:9224–9230PubMedCrossRef
91.
Glauser DA, Schlegel W (2007) The emerging role of FOXO transcription factors in pancreatic beta cells. J Endocrinol 193:195–207PubMedCrossRef
92.
Nishikawa T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9:343–353PubMedCrossRef
Metadata
Title
The WNT signalling pathway and diabetes mellitus
Author
T. Jin
Publication date
01-10-2008
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 10/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-008-1084-y

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