Clinical evidence for an association between familial adenomatous polyposis and type II diabetes

Recent genome wide association (GWA) studies suggested that type II diabetes (T2D) is associated with TCF7L2 (or TCF4) polymorphisms.1 TCF7L2/TCF4 is a transcription factor involved in the Wnt-signaling pathway, which plays an important role in colorectal carcinogenesis.Familial adenomatous polyposis (FAP) is a syndrome caused by germline mutations in the APC gene. APC gene defects lead to nuclear accumulation of β-catenin, and formation of β-catenin/TCF4 complexes, which enhances the expression of the Wnt-target genes.2 Recent studies reported activation of the Wnt-signaling pathway in pancreatic cells in T2D patients, as well as in mice on a high-fat diet.3 On the basis of these observations, we hypothesize that FAP patients are at increased risk of T2D. To evaluate the prevalence of T2D in FAP, we used the Dutch Polyposis Registry Database and the outcome of a recent cross-sectional study on the psychosocial impact of FAP.4 Eligible participants were those with a clinically and/or genetically proven FAP diagnosis. A questionnaire that addressed psychosocial issues and clinical variables, including questions about the presence of diabetes, was mailed in 2006. The study was approved by the ethical committees of both the Netherlands Cancer Institute and the Netherlands Foundation for the Detection of Hereditary Tumours. The prevalence of T2D in the study group was compared with that reported for the Dutch general population.5 The standardized morbidity ratio (SMR) was calculated to evaluate whether the prevalence in the study group differs from that in the general population. The 95% confidence interval was calculated using the program confidence interval analysis, version 1. Information was received on 341 FAP patients. Seventeen patients reported to have diabetes (16 T2D and 1 diabetes type I). All cases were confirmed by medical records and/or the general practitioner. One patient was excluded because of Whipple surgery for duodenal polyposis. The mean age of the remaining 15 T2D patients was 55.3 years (range: 35–75 years). The prevalence of T2D in the study group and in the general population is shown in Table 1. The prevalence of T2D in FAP patients was significantly higher than expected (SMR: 2.22; 95% confidence interval: 1.24–3.65). Recent studies suggested that variants of TCF7L2/TCF4 are associated with the development of T2D.1, 6, 7 Also laboratory studies suggested that the Wnt-signaling pathway is involved in T2D. FAP is caused by APC gene defects, which lead to the activation of this pathway. This is the first clinical study that demonstrated a significantly increased prevalence of T2D in FAP patients, which supports the role of the Wnt-signaling pathway in T2D. Future studies should explore the mechanism of the development of T2D in the presence of an activated Wnt-signaling pathway. M.H. Nieuwenhuis*, K.F.L. Douma , E.M.A. Bleiker , N.K. Aaronson , H. Clevers§ ¶, H.F.A. Vasen [email protected]** , * The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands, Medical Psychology, Academic Medical Centre, Amsterdam, The Netherlands, Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, § Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands, ¶ Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, The Netherlands, ** The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands, Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.