Type 2 Diabetes and TCF7L2 

  • Author: Ali Torkamani, PhD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Nov 14, 2011
 

Overview

Transcription factor 7–like 2 (TCF7L2) variants have been associated with type 2 diabetes in multiple ethnic groups.[1, 2, 3, 4, 5, 6, 7] Specific associated variants increase the risk of type 2 diabetes 1.5-fold in heterozygotes and 2.4-fold in homozygotes, corresponding to a population attributable risk of 21%. This makes TCF7L2 variants the strongest known genetic risk factors for type 2 diabetes.[8]

TCF7L2 is a transcription factor and key component of the Wnt signaling pathway, and it is involved in the development of a wide variety of cell lineages and organs.[9] Potential mechanisms through which TCF7L2 variants influence type 2 diabetes include its role in adipogenesis, myogenesis, and pancreatic islet development, as well as in beta-cell survival and insulin secretory granule function.[10, 11] It is also involved in the transcriptional regulation of the genes for proglucagon and the glucagon-like peptides GLP-1 and GLP-2; these peptides play a role in postprandial insulin secretion.[12]

Finally, TCF7L2 polymorphisms have been associated with impaired insulin secretion, glucose production, and glucose tolerance via direct effects on pancreatic islet beta cells.[13, 14] Indeed, dysregulation of glucose metabolism, decreased processing of proinsulin, and elevated levels of gastric inhibitory peptide and glycated hemoglobin (HbA1c) can be observed in normoglycemic individuals with TCF7L2 polymorphisms before the onset of type 2 diabetes.[15, 16]

Thus, while the specific mechanism driving the development of type 2 diabetes remains unclear, there is sufficient evidence to demonstrate that TCF7L2 variants strongly predict the development of type 2diabetes and/or the progression to diabetes from impaired glucose tolerance.[14, 17]

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Clinical Implications

Although genetic tests for TCF7L2 could help predict the incidence and the rate of onset of type 2 diabetes,[18] the strongest predictors continue to be positive family history, increased body mass index, increased blood pressure, and increased serum levels of triglycerides, apolipoprotein A-1, and liver enzymes, all of which precede inception of metabolic syndrome.[19] In fact, the predictive power of TCF7L2 variants disappears with lifestyle modifications or metformin treatment, while the improved insulin sensitivity resulting from these changes directly oppose the pathological influence of TCF7L2 variants.[20] These data suggest that genetic susceptibility to type 2 diabetes as determined by TCF7L2 variants might prove an actionable indicator for early intervention and disease prevention.[17]

Researchers are also exploring whether TCF7L2 variants might serve as markers for tailoring customized therapeutic regimens. For example, DPP4 is a peptidase that degrades incretins such as GLP-1.[21] DPP4 inhibitors enhance incretin-stimulated insulin secretion and inhibit glucagon release, thereby helping to normalize blood glucose levels. If a negative influence on incretin secretion is confirmed as a major pathological axis in TCF7L2 -driven type 2 diabetes, DPP4 inhibitors could potentially serve as a counterbalance and reverse the effects of TCF7L2 variants on incretin levels.[21] TCF7L2 polymorphisms have been associated with variation in the response to sulfonylurea treatment, but these effects are likely too modest to guide care.[22, 23]

Obviously, the clinical utility of TCF7L2 variants is associated with some caveats. First, the specific type 2 diabetes risk variants of TCF7L2 vary from population to population.[24] Similar effect sizes have been observed in a number of ethnic groups for the most commonly studied TCF7L2 variants, but the research must be expanded further beyond nonwhite populations. Second, although the effect sizes of TCF7L2 variants are relatively large, a much more accurate picture of risk stratification and therapeutic personalization would be informed by a larger collection of predisposition genes rather than TCF7L2 alone. Finally, no studies have unequivocally demonstrated a role for TCF7L2 variants in the management of type 2 diabetes beyond the point of disease onset.

Ultimately, TCF7L2 could prove a promising biomarker for disease prevention for those with an elevated genetic predisposition to type 2 diabetes. In the meantime, however, there is no clinical role for routine screening for TCF7L2, and the presence of TCF7L2 variants that are associated with increased risk of type 2 diabetes should be considered in combination with other known predictors when assessing a patient's individual risk for type 2 diabetes.

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Contributor Information and Disclosures
Author

Ali Torkamani, PhD  Director of Drug Discovery, The Scripps Translational Science Institute; Assistant Professor of Molecular and Experimental Medicine, The Scripps Research Institute

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  2. Sale MM, Smith SG, Mychaleckyj JC, et al. Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes. Oct 2007;56(10):2638-42. [Medline].

  3. Scott LJ, Bonnycastle LL, Willer CJ, et al. Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes. Sep 2006;55(9):2649-53. [Medline].

  4. Groves CJ, Zeggini E, Minton J, et al. Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes. Sep 2006;55(9):2640-4. [Medline].

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  7. Chang YC, Chang TJ, Jiang YD, et al. Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes. Oct 2007;56(10):2631-7. [Medline].

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  11. da Silva Xavier G, Loder MK, McDonald A, Tarasov AI, Carzaniga R, Kronenberger K. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes. Apr 2009;58(4):894-905. [Medline].

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  13. Lyssenko V, Lupi R, Marchetti P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. Aug 2007;117(8):2155-63. [Medline]. [Full Text].

  14. Schafer SA, Tschritter O, Machicao F, et al. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia. Dec 2007;50(12):2443-50. [Medline]. [Full Text].

  15. Gjesing AP, Kjems LL, Vestmar MA, Grarup N, Linneberg A, Deacon CF. Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test. Diabetologia. Jan 2011;54(1):103-10. [Medline].

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  20. Kitabchi AE, Temprosa M, Knowler WC, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. Aug 2005;54(8):2404-14. [Medline]. [Full Text].

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  23. Schroner Z, Javorsky M, Tkacova R, et al. Effect of sulphonylurea treatment on glycaemic control is related to TCF7L2 genotype in patients with type 2 diabetes. Diabetes Obes Metab. Jan 2011;13(1):89-91. [Medline].

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