Clinical Impact of the TCF7L2 Gene rs7903146 Type 2 Diabetes
                    Mellitus Risk Polymorphism in Women with Gestational Diabetes Mellitus: Impaired
                    Glycemic Control and Increased Need of Insulin Therapy

Laura Potasso; Nikolaos Perakakis; Apostolia Lamprinou; Elektra Polyzou; Dimitrios Kassanos; Andreas Peter; Günter Päth; Jochen Seufert; Katharina Laubner

doi:10.1055/a-1008-9223

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2020; 128(10): 663-666
DOI: 10.1055/a-1008-9223

Article

Clinical Impact of the TCF7L2 Gene rs7903146 Type 2 Diabetes Mellitus Risk Polymorphism in Women with Gestational Diabetes Mellitus: Impaired Glycemic Control and Increased Need of Insulin Therapy

Authors

Laura Potasso‡

¹Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Nikolaos Perakakis‡

¹Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

²Current address: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Apostolia Lamprinou

³Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Freiburg, Germany

⁴Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany

⁵German Center for Diabetes Research (DZD), Neuherberg, Freiburg, Germany
Elektra Polyzou

⁶University Hospital Attikon, 3rd Department of Obstetrics and Gynecology, Greece
Dimitrios Kassanos

⁶University Hospital Attikon, 3rd Department of Obstetrics and Gynecology, Greece
Andreas Peter

³Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Freiburg, Germany

⁴Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany

⁵German Center for Diabetes Research (DZD), Neuherberg, Freiburg, Germany
Günter Päth

¹Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Jochen Seufert

¹Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Katharina Laubner

¹Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Abstract

Background The single nucleotide polymorphism in TCF7L2 rs7903146 is associated with an increased risk of type 2 diabetes mellitus and gestational diabetes mellitus. Mechanisms by which this mutation acts, and its impact on the clinical course of the diseases remain unclear. Here we investigated the clinical impact of the T risk allele in women with gestational diabetes mellitus.

Methods We genotyped the C/T polymorphism in 164 Caucasian women with GDM (German n=114; Greek n=50). The impact of the T allele on the results of the 75g oral-glucose-tolerance-test, and on the required therapy (diet/lifestyle or insulin) was investigated.

Results During oral-glucose-tolerance-test, women harboring the T allele displayed significantly higher glucose values at 60 min (p=0.034) and were more likely to require insulin therapy even after adjusting for confounders, such as BMI and age.

Conclusion These results provide evidence that the T risk allele in TCF7L2 rs7903146 is associated with failure in early postprandial glycemic control and requirement of insulin therapy in women with gestational diabetes mellitus, even after adjusting for confounding factors such BMI and age.

key words

gestational diabetes mellitus - TCF7L2 - insulin therapy

Full Text

References

References
1 American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care 2007; 30 Suppl 1 S42-S47.
2 Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 1998; 21 Suppl 2 B161-B167
3 Buchanan TA. Pancreatic B-cell defects in gestational diabetes: Implications for the pathogenesis and prevention of type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism 2001; 86: 989-993. doi:10.1210/jcem.86.3.7339
4 Freathy RM, Hayes MG, Urbanek M. et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: Common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups. Diabetes 2010; 59: 2682-2689.
5 Lauenborg J, Grarup N, Damm P. et al. Common type 2 diabetes risk gene variants associate with gestational diabetes. The Journal of Clinical Endocrinology and Metabolism 2009; 94: 145-150
6 Jin T. Current understanding on role of the wnt signaling pathway effector TCF7L2 in glucose homeostasis. Endocr Rev 2016; 37: 254-277. doi:10.1210/er.2015-1146
7 Cauchi S, El Achhab Y, Choquet H. et al. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: A global meta-analysis. Journal of Molecular Medicine 2007; 85: 777-782.
8 Wu L, Cui L, Tam WH. et al. Genetic variants associated with gestational diabetes mellitus: A meta-analysis and subgroup analysis. Scientific Reports 2016; 6: 30539.
9 Damcott CM, Pollin TI, Reinhart LJ. et al. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: Replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes 2006; 55: 2654-2659.
10 Florez JC. The new type 2 diabetes gene TCF7L2. Current Opinion in Clinical Nutrition and Metabolic Care 2007; 10: 391-396 doi:10.1097/MCO.0b013e3281e2c9be
11 Saxena R, Gianniny L, Burtt NP. et al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006; 55: 2890-2895
12 Renstrom E. Impact of transcription factor 7-like 2 (TCF7L2) on pancreatic islet function and morphology in mice and men. Diabetologia 2012; 55: 2559-2561. doi:10.1007/s00125-012-2659-1
13 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 2007; 50: 2443-2450.
14 Jaghutriz BA, Heni M, Lutz SZ. et al. Gene x Gene Interactions Highlight the role of incretin resistance for insulin secretion. Frontiers in Endocrinology 2019; 10: 72.
15 [Anonymous] . Gestational diabetes mellitus. Diabetes Care 2004; 27 Suppl 1 S88-S90
16 Dutra LA, Costa PG, Velasco LF. et al. Allele-specific PCR assay to genotype SNP rs7903146 in TCF7L2 gene for rapid screening of diabetes susceptibility. Arquivos brasileiros de endocrinologia e metabologia 2008; 52: 1362-1366
17 Lyssenko V, Lupi R, Marchetti P. et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. The Journal of Clinical Investigation 2007; 117: 2155-2163.
18 Hansson O, Zhou Y, Renstrom E. et al. Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes. Current Diabetes Reports 2010; 10: 444-451.
19 Firneisz G, Rosta K, Al-Aissa Z. et al. The MTNR1B rs10830963 variant in interaction with pre-pregnancy BMI is a pharmacogenetic marker for the initiation of antenatal insulin therapy in gestational diabetes mellitus. Int J Mol Sci 2018; 19
20 Sparso T, Bonnefond A, Andersson E. et al. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. Diabetes 2009; 58: 1450-1456.