ESPEYB15 12 Type 2 Diabetes, Metabolic Syndrome and Lipid Metabolism New Mechanism (3 abstracts)
12.3 The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing beta-Cell Function and Hepatic Insulin Sensitivity
Cropano C , Santoro N , Groop L , Dalla Man C , Cobelli C , Galderisi A , Kursawe R , Pierpont B , Goffredo M & Caprio S
Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
To read the full abstract: Diabetes Care 2017;40:1082-1089
Transcription factor 7-like 2 (TCF7L2) is a protein encoded by the TCF7L2 gene located on chromosome 10q25.2-q25.3 and is involved in the development of a wide variety of cell lineages and organs. The rs7903146 single nucleotide polymorphism (SNP) within the TCF7L2 gene was first reported in 2006 by Grant et al. to be associated with T2DM in an Icelandic case-control study4, and is the common variant with the largest effect on T2DM susceptibility discovered to date. However, studies in adolescents were lacking.
Here, Cropano et al. describe, in a youth cohort, that each copy of the T (risk) allele of rs7903146 was associated with a 1.5-2 fold increased odds for IGT, depending on ethnicity. Furthermore, longitudinal follow-up suggested that this TCF7L2 risk genotype is associated with a high risk of maintaining IGT or progressing to T2DM. The T allele of TCF7L2 rs7903146 has profound effects on beta-cell function, as reflected by a reduced disposition index and an altered proinsulin secretory efficiency. Moreover, its effects seem to extend to the liver by reducing insulin’s ability to suppress hepatic endogenous glucose production. These effects seem to occur in parallel, thus playing a critical role in two of the major defects that are key to the development of hyperglycemia. The rs7903146 risk variant in TCF7L2 affects functional beta-cell capacity early in the course of T2DM development in obese adolescents.
4. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature genetics 2006; 38(3): 320-3.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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