Abstract
Aims/hypothesis: We sought to determine: (1) the role of previously described transcription factor 7-like 2 (TCF7L2) variants in type 2 diabetes in African American individuals and in participants of European ancestry; (2) the physiological impact of these variants on glucose homeostasis; and (3) whether the non-coding variants altered TCF7L2 expression in adipocytes and transformed lymphocytes. Methods: Association studies were conducted by genotyping 932 Europid and African American diabetic and control participants. Family studies were conducted in 673 members of 68 Europid families ascertained for at least two diabetic siblings. Metabolic studies were conducted in 585 non-diabetic individuals who had undergone frequently sampled intravenous glucose tolerance tests to determine insulin sensitivity and insulin secretion. Gene expression studies were conducted in 74 adipose samples and 64 muscle samples from non-diabetic individuals with known genotypes and also in 55 lymphoblastoid cell lines. Results: TCF7L2 variants were associated with type 2 diabetes in a Europid case-control population and in families, but not in African Americans. Risk alleles increased the 60 min post-challenge glucose value in Europid families and reduced insulin sensitivity by 45% in Europids, but did not alter insulin secretion. TCF7L2 expression was not altered by genotype and did not correlate with insulin sensitivity or BMI. Conclusions/interpretation: We confirmed TCF7L2 as a risk factor in a population of European descent, where it reduced glucose tolerance and insulin sensitivity, but not insulin secretion. We found no role in African Americans and could not explain the association by altered adipocyte or muscle gene expression.
Original language | English |
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Pages (from-to) | 1621-1630 |
Number of pages | 10 |
Journal | Diabetologia |
Volume | 50 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2007 |
Bibliographical note
Funding Information:Acknowledgements This work was supported by grants from National Institutes of Health/National Institute of Diabetes, Digestive and Kidney Disease (NIH/NIDDK) DK39311 (S. C. Elbein), DK71277 (P. A. Kern) and by the Research Service of the Department of Veterans Affairs (Merit funds to S. C. Elbein, P. A. Kern and N. Rasouli; REAP funds). Participants ascertainment was supported in part by grants from the American Diabetes Association (S. C. Elbein), NIH/NIDDK DK59311 (S. C. Elbein) and by the General Clinical Research Center, grant M01RR14288 from National Center for Research Resources (National Institutes of Health), to the University of Arkansas for Medical Sciences.
Keywords
- Allelic association
- Gene expression
- Insulin resistance
- Insulin secretion
- SNP
- Single nucleotide polymorphism
- Type 2 diabetes
- WNT signalling
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism