Editors' ChoiceMetabolic Disease

Nature Versus Nurture in Newly Diagnosed Type 2 Diabetes

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Science Translational Medicine  05 Jan 2011:
Vol. 3, Issue 64, pp. 64ec2
DOI: 10.1126/scitranslmed.3002072

When Sir Francis Galton initiated the “nature versus nurture” debate, his controversial statements were most readily adopted by the field of psychology. However, the dichotomy is relevant to understanding the development of diseases such as Type 2 diabetes, for which there is an increasing body of evidence implicating genetic variability, or “nature,” in the disease’s etiology as opposed to the role of “nurture,” or environmental insults. The genetic variants most strongly associated with the risk of developing Type 2 diabetes are alleles of the transcription factor 7–like 2 (TCF7L2) gene. Studies to date have investigated diabetes risk alleles of this gene in nondiabetic populations using markers of pancreatic β-cell function and insulin sensitivity (referred to as intermediate phenotypes). In a new study, Bonetti et al. investigate the association of these TCF7L2 gene variants with β-cell function and insulin sensitivity in a population of newly diagnosed Type 2 diabetics. The authors focused on this patient population because the subjects were diabetes-treatment naïve and theoretically endured a limited duration of high blood glucose, two factors that affect the metabolic measures of β-cell function and insulin sensitivity.

The 464 patients assessed were participants of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS). Metabolic measurements were performed, including an oral glucose tolerance test as a measure of β-cell function and a euglycemic insulin clamp to assess insulin sensitivity. The single-nucleotide polymorphisms (SNPs) in TCF7L2 genotyped were rs7901695, rs7903146, rs11196205, and rs12255372. Bonetti et al. observed an association between all of the SNPs, except rs11196205, and lower body mass index. None of the SNPs was associated with β-cell function or insulin sensitivity measurements. In addition, when examining the risk alleles in combination with each other (known as haplotype analysis) two low-frequency TCF7L2 haplotypes were associated with the highest and lowest levels of β-cell function, but there were no associations between these haplotypes and insulin sensitivity. These data all serve to facilitate the identification of populations at risk for the development of Type 2 diabetes; for example, in those individuals with low body mass index the development of Type 2 diabetes may be substantially influenced by genetic variation in TCF7L2 rather than by environmental factors. This information and the examination of allele combinations in the setting of haplotype analyses facilitate the translation of findings in nondiabetic populations to the newly diagnosed population.

This study provides an intriguing investigation of genetic associations observed in one population—nondiabetics—applied to a more metabolically disrupted second population—newly diagnosed Type 2 diabetics—in an attempt to understand disease mechanism. This process may be applied to other diabetic populations as well so as to more intricately define clinical and metabolic phenotypes at the molecular level and further tease apart the relative contributions of nature and nurture to disease.

S. Bonetti et al. Variants and haplotypes of TCF7L2 are associated with β-cell function in patients with newly diagnosed type 2 diabetes: The Verona newly diagnosed Type 2 diabetes study (VNDS) 1. J. Clin. Endocrinol. Metab. 15 December 2010 (10.1210/jc.2010-1677). [Abstract]

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