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TCF7L2 polymorphisms modulate proinsulin levels and ß-cell function in a British Europid population

¹ MRC Epidemiology Unit, Cambridge, UK
² Division of Medicine, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden
³ University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
⁴ Metabolic Disease Group, The Wellcome Trust Sanger Institute, Hinxton, UK
⁵ University of Cambridge, Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK

Correspondence: ruth.loos{at}mrc-epid.cam.ac.uk

Objective and methods:Rapidly accumulating evidence shows that common TCF7L2 polymorphisms confer risk of type 2 diabetes (T2DM) through unknown mechanisms. We examined the association between four TCF7L2 single nucleotide polymorphisms (SNPs), including rs7903146, and measures of insulin sensitivity and insulin secretion in 1697 Europid men and women of the population-based MRC-Ely study.

Results:The T-(minor) allele of rs7903146 was strongly and positively associated with fasting proinsulin (p=4.55x10^–9) and 32,33 split proinsulin (p=1.72x10^–4) relative to total insulin levels; i.e. differences between T/T- and C/C-homozygotes amounted to 21.9% and 18.4% respectively. Notably the insulin-to-glucose ratio (IGR) at 30min OGTT, a frequently used surrogate of first-phase insulin secretion, was not associated with the TCF7L2 SNP (p>0.7). However, the insulin response (IGR) at 60min OGTT, was significantly lower in T-allele carriers (p=3.5x10^–3). The T-allele was also associated with higher HbA1c concentrations (p=1.2x10^–2) and reduced ß-cell function, assessed by HOMA-B (p=2.8x10^–2). Similar results were obtained for the other TCF7L2 SNPs. Of note, both major genes involved in proinsulin processing (PC1, PC2) contain TCF-binding sites in their promoters.

Conclusions:Our findings suggest that the TCF7L2 risk allele may predispose to T2DM by impairing ß-cell proinsulin processing. The risk-allele increases proinsulin levels and diminishes the 60min, but not 30min insulin response during OGTT. The strong association between the TCF7L2 risk-allele and fasting proinsulin, but not insulin levels is notable as in this unselected and largely normoglycaemic population external influences on ß-cell stress are unlikely to be major factors influencing the efficiency of proinsulin processing.

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