© 2007 The Authors. 498 Journal compilation © 2007 Diabetes UK. Diabetic Medicine , 24 , 498–504 DIABETIC Medicine DOI: 10.1111/j.1464-5491.2007.02109.x Correspondence to : Marleen M. J. van Greevenbroek PhD, Laboratory for Molecular Metabolism and Endocrinology, Internal Medicine (UNS 50/Box 14), Maast University, PO Box 616, 6200 MD Maastricht, the Netherlands. E-mail: m.vangreevenbroek@intmed.unimaas.nl Current address of T.W.A.d.B.: GlaxoSmithKline, Translational Medicine and Genetics, Research Triangle Park, NC, USA. Abstract Aims Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose- responsive gene in pancreatic B-cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21-1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM. Methods The frequency distribution of a 3 ′ UTR single nucleotide poly- morphism (SNP) in TXNIP was investigated in subjects with normal glucose tolerance (NGT; n =379), impaired glucose tolerance (IGT; n =228) and Type 2 DM (n =230). Metabolic data were used to determine the effect of this SNP on parameters associated with lipid and glucose metabolism. Results The frequency of the TXNIP variation did not differ between groups, but within the group of diabetic subjects, carriers of the TXNIP-T variant had 1.6-fold higher triglyceride concentrations ( P =0.015; n =136) and a 5.5-mmHg higher diastolic blood pressure ( P =0.02; n =212) than homozygous carriers of the common C-allele, whereas in non-diabetic subjects fasting glucose was 0.26 mmol/l lower ( P =0.002; n =478) in carriers of the T-allele. Moreover, a significant interaction between plasma glucose concentrations and TXNIP polymorphism on plasma triglycerides was observed ( P =0.012; n =544). ConclusionThis is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia. Diabet. Med. 24, 498–504 (2007) Keywords diastolic blood pressure, genetic predisposition, thioredoxin interacting protein (TXNIP), triglyceride, Type 2 diabetes mellitus. Abbreviations apo, apolipoprotein; BMI, body mass index; DBP, diastolic blood pressure; FCHL, familial combined hyperlipidaemia; GCNF, germ cell nuclear factor; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; PCR, polymerase chain reaction; SBP, systolic blood pressure; SNP, single nucleotide polymorphism; T2DM, Type 2 diabetes mellitus; TRX, thioredoxin; TXNIP, thioredoxin interacting protein; USF-1, upstream stimulatory factor 1; VEGF, vascular endothelial growth factor Blackwell Publishing Ltd Oxford, UK DME Diabetic Medicine 0742-3071 Blackwell Publishing, 2007 24 Original Article Original article Thioredoxin interacting protein in diabetes M. M. J. van Greevenbroek et al. Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus M. M. J. van Greevenbroek, V. M. M-J. Vermeulen, E. J. M. Feskens *† , C. T. Evelo ‡ , M. Kruijshoop, B. Hoebee § , C. J. H. van der Kallen and T. W. A. de Bruin Laboratory of Molecular Metabolism and Endocrinology, Cardiovascular Research Institute Maastricht (Carim) and Department of Internal Medicine, Maastricht University, Maastricht, *Centre for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, †Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, ‡BiGCat Bioinformatics, University of Maastricht and Technical University Eindhoven, Maastricht and §Laboratory of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, Bilthoven, the Netherlands Accepted 9 October 2006