Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus.
OBJECTIVE
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 polymorphism (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).


CONCLUSIONS
This 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.
van Greevenbroek
M M J
MM
Laboratory of Molecular Metabolism and Endocrinology, Cardiovascular Research Institute Maastricht and Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands. m.vangreevenbroek@intmed.unimaas.nl
Vermeulen
V M M-J
VM
Feskens
E J M
EJ
Evelo
C T
CT
Kruijshoop
M
M
Hoebee
B
B
van der Kallen
C J H
CJ
de Bruin
T W A
TW
D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000097:blood / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D014280:Triglycerides / Q000032:analysis / Q000097:blood*
D001786:Blood Glucose; D002352:Carrier Proteins; C486715:TXNIP protein, human; D014280:Triglycerides