title: The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus.
abstract: The single-nucleotide polymorphism A/G in the type 2 deiodinase (D2) gene predicts a threonine (Thr) to alanine (Ala) substitution at codon 92 (D2 Thr92Ala) and is associated with insulin resistance in obese patients. Here, this association was investigated in 183 patients with type 2 diabetes mellitus, using homeostasis model assessment. The median fasting plasma insulin in Ala/Ala individuals was significantly higher than in patients with Ala/Thr or Thr/Thr genotypes (19.6 vs. 12.0 vs. 14.8 mIU/ml, respectively; P = 0.004). Assuming a recessive model, the homeostasis model assessment index was higher in the Ala/Ala group when compared with Ala/Thr-Thr/Thr group (8.50 vs. 4.85, P = 0.003). Although this polymorphism has not been associated with changes in D2 kinetics as measured in HEK-293 cells transiently expressing D2 Thr92Ala, we investigated whether such association could be detected in human tissue samples. Remarkably, in thyroid and skeletal muscle samples from subjects homozygous for the Ala allele, D2 velocity was significantly lower than in subjects with Ala/Thr-Thr/Thr genotypes (P = 0.05 and 0.04, respectively). In conclusion, the A/G polymorphism is associated with greater insulin resistance in type 2 diabetes mellitus patients and with lower D2 velocity in tissue samples. These findings suggest that the D2-generated T(3) in skeletal muscle plays a role in insulin resistance.
authors.affiliation: Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Luis Henrique
authors.initials: LH
authors.lastname: Canani
authors.forename: Clarissa
authors.initials: C
authors.lastname: Capp
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Dora
authors.forename: Erika L Souza
authors.initials: EL
authors.lastname: Meyer
authors.forename: Márcia S
authors.initials: MS
authors.lastname: Wagner
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gross
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Maia
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D020641:Polymorphism, Single Nucleotide; D013912:Threonine; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D000409:Alanine; D007453:Iodide Peroxidase; D013912:Threonine; D000097564:Iodothyronine Deiodinase Type II