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

Luis Henrique Canani, Clarissa Capp, José Miguel Dora, Erika L. Souza Meyer, Márcia S. Wagner, John W. Harney, P. Reed Larsen, Jorge L. Gross, Antonio C. Bianco, Ana Luiza Maia

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138 Scopus citations

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 T3 in skeletal muscle plays a role in insulin resistance.

Original languageEnglish (US)
Pages (from-to)3472-3478
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number6
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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