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.

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Data reporting an association between this change and the risk of hypertension (120,121) or insulin resistance/diabetes are conflicting (58,(122)(123)(124). In a recent large case-controlled study of 1057 diabetics and 516 controls, the frequency of Thr92Ala was higher in the diabetic group.…”

“…Thus the absence of D2 would preclude compensation in overt hypo or hyperthyroidism, resulting in increased susceptibility to fracture in both conditions. From a clinical point of view, in a recent study, patients carrying a missense polymorphism in the human DIO2 gene (Thr92Ala), which is associated with lower D2 expression in several tissues (58), display reduced bone mineral density in association with alterations in markers of bone turnover and remodeling (59).…”

“…Pima Indians (119) ( Table 3). This change has been associated with decreased enzyme velocity in human thyroid and skeletal muscle (58), although it is not certain that the coding mutation per se is the cause of the reduction in D2 action. The reduced activity mentioned above may be due to another abnormality in the gene since studies with the mutated D2 protein have not revealed any abnormal function in vitro.…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…Because it has been documented that the D2 Thr92Ala polymorphism is associated with insulin resistance, (28) we also compared insulin sensitivity (HOMA) in the three genotypes. Deviation from Hardy-Weinberg equilibrium was analyzed using a chi-square test.…”

“…(28)(29)(30) The single-nucleotide polymorphism (SNP) in D2 Thr92Ala has been associated with body mass index (BMI) and insulin resistance in subjects with obesity and type 2 diabetes mellitus, (28,29) although this was not confirmed in the Framingham Offspring Study. (31) In a study by Canani and colleagues, (28) the maximal velocity of D2 was decreased by 3-to 10-fold in thyroid and skeletal muscle of carriers of the Thr92Ala polymorphism. This effect was observed in the absence of differences in D2 mRNA level or in the biochemical protein properties of the 92Ala allele.…”