D2 Thr92Ala and PPARγ2 Pro12Ala Polymorphisms Interact in the Modulation of Insulin Resistance in Type 2 Diabetic Patients

Abstract

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator‐activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment—IR (HOMAIR) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMAIR index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMAIR index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMAIR values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.

Polymorphism in the SIRT1 gene and parameters of metabolic syndrome in a sample of the adult Brazilian population

“…Regarding the effects of obesity on thyroid hormones, hypothyroidism is generally associated with some weight gain, although Douyon & Schteingart 40 observed hypothyroidism in less than 10% of obese subjects. Evidence indicates the existence of a polymorphism in the gene encoding deiodinase type 2, the enzyme responsible for the conversion of thyroxine 4 into triiodothyronine 3, which is associated with insulin resistance 41,42 .…”

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

“…Deiodinase polymorphisms may affect intracellular thyroid hormone concentration and thereby lipoprotein metabolism. The effect of the Thr92Ala polymorphism on serum lipid parameters was evaluated in various diabetic and non-diabetic cohorts (5, 32,38,58,59,60,61). No associations between HDL, LDL, total cholesterol, or triglyceride levels and genotype status were found in any of the reports studying this relationship.…”

Mechanisms of thyroid hormone action

“…The inactivation of T4 to form reverse T3 (rT3), mediated by type 3 5-deiodinase (D3), is also important in regulating tissues levels of T3, especially in thyroid axis regulation and sensory development (43,44). Some -but not all -human genetic linkage studies of polymorphisms in D2 have shown an association with obesity and diabetes (45,46).…”