Clinical effect of thiazolidinediones in subjects with disorders of carbohydrate metabolism in case of polymorphism rs1801282

BACKGROUND: The polymorphism rs1801282 (Pro12Ala) may be one of the reasons for the heterogeneous response of patients with carbohydrate metabolism disorders to thiazolidinedione therapy. Studies of this polymorphism in patients with metabolic syndrome (MS) will help identify a group of patients in whom the use of thiazolidinedione is advisable.

AIMS: To assess the clinical effect of thiazolidinediones in patients with metabolic syndrome, depending on the presence of polymorphism rs1801282.

MATERIALS AND METHODS: All patients with newly diagnosed MS with impaired carbohydrate metabolism were included in the open cohort study. All patients were recommended a diet, expansion of physical activity and pioglitazone at a dose of 30 mg per day. After the appointment of the therapy, the patients come to the center back at 12 weeks.

The main outcome in the study assessed in patients with impaired glucose tolerance (IGT) was fasting glycemia and 2 hours after glucose tolerance test, in patients with type 2 diabetes — HbA_1c.

RESULTS: 109 patients were included in the study. Of these, 14 were carriers of rs1801282, the other 95 had a typical PPARγ genotype. After the appointment of therapy in the groups of IGT and type 2 diabetes, improvement of glycemic control was observed. The degree of decrease in fasting plasma glucose and after glucose tolerance test was more pronounced with IGT in patients with polymorphism rs1801282 compared with the rest (plasma fasting plasma glucose level was -0.7 [-0.9, -0.7] vs. -0, 4 [-0.5, -0.3] mmol/L, p=0.001; plasma glucose level 2 hours after glucose tolerance test was -1.1 [-1.8, -0.3] vs. -0.5 [-0.7, -0.1] mmol/L, p=0.031). In patients with type 2 diabetes, no data were obtained for the statistically significant effect of rs1801282 polymorphism on the results of pioglitazone, but there was a tendency for a greater decrease in fasting plasma glucose in the case of carrying the polymorphic gene (-1.9 [-2.2, -1.8] against -1,5 [-1,7, -1,2] mmol/l, p=0,073).

CONCLUSIONS: The study shows the effect of polymorphism rs1801282 on the results of pioglitazone in patients with MS, both in IGT and in type 2 diabetes. Carrying polymorphism leads to a significant decrease in fasting glycemia and after glucose tolerance test in patients with IGT. The tendency to improve the parameters of carbohydrate metabolism (fasting glycemia, HbA_1c) was noted in a subgroup of patients with type 2 diabetes.

metabolic syndrome, diabetes mellitus type 2, glucose intolerance, thiazolidinediones, polymorphism rs1801282 (Pro12Ala)

1. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005;123(6):993-999. DOI:10.1016/j.cell.2005.11.026.

2. Umpierrez G, Dagogo-Jack S. Role of thiazolidinediones in the management of type 2 diabetes: focus on ethnic minority populations. Ethn Dis. 2006;16(1):51-57.

3. DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364(12):1104-1115. DOI:10.1056/nejmoa1010949.

4. Galbete C, Toledo E, Martínez-González MA, et al. Pro12Ala variant of the PPARG2 gene increases body mass index: An updated meta-analysis encompassing 49,092 subjects. Obesity (Silver Spring). 2013;21(7):1486-1495. DOI:10.1002/oby.2015.

5. Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-1645. DOI:10.1161/CIRCULATIONAHA.109.192644.

6. Blüher M, Lübben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care. 2003;26(3):825-831. DOI:10.2337/diacare.26.3.825.

7. Hsieh MC, Lin KD, Tien KJ, et al. Common polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and peroxisome proliferator-activated receptor-gamma coactivator-1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. Metabolism. 2010;59(8):1139-1144. DOI:10.1016/j.metabol.2009.10.030.

8. Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther. 2005;78(2):202-208. DOI:10.1016/j.clpt.2005.04.013.

9. Pei Q, Huang Q, Yang G, et al. PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients’ response to pioglitazone in China. Acta Pharmacol Sin. 2013;34(2):255-261. DOI:10.1038/aps.2012.144.

10. Priya SS, Sankaran R, Ramalingam S, et al Genotype Phenotype Correlation of Genetic Polymorphism of PPAR Gamma Gene and Therapeutic Response to Pioglitazone in Type 2 Diabetes Mellitus- A Pilot Study. J Clin Diagn Res. 2016;10(2):FC11-FC14. DOI:10.7860/jcdr/2016/16494.7331.

11. Ramírez-Salazar M, Pérez-Luque E, Fajardo-Araujo M, et al. Effect of the Pro12Ala polymorphism of the PPAR gamma 2 gene on response to pioglitazone treatment in menopausal women. Menopause. 2008;15(6):1151-1156. DOI:10.1097/gme.0b013e31816d5b2d.

12. Namvaran F, Azarpira N, Rahimi-Moghaddam P, Dabbaghmanesh MH. Polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala in the Iranian population: relation with insulin resistance and response to treatment with pioglitazone in type 2 diabetes. Eur J Pharmacol. 2011;671(1-3):1-6. DOI:10.1016/j.ejphar.2011.09.158.

13. Mtiraoui N, Turki A, Nemr R, et al. Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL, PPARγ, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs. Diabetes Metab. 2012;38(5):444-449. DOI:10.1016/j.diabet.2012.05.002.

14. Wang X, Liu J, Ouyang Y, Fang M, et al. The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population. PLoS One. 2013;8(8):e71985. DOI:10.1371/journal.pone.0071985.