Pharmacogenetic aspects of treatment with oral antidiabetics

Česká verzia

Authors: I. Tkáč
Authors place of work: IV. interná klinika Lekárskej fakulty UPJŠ a UN L. Pasteura Košice, Slovenská republika, prednosta prof. MUDr. Ivan Tkáč, PhD.
Published in the journal: Vnitř Lék 2012; 58(7 a 8): 97-100
Category: 80th Birthday MUDr. Miroslav Mydlík, DrSc.

Summary

Patients with type 2 diabetes present with high variability of therapeutic responses to treatment with oral antidiabetics. This variability stems from psychological and social factors, such as treatment adherence, access to health care and prescribing habits of the physicians, as well as from biological factors. Biological factors are non-genetic and genetic. Non-genetic factors include disease duration (reflects residual function of β cells), body weight, kidney function, liver function etc. Among genetic factors, genes associated with pharmacokinetics as well as pharmacodynamics of oral antidiabetic agents have been studied. Cytochrom P450 2C9 coded by the CYP2C9 gene is the most important of the enzymes affecting pharmacokinetics of sulfonylurea. Presence of non-synonymic variants of this gene leads to slower catabolism of sulfonylurea and thus its increased effect. Of the genes associated with the effect of sulfonylurea, pharmacogenetics are affected by the KCNJ11 and ABCC8 gene variants that code the ATP-dependent potassium channel proteins (K_ATP). Pharmacogenomic studies in type 2 diabetes mellitus patients showed an increased effect of sulfonylurea derivatives in bearers of high risk polymorphic alleles of these genes. Other genes with proven association with the sulfonylurea effect include TCF7L2 gene, the variants of which are the most closely associated with type 2 diabetes mellitus. The effect of sulfonylurea was significantly lower in carriers of the risk allele. With respect to treatment with metformin, variants of the genes associated with pharmacokinetics of metformin are the best described. These specifically include genes coding organic cation transporters OCT1, OCT2 and MATE1, which facilitate transport of metformin into liver cells and renal tubules as well as transport of metformin from the kidneys into urine. Variants of these genes have been associated with reduced as well as increased response to metformin, depending on localization of the transporter and the effect of polymorphism on its function. Only one genome-wide association study has been performed so far and found an association between a polymorphism near the ATM gene with the effect of metformin. However, it is not clear in what way the product of this gene, involved in the process of DNA reparation, affects the effect of metformin. The presence of variants of these genes led to a different effect of various antidiabetics expressed as reduced HbA1 in a range of 0.3–0.6% depending on patient genotype (appears to be clinically significant). Therefore, future use of a panel of polymorphisms of the discussed genes for personalization of type 2 diabetes mellitus treatment cannot be ruled out.

Key words:
pharmacogenetics – type 2 diabetes mellitus – sulfonylurea derivatives – metformin – personalized medicine

Zdroje

1. Zhou K, Donnelly YL, Burch L et al. Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: A Go-DARTS Study. Clin Pharmacol Ther 2010; 87: 52–56.

2. Hammings KSC, Soliman D, Matemisz LC et al. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K+ channel. Diabetes 2009; 58: 2419–2424.

3. Pearson ER, Flechtner I, Njolstad PR et al. for the Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir 6.2 mutations. N Engl J Med 2006: 355: 467–477.

4. Feng I, Mao G, Ren X et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 2008; 31: 1939–1944.

5. Javorsky M, Klimcakova L, Schroner Z et al. KCNJ11 gene E23K variant and therapeutic response to sulfonylureas. Eur J Inter Med 2012; 23: 245–249.

6. He Y, Zhang R, Shao X et al. Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients. Acta Farmacol Sin 2008; 29: 983–989.

7. Pearson ER, Donelly LA, Kimber C et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas. A GoDARTs Study. Diabetes 2007; 56: 2178–2182.

8. Schroner Z, Javorsky M, Tkacova R et al. Effect of sulphonylurea treatment on glycaemic control is related to TCF7L2 genotype in patients with type 2 diabetes. Diabetes Obes Metab 2011; 13: 89–91.

9. Holstein A, Hahn M, Körner A et al. TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes. BMC Med Genet 2011; 12: 30.

10. Gaulton KJ, Nammo T, Pasquali L et al. A map of open chromatin in human pancreatic islets. Nat Genet 2010; 42: 255–259.

11. Becker ML, Visser LE, van Schaik RHN et al. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenetics J 2009; 9: 242–247.

12. Zhou K, Donnelli LA, Kimber CH et al. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: A GoDARTS Study. Diabetes 2009; 58: 1434–1439.

13. Becker ML, Visser LE, van Schaik RHN et al. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: A preliminary study. Diabetes 2009; 58: 745–749.

14. Jablonski KA, Mc Ather JB, De Bakker PIW et al. For the Diabetes Prevention Program Research Group. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the Diabetes Prevention Program. Diabetes 2010; 59: 2672–2681.

15. Kang ES, Park SY, Kim HJ et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther 2005; 78: 202–208.

16. Kang ES, Park SY, Kim HJ et al. The influence of adiponectin gene polymorphism on the rosiglitazone response in patients with type 2 diabetes. Diabetes Care 2005; 28: 1139–1144.

17. Zhou K, Bellenguez C, Spencer CC et al. The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group & The Welcome Trust Case Control Consortium 2. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 2011; 43: 117–120.

18. Huang C, Florez JC Pharmacogenetics in type 2 diabetes: potential implications for clinical practice. Genome Med 2011; 3: 76.