Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Pharmacology

Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients

Abstract

Aim:

The aim of this study was to investigate the association of KCNJ11 E23K and ABCC8 exon16–3T/C with the therapeutic effect of repaglinide in patients with type 2 diabetes.

Methods:

A total of 100 Chinese patients with newly diagnosed type 2 diabetes were treated with repaglinide for 24 weeks. Arginine stimulation tests were performed to evaluate beta cell function. Gene variations were detected with PCR-restriction fragment length polymorphism. Responders were defined by a greater than 25% decrease in fasting plasma glucose or a greater than 20% decrease in hemoglobin A1c (HbA1c) values (or both) after the 24 week repaglinide treatment.

Results:

Both baseline HbA1c and the decrease of HbA1c were significantly higher in patients with E/K and K/K genotypes of the KCNJ11 E23K variant when compared with E/E homozygotes (P=0.0103 and 0.0221, respectively). The decrease in 2 h postprandial plasma glucose (2hPG) was significantly greater in E/K heterozygotes than E/E homozygotes (P =0.0367). There was a significant difference in the response rate to repaglinide treatment between the E and K alleles (68% vs 82%, P =0.0324). The changes in fasting insulin and the homeostasis model assessment of insulin resistance were significantly greater in patients with ABCC8 exon16–3 C/C versus the T/C and T/T genotypes (P =0.0372 and 0.0274, respectively).

Conclusion:

The KCNJ11 E23K variant was associated with the therapeutic effect of repaglinide. In addition, The C/C homozygotes of the ABCC8 exon16–3T/C variant responded better to repaglinide in insulin sensitivity than the T/C and T/T genotypes.

References

  1. 1

    Hatorp V . Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2002; 41: 471–83.

    CAS  Article  Google Scholar 

  2. 2

    Sesti G, Laratta E, Cardellini M, Andreozzi F, Del Guerra S, Irace C, et al. The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5′-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91: 2334–9.

    CAS  Article  Google Scholar 

  3. 3

    Grell W, Hurnaus R, Griss G, Sauter R, Rupprecht E, Mark M, et al. Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998; 41: 5219–46.

    Article  Google Scholar 

  4. 4

    Rizzo MR, Barbieri M, Grella R, Passariello N, Barone M, Paolisso G . Repaglinide is more efficient than glimepiride on insulin secretion and post–prandial glucose excursions in patients with type 2 diabetes. A short term study. Diabetes Metab 2004; 30: 81–9.

    CAS  Article  Google Scholar 

  5. 5

    Owens DR, Luzio SD, Ismail I, Bayer T . Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. Diabetes Care 2000; 23: 518–23.

    CAS  Article  Google Scholar 

  6. 6

    Gromada J, Dissing S, Kofod H, Frokjaer-Jensen J . Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells. Diabetologia 1995; 38: 1025–32.

    CAS  Article  Google Scholar 

  7. 7

    Hansen AM, Hansen JB, Carr RD, Ashcroft FM, Wahl P . Kir6.2-dependent high-affinity repaglinide binding to beta–cell K(ATP) channels. Br J Pharmacol 2005; 144: 551–7.

    CAS  Article  Google Scholar 

  8. 8

    Dabrowski M, Wahl P, Holmes WE, Ashcroft FM . Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channels. Diabetologia 2001; 44: 747–56.

    CAS  Article  Google Scholar 

  9. 9

    Seino S . ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol 1999; 61: 337–62.

    CAS  Article  Google Scholar 

  10. 10

    Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, et al. Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes 2006; 55: 2379–86.

    CAS  Article  Google Scholar 

  11. 11

    Laukkanen O, Pihlajamaki J, Lindstrom J, Eriksson J, Valle T, Hamalainen H, et al. Polymorphisms of the SURl (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study. J Clin Endocrinol Metab 2004; 89: 6286–90.

    CAS  Article  Google Scholar 

  12. 12

    Balkau B, Charles MA . Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999; 16: 442–3.

    CAS  Article  Google Scholar 

  13. 13

    Larsson H, Ahren B . Glucose-dependent arginine stimulation test for characterization of islet function: studies on reproducibility and priming effect of arginine. Diabetologia 1998; 41: 772–7.

    CAS  Article  Google Scholar 

  14. 14

    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–9.

    CAS  Article  Google Scholar 

  15. 15

    Marbury T, Huang WC, Strange P, Lebovitz H . Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract 1999; 43: 155–66.

    CAS  Article  Google Scholar 

  16. 16

    Jovanovic L, Dailey G 3rd, Huang WC, Strange P, Goldstein BJ . Repaglinide in type 2 diabetes: a 24-week, fixed-dose efficacy and safety study. J Clin Pharmacol 2000; 40: 49–57.

    CAS  Article  Google Scholar 

  17. 17

    Gerstein HC, Garon J, Joyce C, Rolfe A, Walter CM . Pre-prandial vspost-prandial capillary glucose measurements as targets for repaglinide dose titration in people with diet-treated or metformin-treated Type 2 diabetes: a randomized controlled clinical trial. Diabet Med 2004; 21: 1200–3.

    CAS  Article  Google Scholar 

  18. 18

    Van Gaal LF, Van Acker KL, De Leeuw IH . Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes. Diabetes Res Clin Pract 2001; 53: 141–8.

    CAS  Article  Google Scholar 

  19. 19

    Moses RG, Gomis R, Frandsen KB, Schlienger JL, Dedov I . Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care 2001; 24: 11–5.

    CAS  Article  Google Scholar 

  20. 20

    Li J, Tian H, Li Q, Wang N, Wu T, Liu Y, et al. Improvement of insulin sensitivity and beta-cell function by nateglinide and repaglinide in type 2 diabetic patients - a randomized controlled double-blind and double-dummy multicentre clinical trial. Diabetes Obes Metab 2007; 9: 558–65.

    CAS  Article  Google Scholar 

  21. 21

    Liu Z, Zhang YW, Feng QP, Li YF, Wu GD, Zuo J, et al. Association analysis of 30 type 2 diabetes candidate genes in Chinese Han population. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2006; 28: 124–8.

    PubMed  Google Scholar 

  22. 22

    Ji L, Han X, Wang H . Sulfonylurea receptor gene polymorphism is associated with non-insulin dependent diabetes mellitus in Chinese population. Zhonghua Yi Xue Za Zhi 1998; 78: 774–5 (in Chinese).

    CAS  PubMed  Google Scholar 

  23. 23

    Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003; 52: 568–72.

    CAS  Article  Google Scholar 

  24. 24

    Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 2003; 52: 573–7.

    CAS  Article  Google Scholar 

  25. 25

    Riedel MJ, Steckley DC, Light PE . Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. Hum Genet 2005; 116: 133–45.

    CAS  Article  Google Scholar 

  26. 26

    Schwanstecher C, Meyer U, Schwanstecher M . K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 2002; 51: 875–9.

    CAS  Article  Google Scholar 

  27. 27

    Zychma MJ, Gumprecht J, Strojek K, Grzeszczak W, Moczulski D, Trautsolt W, et al. Sulfonylurea receptor gene 16–3 polymorphism-association with sulfonylurea or insulin treatment in type 2 diabetic subjects. Med Sci Monit 2002; 8: 512–5.

    Google Scholar 

  28. 28

    Hart LM, Dekker JM, van Haeften TW, Ruige JB, Stehouwer CD, Erkelens DW, et al. Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus. Diabetologia 2000; 43: 515–9.

    CAS  Article  Google Scholar 

  29. 29

    Boden G, Shulman GI . Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 2002; 32 Suppl 3: 14–23.

    CAS  Article  Google Scholar 

  30. 30

    Rizzo MR, Barbieri M, Grella R, Passariello N, Paolisso G . Repaglinide has more beneficial effect on cardiovascular risk factors than glimepiride: data from meal-test study. Diabetes Metab 2005; 31 (Pt 1): 255–60.

    CAS  Article  Google Scholar 

  31. 31

    Elbein SC, Sun J, Scroggin E, Teng, K, Hasstedt SJ . Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes. Diabetes Care 2001; 24: 472–8.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Wei-ping Jia.

Additional information

This work was funded by the Key Project from Science and Technology Commission of Shanghai Municipality, China (No 01DZ002 [1]), the National 973 Program (No 2006CB503901), and by the Program for Shanghai Outstanding Medical Academic Leader (No LJ06010).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

He, Yy., Zhang, R., Shao, Xy. et al. Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients. Acta Pharmacol Sin 29, 983–989 (2008). https://doi.org/10.1111/j.1745-7254.2008.00840.x

Download citation

Keywords

  • repaglinide
  • polymorphism
  • pharmacogenomics
  • type 2 diabetes

Further reading

Search

Quick links