Phenotypic and genetic characteristics of patients with type 2 diabetes with different responses to metformin therapy in Novosibirsk region

Aim: The purpose of this study was to examine the phenotypic and genetic characteristics of patients with type 2 diabetes mellitus (T2DM) with different responses to treatment with metformin (MF) in the Novosibirsk region. 

Materials and methods: We examined 460 patients with T2DM in the Novosibirsk region. Patients were divided into groups according to their HbA1c level: patients who achieved the target HbA1c level during MF therapy (n = 209) and those who did not reach the target HbA1c level (n=251). Genotyping of ATM (rs11212617) was performed using polymerase chain reaction by TaqMan. 

Results: Patients who achieved the target HbA1c level during MF treatment (good response) were older (61. 1±9. 1 years vs. 57. 4±8. 4 years, p=0. 001), had later onset of diabetes (54. 6 ± 10. 1 years vs. 49. 2±8. 5 years, p = 0. 0001) and shorter duration of diabetes (6. 5±5. 9 years vs. 8. 2±6. 1 years, p=0. 03) compared with those who did not achieve the target HbA1c level. There was no statistically significant association between ATM rs11212617 and achieving the target HbA1c level among all patients [odds ratio (OR)=0. 94, 95% confidence interval = (0. 73–1. 23), p=0. 67] or those with MF monotherapy [OR=0. 90, (0. 65–1. 25), p=0. 54] or combination therapy [OR=1. 02, (0. 72–1. 43), p=0. 92]. There was an effect of age on response to MF therapy in all three groups (all patients: p=0. 001, MF monotherapy group: p=0. 04, combination therapy group: p=0. 0009). In the MF monotherapy group, low dose MF was associated with a good response (p=0. 03), and in the combination therapy group, males were more likely to have a good response (p=0. 003). Patients with genotype C/C or A/C for ATM (rs11212617) compared with those with genotype A/A were more likely to have high levels of triglycerides [2. 33 (1. 52–4. 2) mmol/l, 2. 09 (1. 35–3. 0) mmol/l and 1. 99 (1. 49–3. 21) mmol/l, respectively, p=0. 001], coronary heart disease (CHD) (13. 4%, 13. 4% and 9. 6%, respectively, p=0. 009) and myocardial infarction (7. 8%, 3. 2% and 4. 0%, respectively, p=0. 001). 

Conclusion: Patients with T2DM who had a good response to MF therapy were older, more likely to be male and had a later onset of T2DM. Genotype C/C for ATM rs11212617 was associated with high triglycerides, CHD and myocardial infarction. ATM rs11212617 was not associated with response to MF therapy in the Novosibirsk region. 

1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi: 10.2337/dc14-2441

2. Дедов И.И., Шестакова М.В., Галстян Г.Р., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Под редакцией И.И. Дедова, М.В. Шестаковой (7-й выпуск) // Сахарный диабет. – 2015. – Т. 18. – №1S – C. 1-112. [Dedov II, Shestakova MV, Galstyan GR, et al. Standards of specialized diabetes care. Edited by Dedov I.I., Shestakova M.V. (7th edition). Diabetes mellitus. 2015;18(1S):1-112. (in Russ)] doi: 10.14341/DM20151S1-112

3. Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550-554. doi: 10.1056/NEJM199508313330903

4. Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270. doi: 10.1042/CS20110386

5. Johnson AB, Webster JM, Sum CF, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism. 1993;42(9):1217-1222. doi: 10.1016/0026-0495(93)90284-u

6. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174. doi: 10.1172/JCI13505

7. Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A. 2010;107(50):21830-21835. doi: 10.1073/pnas.0912793107

8. Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11(6):554-565. doi: 10.1016/j.cmet.2010.04.001

9. Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355-2369. doi: 10.1172/JCI40671

10. Steinberg GR, Kemp BE. AMPK in Health and Disease. Physiol Rev. 2009;89(3):1025-1078. doi: 10.1152/physrev.00011.2008

11. GoDarts, Group UDPS, Wellcome Trust Case Control C, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43(2):117-120. doi: 10.1038/ng.735

12. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81-98. doi: 10.2165/11534750-000000000-00000

13. Ruan H, Lodish HF. Regulation of insulin sensitivity by adipose tissue-derived hormones and inflammatory cytokines. Curr Opin Lipidol. 2004;15(3):297-302.

14. Hara T, Fujiwara H, Shoji T, et al. Decreased plasma adiponectin levels in young obese males. J Atheroscler Thromb. 2003;10(4):234-238.

15. De Jager J, Kooy A, Lehert P, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2005;257(1):100-109. doi: 10.1111/j.1365-2796.2004.01420.x

16. Zhou Y, Guo Y, Ye W, et al. RS11212617 is associated with metformin treatment response in type 2 diabetes in Shanghai local Chinese population. Int J Clin Pract. 2014;68(12):1462-1466. doi: 10.1111/ijcp.12534

17. van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012;55(7):1971-1977. doi: 10.1007/s00125-012-2537-x

18. Florez JC, Jablonski KA, Taylor A, et al. The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program. Diabetes Care. 2012;35(9):1864-1867. doi: 10.2337/dc11-2301

19. Vilvanathan S, Gurusamy U, Mukta V, et al. Allele and genotype frequency of a genetic variant in ataxia telangiectasia mutated gene affecting glycemic response to metformin in South Indian population. Indian J Endocrinol Metab. 2014;18(6):850-854. doi: 10.4103/2230-8210.119944

20. Schiekofer S, Bobak I, Kleber ME, et al. Association between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men. Diab Vasc Dis Res. 2014;11(1):60-63. doi: 10.1177/1479164113514232