Main Article Content
Type 2 diabetes mellitus (T2DM) is a slowly-progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. The goals of the treatment strategies for T2DM are to minimize long-term micro- and macrovascular complications by achieving an optimized glycemic control. Metformin is a first-line therapy for type 2 diabetes mellitus, and is one of the most commonly prescribed drugs worldwide. However, the glycemic response to metformin is quite variable. Some patients still have a high glucose level while receiving metformin as well as have serious side effects. Inter-individual variability in response to metformin is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1-3, SLC47A1 and SLC47A2) actively involved in glycemic management of metformin.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our edition uses the copyright terms of Creative Commons for open access journals.
Authors, who are published in this journal, agree with the following terms:
- The authors retain rights for authorship of their article and grant to the edition the right of first publication of the article on a Creative Commons Attribution 4.0 International License, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
- Directing the article for the publication to the editorial board (publisher), the author agrees with transmitting of rights for the protection and using the article, including parts of the article, which are protected by the copyrights, such as the author’s photo, pictures, charts, tables, etc., including the reproduction in the media and the Internet; for distributing; for the translation of the manuscript in all languages; for export and import of the publications copies of the writers’ article to spread, bringing to the general information.
- The rights mentioned above authors transfer to the edition (publisher) for the unlimited period of validity and on the territory of all countries of the world.
- The authors guarantee that they have exclusive rights for using of the article, which they have sent to the edition (publisher). The edition (the publisher) is not responsible for the violation of given guarantees by the authors to the third parties.
- The authors have the right to conclude separate supplement agreements that relate to non-exclusive distribution of their article in the form in which it had been published in the journal (for example, to upload the work to the online storage of the journal or publish it as part of a monograph), provided that the reference to the first publication of the work in this journal is included.
- The policy of the journal permits and encourages the publication of the article in the Internet (in institutional repository or on a personal website) by the authors, because it contributes to productive scientific discussion and a positive effect on efficiency and dynamics of the citation of the article.
Pan’kiv VI. Possibilities of medicamental prevention of type 2 diabetes mellitus. International Journal of Endocrinology. 2013;5:107–112. (Ukrainian)
Кharroubi АТ. Diabetes mellitus: The epidemic of the century. World journal of diabetes. 2015;6:850.
Pan’kiv VI. Diabetes mellitus: definition, epidemiology, risk factors. International Journal of Endocrinology. 2013;7:95–104. (Ukrainian)
Маn’kovsky BN. Therapy of type 2 diabetes mellitus: unrealized necessities and new possibilities. Diabet, ozhyrinnia, metabolichny syndrome. 2014;4:37-41. (Russian)
Holman RR, Paul SK, Bethel MA, Matthews DR.10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine. 2008;15:1577–1589.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). The Lancet. 1998;352:854–865.
UK Prospective Diabetes Study Group. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diabetes Care. 1998;21:87–92.
Маn’kovsky BN, Коndratskaya IN, Panchenko AV. Hypolipidemic therapy for patients with type 2 diabetes mellitus. Diabet, ozhyrinnia, metabolichny syndrome. 2014;6:59-63. (Russian)
Nakaz MOZ Ukrainy vid 21.12.2012 № 1118 «About a statement and introduction of medical and technological documents from standardization of medicare at type 2 diabetes mellitus 2». – URL: http://www.moz.gov.ua/ua/portal/dn_20121221_1118.html (Ukrainian)
Compatible clinical protocol of primary and secondary (specialized) medicare at type 2 diabetes mellitus, ratified by Ministry of Health of Ukraine 21.12.2012 №1118. URL: http://www.moz.gov.ua/docfiles/dod1118_2_2012.pdf (Ukrainian)
Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35:731–737.
Standards of Medical Care in Diabetes 2016. Diabetes Care. 2016;39(Suppl.1):1-112. URL: http://diabetesjournals.org/ content/39/Supplement_1.toc. DOI: 10.2337/diaclin.34.1.00
Stratton IM, Adler AI, Neil H.A. et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412.
Коvalenko NV. Kompendium – medicinal preparations. Kyiv: Morion, 2015. – URL: http://compendium.com.ua/info/169554/gljukofazh. (Russian)
Singh S, Usman K., Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes. 2016;7:302–315.
Gloyn AL, McCarthy MI. Genetics in Diabetes: Type 2 Diabetes and Related Traits. 2014;192 р. (Karger Medical and Scientific Publishers).
DeGorter MK, Xia CQ, Yang JJ. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2012;52:249–273.
Коnonenko IV, Маyorov АY, Коksharova EO. Pharmacogenetics of hypoglycemic preparations. Diabetes mellitus. 2015;18:28–34. (Russian)
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348 Pt 3: 607-614 [PMID: 10839993]
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-1174 [PMID: 11602624 DOI: 10.1172/JCI13505]
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122: 253-270 [PMID: 22117616 DOI: 10.1042/CS20110386]
Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci USA 2005; 102: 17923-17928 [PMID: 16330770 DOI: 10.1073/pnas.0506483102]
Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, Ogawa O, Inui K. Identification and functional charact¬erization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 2006; 17: 2127-2135 [PMID: 16807400 DOI: 10.1681/ASN.2006030205]
Saxena M, Srivastava N, Banerjee M. Genetic association of adiponectin gene polymorphisms (+45T/G and +10211T/G) with type 2 diabetes in North Indians. Diabetes Metab Syndr 2012; 6: 65-69 [PMID: 23153972 DOI: 10.1016/j.dsx.2012.08.008]
Gautam S, Pirabu L, Agrawal CG, Banerjee M. CD36 gene variants and their association with type 2 diabetes in an Indian population. Diabetes Technol Ther 2013; 15: 680-687 [PMID: 23844572 DOI: 10.1089/dia.2012.0326]
Saxena M, Srivastava N, Banerjee M. Association of IL-6, TNF-б and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Biol Rep 2013; 40: 6271-6279 [PMID: 24057184 DOI: 10.1007/s11033-013-2739-4]
Vats P, Chandra H, Banerjee M. Glutathione S-transferase and catalase gene polymorphism with type 2 diabetes mellitus. Dieses Mol Med 2013; 1: 46-53 [DOI: 10.5455/dmm.20131027101207]
Vats P, Sagar N, Singh TP, Banerjee M. Association of Superoxide dismutases (SOD1 and SOD2) and Glutathione peroxidase 1 (GPx1) gene polymorphisms with type 2 diabetes mellitus. Free Radic Res 2015; 49: 17-24 [PMID: 25283363 DOI: 10.3109/10715762.2014.971782]
Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Mol Diagn Ther 2012; 16: 285-302 [PMID: 23018631]
Garduсo-Diaz SD, Khokhar S. Prevalence, risk factors and complications associated with type 2 diabetes in migrant South Asians. Diabetes Metab. Res. Rev. 2012;28(1):6-24.
Nachman, Michael W. (2001). Single nucleotide polymorphisms and recombination rate in humans. Trends in genetics 17 (9):481–485.
Pan’kiv VI. Individual going to treatment of type 2 diabetes mellitus: when, to whom and what alternative variants, except metformin. International Journal of Endocrinology. 2013;8:36-9. (Ukrainian)
Jacobs C, Pearce B, Du Plessis M, Hoosain N, Benjeddou M. Genetic polymorphisms and haplotypes of the organic cation transporter 1 gene (SLC22A1) in the Xhosa population of South Africa. Genet Mol Biol 2014; 37: 350-359 [PMID: 25071399 DOI: 10.1590/S1415-47572014005000002]
Umamaheswaran G, Praveen RG, Damodaran SE, Das AK, Adithan C. Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients. Clin Exp Med 2015; 15: 511-517 [PMID: 25492374 DOI: 10.1007/s10238-014-0322-5]
Xiao D, Guo Y, Li X, Yin JY, Zheng W, Qiu XW, Xiao L, Liu RR, Wang SY, Gong WJ, Zhou HH, Liu ZQ. The Impacts of SLC22A1 rs594709 and SLC47A1 rs2289669 Polymorphisms on Metformin Therapeutic Efficacy in Chinese Type 2 Diabetes Patients. Int J Endocrinol 2016; 2016: 4350712 [PMID: 26977146 DOI: 10.1155/2016/4350712]
Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 2008; 83: 273-280 [PMID: 17609683 DOI: 10.1038/sj.clpt.6100275]
Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, Hattersley AT, McCarthy MI, Morris AD, Palmer CN, Pearson ER. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes 2009; 58: 1434-1439 [PMID: 19336679 DOI: 10.2337/db08-0896]
Becker ML, Visser LE, van Schaik RH, et al. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J. 2009;9(4):242-247. doi: 10.1038/tpj.2009.15
Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, Inui K. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 2002; 13: 866-874 [PMID: 11912245]
Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics 2008; 18: 637-645 [PMID: 18551044 DOI: 10.1097/FPC.0b013e328302cd41]
Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Clark AG, Herskowitz I, Giacomini KM. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 2002; 12: 395-405 [PMID: 12142729 DOI: 10.1097/00008571-200207000-00007]
Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T, Kamba T, Ogawa O, Inui K. Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet 2008; 53: 607-614 [PMID: 18414781 DOI: 10.1007/s10038-008-0288-9]
Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics 2008; 9: 415-422 [PMID: 18384255 DOI: 10.2217/146224126.96.36.1995]
Zolk O, Solbach TF, Kцnig J, Fromm MF. Functional characterization of the human organic cation transporter 2 variant p.270Ala& gt; Ser. Drug Metab Dispos 2009; 37: 1312-1318 [PMID: 19251820 DOI: 10.1124/dmd.108.023762]
Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, Urban TJ, Chen L, Yee SW, Choi JH, Huang Y, Brett CM, Burchard EG, Giacomini KM. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics 2009; 19: 497-504 [PMID: 19483665 DOI: 10.1097/FPC.0b013e32832cc7e9]
Song IS, Shin HJ, Shim EJ, Jung IS, Kim WY, Shon JH, Shin JG. Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther 2008; 84: 559-562 [PMID: 18401339 DOI: 10.1038/clpt.2008.61]
Hou W, Zhang D, Lu W, Zheng T, Wan L, Li Q, Bao Y, Liu F, Jia W. Polymorphism of organic cation transporter 2 improves glucose-lowering effect of metformin via influencing its pharmacokinetics in Chinese type 2 diabetic patients. Mol Diagn Ther 2015; 19: 25-33 [PMID: 25573751 DOI: 10.1007/s40291-014-0126-z]
Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, Portman MA, Chen E, Ferrin TE, Sali A, Giacomini KM. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics 2010; 20: 687-699 [PMID: 20859243 DOI: 10.1097/FPC.0b013e32833fe789]
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. 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 [PMID: 19228809 DOI: 10.2337/db08-1028]
Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, Hanson RL, Saxena R, Fowler S, Shuldiner AR, Knowler WC, Altshuler D, Florez JC. 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 [PMID: 20682687 DOI: 10.2337/db10-0543]
He R, Zhang D, Lu W, Zheng T, Wan L, Liu F, Jia W. SLC47A1 gene rs2289669 G>A; A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients. Diabetes Res Clin Pract 2015; 109: 57-63 [PMID: 26004431 DOI: 10.1016/j.diabres.2015.05.003]
Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, Mefford JA, Hesselson SE, Schlessinger A, Jenkins G, Castro RA, Johns SJ, Stryke D, Sali A, Ferrin TE, Witte JS, Kwok PY, Roden DM, Wilke RA, McCarty CA, Davis RL, Giacomini KM. A common 5’-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 2011; 90: 674-684 [PMID: 21956618 DOI: 10.1038/clpt.2011.165]
Raman R., Gupta A., Krishna S. et al. Prevalence and risk factors for diabetic microvascular complications in newly diagnosed type II diabetes mellitus. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, report 27). J. Diabetes Complications. 2012;26(2):123-128.
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333:541–549.
Pasiechko NV. Efficiency of metformin in patients with obesity and hyperinsulinism on the stage of prediabetes. International Journal of Endocrinology. 2012, 2: 83-86.(Ukrainian)
About claim of protocols of medicare to the children after speciality "Child's endocrinology": order of МОZ of Ukraine 27.04.06 № 254. — URL : http://www.moz.gov.ua. (Ukrainian)
Gong Li et al. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics 20102; 820.
Papanas N, Maltezos E, Mikhailidis DP. Metformin and cancer: licence to heal? Expert Opin Investig Drugs. 2010;19:913–917.
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA. et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–1685.
Кaterenchuk VI. Current therapy of type 2 diabetes mellitus. Vnutrishnua medycyna. 2009;4:16. (Ukrainian)
UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol. 2011;201:105–167.
Shikata E. et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. Journal of human genetics. 2007;52:117-122.