The Role of Pharmacogenetics in the Treatment of Diabetes Mellitus / ULOGA FARMAKOGENETIKE U LEČNJU DIJABETES MELITUSA

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Diabetes mellitus is a heterogeneous group of disorders in which particular disease phenotypes can be characterized by a specific etiology and/or pathogenesis of the disease, but in many cases its classification is greatly impeded due to significant phenotype overlapping. Diabetes is a wordwide epidemic with significant health and economic consequences. The frequency of type 2 diabetes (T2D) is much higher than type 1 diabetes (T1D). In adults, around 285 million people suffer from T2DM with a projected rise to 438 million in the next 20 years. A variety of pharmacological treatments exist for patients with T2D, in addition to dietary and physical activity. Pharmacologically, diabetes is treated with nine major classes of approved drugs, including insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, a-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Treatment strategy for T2D is based mostly on oral hypoglycemic drug (OHD) efficacy assessed usually by HbA1c and/or fasting plasma glucose. The patients are often treated with more than one OHD in combination with the purpose to receive more effective treatment. Characterization of drug response is expected to substantially increase the ability to provide patients with the most effective treatment strategy. If pharmacogenetic testing for diabetes drugs could be used to predict treatment outcome, appropriate measures could be taken to treat T2D more efficiently. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs, the most used OHD. A comprehensive review of the pharmacogenetic studies of specific OHD is presented in this article. Understanding the pharmacogenetics of these drugs will provide critical baseline information for the development and implementation of a genetic screening program into therapeutic decision making, enabling a personalized medicine approach for T2D patients.

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  • 1. Topić E. Pharmacogenomics and Personalized Medicine.In: Topić E Meško Brguljan P Blaton V eds.: New Trends in Classification Monitoring and Management of Metabolic Syndrome. Handbook Medicinska naklada Za greb 2006; p. 5-12. ( accessed 30 August 2013)

  • 2. Gerstein HC Yusuf S Bosch J Pogue J Sheridan P Dinccag N Hanefeld M Hoogwerf B Laakso M Mohan V et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096-105. [PubMed]

  • 3. Knowler WC Barrett-Connor E Fowler SE Hamman RF Lachin JM Walker EA Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403. (PMC free article) [PubMed]

  • 4. Knowler WC Hamman RF Edelstein SL Barrett-Connor E Ehrmann DA Walker EA Fowler SE Nathan DM Kahn SE. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 2005; 54: 1150-6. (PMC free article) [PubMed]

  • 5. Topić E. Pharmacogenomics and personalized medicine. In: Topić E Mesko Brguljan P Blaton V eds. The 7th EFCC Continuous Postgraduate Course in Clinical Chemistry: New trends in diagnosis monitoring and management using molecular diagnosis methods. Zagreb Medi cinska naklada; 2007; p. 33-44. ( accessed 30 August 2013)

  • 6. A haplotype map of the human genome. Nature 2005; 437: 1299-320. PMC free article [PubMed]

  • 7. Aberg K Adkins DE Bukszar J Webb BT Caroff SN Miller del D Sebat J Stroup S Fanous AH Vladimirov VI et al. Genomewide association study of movementrelated adverse antipsychotic effects. Biol Psychiatry 2010; 67: 279-82. (PMC free article) [PubMed]

  • 8. National Institutes of Health GWAS Catalog;

  • 9. DiStefano J Watanabe RM. Pharmacogenetics of Anti- Diabetes drugs. Pharmaceuticals (Basel) 2010 August 1; 3(8): 2610-46. doi: 10.3390/ph3082610

  • 10. Marchetti P Lupi R Del Guerra S Bugliani M D'Aleo V Occhipinti M Boggi U Marselli L Masini M. Goals of treatment for type 2 diabetes: beta-cell preservation for glycemic control. Diabet Care 2009; 32: 178-83. (PMC free article) [PubMed]

  • 11. National Diabetes Statistics 2007 Fact Sheet. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda DC USA: 2007.

  • 12. Poulsen P Kyvik KO Vaag A Beck-Nielsen H.Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance-a populationbased twin study. Diabetologia 1999; 42: 139-45. [PubMed]

  • 13. Klein BE Klein R Moss SE Cruickshanks KJ. Parental history of diabetes in a population-based study. Diabet Care 1996; 19: 827-30. [PubMed]

  • 14. Knowler WC Pettitt DJ Savage PJ Bennett PH. Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 1981; 113: 144-56. [PubMed]

  • 15. Zimmet P King H Taylor R Raper LR Balkau B Borger J Heriot W Thoma K. The high prevalence of diabetes mellitus impaired glucose tolerance and diabetic retino pathy in Nauru-the 1982 survey. Diabet Res (Edinburgh Lothian) 1984; 1: 13-18. [PubMed]

  • 16. Zimmet P Dowse G Finch C Serjeantson S King H. The epidemiology and natural history of NIDDM - lessons from the South Pacific. Diabet Metab Rev 1990; 6: 91-124. [PubMed]

  • 17. Gungor N Arslanian S. Pathophysiology of type 2 dia bet es mellitus in children and adolescents: treatment im plications. Treat Endocrinol 2002; 1: 359-71. [PubMed]

  • 18. Semiz S Dujić T Čaušević A. Pharmacogenetics and personalized treatment of type 2 diabetes. Biochemia Medica 2013; 23(2): 154-71.

  • 19. Hoerger TJ Segel JE Gregg EW Saaddine JB. Is glycemic control improving in U.S. adults? Diabet Care 2008; 31: 81-6. [PubMed]

  • 20. Bozkurt O de Boer A Grobbee DE Heerdink ER Burger H Klungel OH. Pharmacogenetics of glucoselowering drug treatment: a systematic review. Mol Diagn Ther 2007; 11: 291-302. [PubMed]

  • 21. Kahn SE Haffner SM Heise MA Herman WH Holman RR Jones NP Kravitz BG Lachin JM O'Neill MC Zin man B Viberti G. Glycemic durability of rosiglitazone metformin or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43. [PubMed]

  • 22. Kirchheiner J Roots I Goldammer M Rosenkranz B Brockmoller J. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005; 44: 1209-25. [PubMed]

  • 23. Marc J. Genetic susceptibility to metabolic syndrome. In: Topić E Meško Brguljan P Blaton V eds. New Trends In Classification Monitoring And Management Of Me tabolic Syndrome. Handbook Medicinska naklada Za greb 2006; p. 5-12. ( accessed 30 August 2013)

  • 24. Topić E. Genetic Aspects Of Diabetes Mellitus. In: Topić E ed. New Trends in Classification Monitoring and Management of Diabetes Mellitus. Handbook. Medicinska naklada Zagreb 2001. p. 5-12. ( accessed 30 August 2013)

  • 25. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998; 352: 837-53. [PubMed]

  • 26. Levy J Atkinson AB Bell PM McCance DR Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med 1998; 15: 290-6. [PubMed]

  • 27. Pearson ER Flechtner I Njolstad PR Malecki MT Flanagan SE Larkin B Ashcroft FM Klimes I Codner E Iotova V et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355: 467-77. [PubMed]

  • 28. Patch AM Flanagan SE Boustred C Hattersley AT Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabet Obes Metab 2007; 9: 28-39. [PubMed]

  • 29. Babenko AP Polak M Cave H Busiah K Czernichow P Scharfmann R Bryan J Aguilar-Bryan L Vaxillaire M Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355: 456-66. [PubMed]

  • 30. Hani EH Clement K Velho G Vionnet N Hager J Philippi A Dina C Inoue H Permutt MA Basdevant A et al. Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians. Diabetes 1997; 46: 688-94. [PubMed]

  • 31. Inoue H Ferrer J Welling CM Elbein SC Hoffman M Mayorga R Warren-Perry M Zhang Y Millns H Turner R et al. Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians. Diabetes 1996; 45: 825-31. [PubMed]

  • 32. Tarasov AI Nicolson TJ Riveline JP Taneja TK Baldwin SA Baldwin JM Charpentier G Gautier JF Froguel P Vaxillaire M et al. A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults. Diabetes 2008; 57: 1595-604. [PubMed]

  • 33. Nikolac N Šimundić AM Katalinić D Topić E Čipak A Zjačić Rotkvić V. Metabolic control in type 2 diabetes is associated with sulfonylurea receptor-1 (SUR-1) but not with KCNJ11 polymorphisms. Arch Med Res 2009; 40: 387-92.

  • 34. Nikolac N Šimundić AM Šaračević A Katalinić D. ABCC8 polymorphisms are associated with triglyceride concentration in type 2 diabetics on sulfonylurea therapy. Genet Test Mol Biomarkers 2012; 16: 924-30.

  • 35. Zhang H Liu X Kuang H Yi R Xing H. Association of sulfonylurea receptor 1 genotype with therapeutic response to gliclazide in type 2 diabetes. Diabet Res Clin Pract 2007; 77: 58-61. [PubMed]

  • 36. Feng Y Mao G Ren X Xing H Tang G Li Q Li X Sun L Yang J Ma W et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabet Care 2008; 31: 1939-44. (PMC free article) [PubMed]

  • 37. Miki T Nagashima K Tashiro F Kotake K Yoshitomi H Tamamoto A Gonoi T Iwanaga T Miyazaki J Seino S. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci USA 1998; 95: 10402-6. (PMC free article) [PubMed]

  • 38. Dunne MJ Kane C Shepherd RM Sanchez JA James RF Johnson PR Aynsley-Green A Lu S Clement JPT Lindley KJ et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997; 336: 703-6. [PubMed]

  • 39. Thomas P Ye Y Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5: 1809-12. [PubMed]

  • 40. Gloyn AL Pearson ER Antcliff JF Proks P Bruining GJ Slingerland AS Howard N Srinivasan S Silva JM Molnes J et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350: 1838-49. [PubMed]

  • 41. Barroso I Luan J Middelberg RP Harding AH Franks PW Jakes RW Clayton D Schafer AJ O'Rahilly S Wareham NJ. Candidate gene association study in type 2 diabetes indicates a role for genes involved in betacell function as well as insulin action. PLoS Biol 2003; 1: 20. (PMC free article) [PubMed]

  • 42. Florez JC Burtt N de Bakker PI Almgren P Tuomi T Holmkvist J Gaudet D Hudson TJ Schaffner SF Daly MJ Hirschhorn JN Groop L Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 2004; 53: 1360-68. [PubMed]

  • 43. Gloyn AL Weedon MN Owen KR Turner MJ Knight BA Hitman G Walker M Levy JC Sampson M Halford S McCarthy MI Hattersley AT Frayling TM. 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. [PubMed]

  • 44. Hansen SK Nielsen EM Ek J Andersen G Glumer C Carstensen B Mouritzen P Drivsholm T Borch-Johnsen K Jorgensen T et al. Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 3629-37. [PubMed]

  • 45. Inoue H Ferrer J Warren-Perry M Zhang Y Millns H Turner RC Elbein SC Hampe CL Suarez BK Inagaki N et al. Sequence variants in the pancreatic islet betacell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes 1997; 46: 502-7. [PubMed]

  • 46. Love-Gregory L Wasson J Lin J Skolnick G Suarez B Permutt MA. E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of Type II diabetes in Caucasians as the PPARgamma Pro12Ala variant. Diabetologia 2003; 46: 136-7. [PubMed]

  • 47. Sakura H Wat N Horton V Millns H Turner RC Ashcroft FM. Sequence variations in the human Kir6.2 gene a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia 1996; 39: 1233-6. [PubMed]

  • 48. Hart LM van Haeften TW Dekker JM Bot M Heine RJ Maassen JA. Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta-cell. Diabetes 2002; 51: 3135-8. [PubMed]

  • 49. Gloyn AL Hashim Y Ashcroft SJ Ashfield R Wiltshire S Turner RC. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53. Diabet Med 2001; 18: 206-12. [PubMed]

  • 50. Sesti G Laratta E Cardellini M Andreozzi F Del Guerra S Irace C Gnasso A Grupillo M Lauro R Hribal ML 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. [PubMed]

  • 51. Holstein A Hahn M Stumvoll M Kovacs P. The E23K variant of KCNJ11 and the risk for severe sulfonylureainduced hypoglycemia in patients with type 2 diabetes. Horm Metab Res 2009; 41: 387-90. [PubMed]

  • 52. Kirchheiner J Bauer S Meineke I Rohde W Prang V Meisel C Roots I Brockmoller J. Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics 2002; 12: 101-9. [PubMed]

  • 53. Kirchheiner J Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16. [PubMed]

  • 54. Topić E Stefanović M Samardžija M. Association between the CYP2C9 polymorphism and drug metabolism phenotype. Clin Chem Lab Med 2004; 42/1: 72-8.

  • 55. Aithal GP Day CP Kesteven PJ Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-19. [PubMed]

  • 56. Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349-55. [PMC free article] [PubMed]

  • 57. Van der Weide J Steijns LS van Weelden MJ de Haan K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmaco genetics 2001; 11: 287-91. [PubMed]

  • 58. Niemi M Cascorbi I Timm R Kroemer HK Neuvonen PJ Kivisto KT. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 2002; 72: 326-32. [PubMed]

  • 59. Tomalik-Scharte D. Application of pharmacogenetics in dose individualization in diabetes psychiatry cancer and cardiology. In: Topić E Meško Brguljan P Blaton V eds. New Trends in Classification Monitoring and Ma na ge ment using Molecular Methods. Handbook Me di cinska naklada Zagreb; 2007; p. 56-64. ( accessed 30 August 2013)

  • 60. Kirchheiner J Brockmoller J Meineke I Bauer S Rohde W Meisel C Roots I. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther 2002; 71: 286-96. [PubMed]

  • 61. Zhang Y Si D Chen X Lin N Guo Y Zhou H Zhong D. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. Br J Clin Pharmacol 2007; 64: 67-74. (PMC free article) [PubMed]

  • 62. Xu H Murray M McLachlan AJ. Influence of genetic polymorphisms on the pharmacokinetics and pharmaco- dynamics of sulfonylurea drugs. Curr Drug Metab 2009; 10: 643-58. [PubMed]

  • 63. Rogers JF Nafziger AN Bertino JS Jr. Pharmaco genetics affects dosing efficacy and toxicity of cytochrome P450-metabolized drugs. Am J Med 2002; 113: 746-50. [PubMed]

  • 64. Wijnen PA Op den Buijsch RA Drent M Kuijpers PM Neef C Bast A Bekers O Koek GH. Review article: The prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment Pharmacol Ther 2007; 26: 211-19. [PubMed]

  • 65. Pearson ER Donnelly LA Kimber C Whitley A Doney AS McCarthy MI Hattersley AT Morris AD Palmer CN. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007; 56: 2178-82. [PubMed]

  • 66. Sesti G Marini MA Cardellini M Sciacqua A Frontoni S Andreozzi F Irace C Lauro D Gnasso A Federici M et al. The Arg972 variant in insulin receptor substrate- 1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. Diabet Care 2004; 27: 1394-8. [PubMed]

  • 67. Becker ML Aarnoudse AJ Newton-Cheh C Hofman A Witteman JC Uitterlinden AG Visser LE Stricker BH. Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea. Pharmacogenet Genomics 2008; 18: 591-7. [PubMed]

  • 68. Leabman MK Huang CC DeYoung J Carlson EJ Taylor TR de la Cruz M Johns SJ Stryke D Kawamoto M Urban TJ et al. Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci USA 2003; 100: 5896-901. (PMC free article) [PubMed]

  • 69. Yin OQ Tomlinson B Chow MS. Variability in renal clearance of substrates for renal transporters in Chinese subjects. J Clin Pharmacol 2006; 46: 157-63. [PubMed]

  • 70. Zhou G Myers R Li Y Chen Y Shen X Fenyk-Melody J Wu M Ventre J Doebber T Fujii N et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-74. (PMC free article) [PubMed]

  • 71. Kim YD Park KG Lee YS Park YY Kim DK Nedumaran B Jang WG Cho WJ Ha J Lee IK et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 2008; 57: 306-14. [PubMed]

  • 72. Shaw RJ Lamia KA Vasquez D Koo SH Bardeesy N Depinho RA Montminy M Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 1642-6. [PMC free article] [PubMed]

  • 73. Patane G Piro S Rabuazzo AM Anello M Vigneri R Purrello F. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes 2000; 49: 735-40. [PubMed]

  • 74. Dresser MJ Leabman MK Giacomini KM. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 2001; 90: 397-421. [PubMed]

  • 75. Wang DS Jonker JW Kato Y Kusuhara H Schinkel AH Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exper Ther 2002; 302: 510-15. [PubMed]

  • 76. Shu Y Sheardown SA Brown C Owen RP Zhang S Castro RA Ianculescu AG Yue L Lo JC Burchard EG et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117: 1422-31. (PMC free article) [PubMed]

  • 77. Shu Y Brown C Castro RA Shi RJ Lin ET Owen RP Sheardown SA Yue L Burchard EG Brett CM et al. Effect of genetic variation in the organic cation transporter 1 OCT1 on metformin pharmacokinetics. Clin Phar macol Ther 2008; 83: 273-80. (PMC free article) [PubMed]

  • 78. 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: 637-45. [PubMed]

  • 79. 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: 559-62. [PubMed]

  • 80. Fujita T Urban TJ Leabman MK Fujita K Giacomini KM. Transport of drugs in the kidney by the human organic cation transporter OCT2 and its genetic variants. J Pharm Sci 2006; 95: 25-36. [PubMed]

  • 81. Chen Y Li S Brown C Cheatham S Castro RA Leabman MK Urban TJ Chen L Yee SW Choi JH et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics 2009; 19: 497-504. (PMC free article) [PubMed]

  • 82. Tzvetkov MV Vormfelde SV Balen D Meineke I Schmidt T Sehrt D Sabolic I Koepsell H Brockmoller J. The effects of genetic polymorphisms in the organic cation transporters OCT1 OCT2 and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009; 86: 299-306. [PubMed]

  • 83. 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: 17923-8. (PMC free article) [PubMed]

  • 84. 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: 745-9. (PMC free article) [PubMed]

  • 85. Otto C Lehrke M Goke B. Novel insulin sensitizers: pharmacogenomic aspects. Pharmacogenomics 2002; 3: 99-116. [PubMed]

  • 86. Braissant O Foufelle F Scotto C Dauca M Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPARalpha -beta and -gamma in the adult rat. Endocrinology 1996; 137: 354-66. [PubMed]

  • 87. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507-14. [PubMed]

  • 88. Aronoff S Rosenblatt S Braithwaite S Egan JW Mathisen AL Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglita zone 001 Study Group. Diabet Care 2000; 23: 1605-11. [PubMed]

  • 89. Scherbaum WA Goke B. Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind placebo-controlled study. Horm Metab Res 2002; 34: 589-95. [PubMed]

  • 90. Izumi T Enomoto S Hoshiyama K Sasahara K Sugiyama Y. Pharmacokinetic stereoselectivity of troglitazone an antidiabetic agent in the KK mouse. Biopharm Drug Dispos 1997; 18: 305-24. [PubMed]

  • 91. Yamazaki H Shibata A Suzuki M Nakajima M Shi mada N Guengerich FP Yokoi T. Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos 1999; 27: 1260-6. [PubMed]

  • 92. Tanis SP Parker TT Colca JR Fisher RM Kletzein RF. Synthesis and biological activity of metabolites of the antidiabetic antihyperglycemic agent pioglitazone. J Med Chem 1996; 39: 5053-63. [PubMed]

  • 93. Fujita Y Yamada Y Kusama M Yamauchi T Kamon J Kadowaki T Iga T. Sex differences in the pharmacokinetics of pioglitazone in rats. Comp Biochem Physiol C Toxicol Pharmacol 2003; 136: 85-94. [PubMed]

  • 94. Nowak SN Edwards DJ Clarke A Anderson GD Jaber LA. Pioglitazone: effect on CYP3A4 activity. J Clin Pharmacol 2002; 42: 1299-302. [PubMed]

  • 95. Deeb SS Fajas L Nemoto M Pihlajamaki J Mykkanen L Kuusisto J Laakso M Fujimoto W Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity lower body mass index and improved insulin sensitivity. Nat Genet 1998; 20: 284-7. [PubMed]

  • 96. Altshuler D Hirschhorn JN Klannemark M Lindgren CM Vohl MC Nemesh J Lane CR Schaffner SF Bolk S Brewer C et al. The common PPARg Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76-80. [PubMed]

  • 97. Matthews DR Hosker JP Rudenski AS Naylor BA Treacher DF Turner RC. Homeostasis model assessment: Insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-19. [PubMed]

  • 98. Florez JC Jablonski KA Sun MW Bayley N Kahn SE Shamoon H Hamman RF Knowler WC Nathan DM Altshuler D. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab 2007; 92: 1502-9. (PMC free article) [PubMed]

  • 99. Bluher M Lubben G Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPARgamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabet Care 2003; 26: 825-31. [PubMed]

  • 100. Wolford JK Yeatts KA Dhanjal SK Black MH Xiang AH Buchanan TA Watanabe RM. Sequence Variation in PPARG May Underlie Differential Response to Troglitazone. Diabetes 2005; 54: 3319-25. (PMC free article) [PubMed]

  • 101. Florez JC. Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008. J Clin Endocrinol Metab 2008; 93: 4633-42. (PMC free article) [PubMed]

  • 102. Nelson MR Bacanu SA Mosteller M Li L Bowman CE Roses AD Lai EH Ehm MG. Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions. Pharmacogenomics J 2009; 9: 23-33.[PubMed]

  • 103. Mason CC Hanson RL Knowler WC. Progression to type 2 diabetes characterized by moderate then rapid glucose increases. Diabetes 2007; 56: 2054-61.[PubMed]

  • 104. Bergman RN Zaccaro DJ Watanabe RM Haffner SM Saad MF Norris JM Wagenknecht LE Hokason JE Rotter JI Rich SS. Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. Diabetes 2003; 52: 2168-74. [PubMed]

  • 105. Hucking K Watanabe RM Stefanovski D Bergman RN. OGTT-derived measures of insulin sensitivity are confounded by factors other than insulin sensitivity itself. Obesity 2008; 16: 1938-45. (PMC free article) [PubMed]

  • 106. Kubota N Terauchi Y Miki H Tamemoto H Yamauchi T Komeda K Satoh S Nakano R Ishii C Sugiyama T et al. PPARg mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999; 4: 597-609. [PubMed]

  • 107. Yamauchi T Waki H Kamon J Murakami K Motojima K Komeda K Miki H Kubota N Terauchi Y Tsuchida A et al. Inhibition of RXR and PPARg ameliorates dietinduced obesity and type 2 diabetes. J Clin Invest 2001; 108: 1001-13. (PMC free article) [PubMed]

  • 108. Otto C Lehrke M Goke B. Novel insulin sensitizers: pharmacogenomic aspects. Pharmacogenomics 2002; 3: 99-116. [PubMed]

  • 109. Babić N. Clinical pharmacogenomics of personalized medicine. J Med Biochem 2012; 31: 281-6.

  • 110. Okuno A Tamemoto H Tobe K Ueki K Mori Y Iwamoto K Umesono K Akanuma Y Fujiwara T Horikoshi H et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101: 1354-61.

  • 111. Bećarević M Seferović J Ignjatović S Singh S Majkić- Singh N. Adiponectin non-esterified fatty acids and antiphospholipid antibodies in type II Diabetes Mellitus. J Med Biochem 2012; 31: 199-204.

  • 112. Izumi T Hoshiyama K Enomoto S Sasahara K Sugiyama Y. Pharmacokinetic steroselectivity of troglitazone an antidiabetic agent in the KK mouse. Bio pharm Drug Dispos 1997; 18: 305-24. [PubMed]

  • 113. Pajvani UB Hawkins M Combs TP Rajala MW Doebber T Berger JP Wagner JA Wu M Knopps A Xiang AH et al. Complex distribution not absolute amount of adiponectin correlates with thiazolidinedione- mediated improvement in insulin sensitivity. J Biol Chem 2004; 279: 12152-62. [PubMed]

  • 114. Kang ES Park SY Kim HJ Ahn CW Nam M Cha BS Lim SK Kim KR Lee HC. The influence of adiponectin gene polymorphism on the rosiglitazone response in patients with type 2 diabetes. Diabet Care 2005; 28: 1139-44. [PubMed]

  • 115. Liu HL Lin YG Wu J Sun H Gong ZC Hu PC Yin JY Zhang W Wang D Zhou HH et al. Impact of genetic polymorphisms of leptin and TNF-a on rosiglitazone response in Chinese patients with type 2 diabetes. Eur J Clin Pharmacol 2008; 64: 663-71. [PubMed]

  • 116. Makino H Shimizu I Murao S Kondo S Tabara Y Fujiyama M Fujii Y Takada Y Nakai K Izumi K et al. A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes. Endocr J 2009; 56: 1049-58. [PubMed]

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