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Le J, Chen Y, Yang W, Chen L, Ye J. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta Pharm Sin B 2024; 14:437-454. [PMID: 38322335 PMCID: PMC10840401 DOI: 10.1016/j.apsb.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/10/2023] [Accepted: 08/09/2023] [Indexed: 02/08/2024] Open
Abstract
Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
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Affiliation(s)
- Jiamei Le
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yilong Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Wei Yang
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Jianping Ye
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
- Research Center for Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
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2
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Ragia G, Atzemian N, Maslarinou A, Manolopoulos VG. SLCO1B1 c.521T>C gene polymorphism decreases hypoglycemia risk in sulfonylurea-treated type 2 diabetic patients. Drug Metab Pers Ther 2022; 37:347-352. [PMID: 36169244 DOI: 10.1515/dmpt-2022-0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/02/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Pharmacogenomics can explain some of the heterogeneity of sulfonylurea (SU)-related hypoglycemia risk. Recently, a role of OATP1B1, encoded by SLCO1B1 gene, on SU liver transport prior of metabolism has been uncovered. The aim of the present study was to explore the potential association of SLCO1B1 c.521T>C polymorphism, leading to reduced OATP1B1 function, with SU-related hypoglycemia risk. METHODS Study cohort consists of 176 type 2 diabetes patients treated with the SUs glimepiride or gliclazide. 92 patients reported SU-related hypoglycemia, while 84 patients had never experienced a hypoglycemic event. Patients were previously genotyped for CYP2C9 *2 and *3 variant alleles that lead to decreased enzyme activity of the SU metabolizing enzyme CYP2C9 and have been associated with increased SU-related hypoglycemia risk. SLCO1B1 c.521T>C polymorphism was genotyped by use of PCR-RFLP analysis. RESULTS SLCO1B1 c.521TC genotype frequency was significantly lower in hypoglycemic cases than non-hypoglycemic controls (15.2% vs. 32.1%, p=0.008). In an adjusted model, c.521TC genotype significantly reduced the risk of hypoglycemia (OR 0.371; 95% C.I. 0.167-0.822; p=0.015). In CYP2C9 intermediate metabolizers (n=54) c.521TC genotype frequency was significantly decreased in cases compared to controls (3 out of 36 cases, 8.3% vs. 7 out of 18 controls, 38.9%, p=0.012). A similar albeit not significant difference of SLCO1B1 c.521TC genotype was present in CYP2C9 extensive metabolizers (n=120) (18.2% in cases vs. 30.8% in controls, p=0.113). CONCLUSIONS We have found a protective effect of SLCO1B1 c.521C variant on SU-related hypoglycemia risk both independently and in interaction with CYP2C9 phenotypes. Our results suggest a possible linkage of SLCO1B1 c.521T>C polymorphism with variants in other genes impairing OATPs expressed in pancreatic islets that could interfere with SU tissue distribution.
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Affiliation(s)
- Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Natalia Atzemian
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Anthi Maslarinou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Vangelis G Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece.,Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
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3
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Development of pharmacogenomic algorithm to optimize nateglinide dose for the treatment of type 2 diabetes mellitus. Pharmacol Rep 2022; 74:1083-1091. [PMID: 35932448 DOI: 10.1007/s43440-022-00400-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy. METHODS Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and Cmax (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies. RESULTS The MLR models of AUC and Cmax explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28 mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion. CONCLUSION CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.
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Wang T, Song JF, Zhou XY, Li CL, Yin XX, Lu Q. PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms affect therapeutic efficacy of nateglinide in Chinese patients with type 2 diabetes mellitus. BMC Med Genomics 2021; 14:267. [PMID: 34772419 PMCID: PMC8588701 DOI: 10.1186/s12920-021-01108-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/18/2021] [Indexed: 01/16/2023] Open
Abstract
Background Genetic polymorphisms in the PPARD and NOS1AP is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This study was designed to investigate a potential association of PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms with efficacy of nateglinide in newly diagnosed Chinese patients with type 2 diabetes mellitus (T2DM). Methods Sixty patients with newly diagnosed T2DM were enrolled to identify PPARD rs2016520 and NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay (PCR–RFLP). All subjects were treated with nateglinide (360 mg/day) for 8 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 8 weeks of nateglinide treatment. Results After nateglinide treatment for 8 consecutive weeks, patients with at least one C allele of PPARD rs2016520 showed a smaller decrease in post plasma glucose (PPG), homeostasis model assessment for beta cell function (HOMA-B) than those with the TT genotype did (P < 0.05). In patients with the AA genotype of NOS1AP rs12742393, the drug showed better efficacy with respect to levels of fasting plasma glucose (FPG), fasting serum insulin (FINS), HOMA-B and homeostasis model assessment for insulin resistance (HOMA-IR) than in patients with the AC + CC genotype (P < 0.05). NOS1AP rs12742393 genotype distribution and allele frequency were associated with responsiveness of nateglinide treatment (P < 0.05). Conclusions The PPARD rs2016520 and NOS1AP rs12742393 polymorphisms were associated with nateglinide monotherapy efficacy in Chinese patients with newly diagnosed T2DM. Trial registration Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.
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Affiliation(s)
- Tao Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.,Department of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jin-Fang Song
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.,Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xue-Yan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Cheng-Lin Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Xiao-Xing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
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Song JF, Zhang J, Zhang MZ, Ni J, Wang T, Zhao YQ, Khan NU. Evaluation of the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating type 2 diabetes among Chinese Han patients. BMC Med Genomics 2021; 14:156. [PMID: 34118937 PMCID: PMC8196487 DOI: 10.1186/s12920-021-01004-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/01/2021] [Indexed: 12/02/2022] Open
Abstract
Genetic polymorphisms in the MTNR1B gene is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This prospective case-control study was designed to investigate the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating T2DM. We genotyped untreated T2DM patients (N = 200) and healthy controls (N = 200) using the method of the high resolution of melting curve (HRM). Newly diagnosed T2DM patients (n = 60) with CYP2C9*1 and SLCO1B1 521TT genotypes were enrolled and given oral nateglinide (360 mg/d) for 8 weeks. The outcome was measured by collecting the venous blood samples before and at the 8th week of the treatment. The risk G allelic frequency of MTNR1B rs10830963 was higher in T2DM patients than the healthy subjects (P < 0.05). Post 8-week of treatment, newly diagnosed T2DM patients showed a less reduction in fasting plasma glucose levels and less increase in the carriers of genotype CG + GG at rs10830963 when compared with the CC genotype (P < 0.05). MTNR1B rs10830963 polymorphism was associated with the therapeutic efficacy of nateglinide in T2DM patients. Also, the CC homozygotes had a better effect than G allele carriers.Trial registration Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.
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Affiliation(s)
- Jin-Fang Song
- Department of Pharmacy, Affiliated Hospital of Jiangnan University , No.1000, Hefeng Road, Wuxi, 214000, China
| | - Jie Zhang
- School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Ming-Zhu Zhang
- Department of Pharmacy, Shandong Province Third Hospital, Jinan, 250000, China
| | - Jiang Ni
- Department of Pharmacy, Affiliated Hospital of Jiangnan University , No.1000, Hefeng Road, Wuxi, 214000, China
| | - Tao Wang
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221000, China
| | - Yi-Qing Zhao
- Department of Pharmacy, Affiliated Hospital of Jiangnan University , No.1000, Hefeng Road, Wuxi, 214000, China.
| | - Naveed Ullah Khan
- Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
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6
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Sayed S, Nabi AHMN. Diabetes and Genetics: A Relationship Between Genetic Risk Alleles, Clinical Phenotypes and Therapeutic Approaches. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:457-498. [PMID: 32314317 DOI: 10.1007/5584_2020_518] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unveiling human genome through successful completion of Human Genome Project and International HapMap Projects with the advent of state of art technologies has shed light on diseases associated genetic determinants. Identification of mutational landscapes such as copy number variation, single nucleotide polymorphisms or variants in different genes and loci have revealed not only genetic risk factors responsible for diseases but also region(s) playing protective roles. Diabetes is a global health concern with two major types - type 1 diabetes (T1D) and type 2 diabetes (T2D). Great progress in understanding the underlying genetic predisposition to T1D and T2D have been made by candidate gene studies, genetic linkage studies, genome wide association studies with substantial number of samples. Genetic information has importance in predicting clinical outcomes. In this review, we focus on recent advancement regarding candidate gene(s) associated with these two traits along with their clinical parameters as well as therapeutic approaches perceived. Understanding genetic architecture of these disease traits relating clinical phenotypes would certainly facilitate population stratification in diagnosing and treating T1D/T2D considering the doses and toxicity of specific drugs.
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Affiliation(s)
- Shomoita Sayed
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - A H M Nurun Nabi
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
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7
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Khatami F, Mohajeri-Tehrani MR, Tavangar SM. The Importance of Precision Medicine in Type 2 Diabetes Mellitus (T2DM): From Pharmacogenetic and Pharmacoepigenetic Aspects. Endocr Metab Immune Disord Drug Targets 2020; 19:719-731. [PMID: 31122183 DOI: 10.2174/1871530319666190228102212] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/18/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Type 2 Diabetes Mellitus (T2DM) is a worldwide disorder as the most important challenges of health-care systems. Controlling the normal glycaemia greatly profit long-term prognosis and gives explanation for early, effective, constant, and safe intervention. MATERIAL AND METHODS Finding the main genetic and epigenetic profile of T2DM and the exact molecular targets of T2DM medications can shed light on its personalized management. The comprehensive information of T2DM was earned through the genome-wide association study (GWAS) studies. In the current review, we represent the most important candidate genes of T2DM like CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1, and HNF homeoboxes. Different genetic variations of a candidate gene can predict the efficacy of T2DM personalized strategy medication. RESULTS SLCs and AMPK variations are considered for metformin, CYP2C9, KATP channel, CDKAL1, CDKN2A/2B and KCNQ1 for sulphonylureas, OATP1B, and KCNQ1 for repaglinide and the last but not the least ADIPOQ, PPAR-γ, SLC, CYP2C8, and SLCO1B1 for thiazolidinediones response prediction. CONCLUSION Taken everything into consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad R Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed M Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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8
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Mannino GC, Andreozzi F, Sesti G. Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine. Diabetes Metab Res Rev 2019; 35:e3109. [PMID: 30515958 PMCID: PMC6590177 DOI: 10.1002/dmrr.3109] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision-making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale.
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Affiliation(s)
- Gaia Chiara Mannino
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
| | - Francesco Andreozzi
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
| | - Giorgio Sesti
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
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9
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Yang P, Heredia VO, Beltramo DM, Soria NW. Pharmacogenetics and personalized treatment of type 2 diabetes mellitus. Int J Diabetes Dev Ctries 2016. [DOI: 10.1007/s13410-016-0517-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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10
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Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes 2016; 7:302-315. [PMID: 27555891 PMCID: PMC4980637 DOI: 10.4239/wjd.v7.i15.302] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.
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Lyssenko V, Bianchi C, Del Prato S. Personalized Therapy by Phenotype and Genotype. Diabetes Care 2016; 39 Suppl 2:S127-36. [PMID: 27440825 DOI: 10.2337/dcs15-3002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Valeriya Lyssenko
- Department of Translational Pathophysiology, Steno Diabetes Center A/S, Gentofte, Denmark Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Cristina Bianchi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Dawed AY, Zhou K, Pearson ER. Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2016; 9:17-29. [PMID: 27103840 PMCID: PMC4827904 DOI: 10.2147/pgpm.s84854] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is one of the leading causes of morbidity and mortality, consuming a significant proportion of public health spending. Oral hypoglycemic agents (OHAs) are the frontline treatment approaches after lifestyle changes. However, huge interindividual variation in response to OHAs results in unnecessary treatment failure. In addition to nongenetic factors, genetic factors are thought to contribute to much of such variability, highlighting the importance of the potential of pharmacogenetics to improve therapeutic outcome. Despite the presence of conflicting results, significant progress has been made in an effort to identify the genetic markers associated with pharmacokinetics, pharmacodynamics, and ultimately therapeutic response and/or adverse outcomes to OHAs. As such, this article presents a comprehensive review of current knowledge on pharmacogenetics of OHAs and provides insights into knowledge gaps and future directions.
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Affiliation(s)
- Adem Yesuf Dawed
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
| | - Kaixin Zhou
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
| | - Ewan Robert Pearson
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
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13
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Kleinberger JW, Pollin TI. Personalized medicine in diabetes mellitus: current opportunities and future prospects. Ann N Y Acad Sci 2015; 1346:45-56. [PMID: 25907167 DOI: 10.1111/nyas.12757] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. In addition, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity-onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes.
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Affiliation(s)
- Jeffrey W Kleinberger
- Division of Endocrinology, Diabetes, and Nutrition and Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Toni I Pollin
- Division of Endocrinology, Diabetes, and Nutrition and Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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14
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Maeda K. Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs. Biol Pharm Bull 2015; 38:155-68. [DOI: 10.1248/bpb.b14-00767] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Kazuya Maeda
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences,
The University of Tokyo
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15
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Abstract
Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.
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Affiliation(s)
- Miao Chen
- Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China
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Varma MVS, Scialis RJ, Lin J, Bi YA, Rotter CJ, Goosen TC, Yang X. Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide. AAPS JOURNAL 2014; 16:736-48. [PMID: 24839071 DOI: 10.1208/s12248-014-9614-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 04/26/2014] [Indexed: 11/30/2022]
Abstract
The purpose of this study is to characterize the involvement of hepato-biliary transport and cytochrome-P450 (CYP)-mediated metabolism in the disposition of glyburide and predict its pharmacokinetic variability due to drug interactions and genetic variations. Comprehensive in vitro studies suggested that glyburide is a highly permeable drug with substrate affinity to multiple efflux pumps and to organic anion transporting polypeptide (OATP)1B1 and OATP2B1. Active hepatic uptake was found to be significantly higher than the passive uptake clearance (15.8 versus 5.3 μL/min/10(6)-hepatocytes), using the sandwich-cultured hepatocyte model. In vitro, glyburide is metabolized (intrinsic clearance, 52.9 μL/min/mg-microsomal protein) by CYP3A4, CYP2C9, and CYP2C8 with fraction metabolism of 0.53, 0.36, and 0.11, respectively. Using these in vitro data, physiologically based pharmacokinetic models, assuming rapid-equilibrium between blood and liver compartments or permeability-limited hepatic disposition, were built to describe pharmacokinetics and evaluate drug interactions. Permeability-limited model successfully predicted glyburide interactions with rifampicin and other perpetrator drugs. Conversely, model assuming rapid-equilibrium mispredicted glyburide interactions, overall, suggesting hepatic uptake as the primary rate-determining process in the systemic clearance of glyburide. Further modeling and simulations indicated that the impairment of CYP2C9 function has a minimal effect on the systemic exposure, implying discrepancy in the contribution of CYP2C9 to glyburide clearance.
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Affiliation(s)
- Manthena V S Varma
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA,
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Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application. BIOMED RESEARCH INTERNATIONAL 2014; 2014:926713. [PMID: 24864266 PMCID: PMC4016836 DOI: 10.1155/2014/926713] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 03/22/2014] [Indexed: 02/06/2023]
Abstract
With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10−8). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.
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18
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Manolopoulos VG, Ragia G. Pharmacogenomics of Oral Antidiabetic Drugs. HANDBOOK OF PHARMACOGENOMICS AND STRATIFIED MEDICINE 2014:683-713. [DOI: 10.1016/b978-0-12-386882-4.00030-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Semiz S, Dujic T, Causevic A. Pharmacogenetics and personalized treatment of type 2 diabetes. Biochem Med (Zagreb) 2013; 23:154-71. [PMID: 23894862 PMCID: PMC3900064 DOI: 10.11613/bm.2013.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide epidemic with considerable health and economic consequences. T2DM patients are often treated with more than one drug, including oral antidiabetic drugs (OAD) and drugs used to treat diabetic complications, such as dyslipidemia and hypertension. If genetic testing could be employed to predict treatment outcome, appropriate measures could be taken to treat T2DM more efficiently. Here we provide a review of pharmacogenetic studies focused on OAD and a role of common drug-metabolizing enzymes (DME) and drug-transporters (DT) variants in therapy outcomes. For example, genetic variations of several membrane transporters, including SLC2A1/2 and SLC47A1/2 genes, are implicated in the highly variable glycemic response to metformin, a first-line drug used to treat newly diagnosed T2DM. Furthermore, cytochrome P450 (CYP) enzymes are implicated in variation of sulphonylurea and meglitinide metabolism. Additional variants related to drug target and diabetes risk genes have been also linked to interindividual differences in the efficacy and toxicity of OAD. Thus, in addition to promoting safe and cost-effective individualized diabetes treatment, pharmacogenomics has a great potential to complement current efforts to optimize treatment of diabetes and lead towards its effective and personalized care.
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Affiliation(s)
- Sabina Semiz
- Department of Biochemistry and Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
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van Leeuwen N, Swen JJ, Guchelaar HJ, ’t Hart LM. The Role of Pharmacogenetics in Drug Disposition and Response of Oral Glucose-Lowering Drugs. Clin Pharmacokinet 2013; 52:833-54. [PMID: 23719679 DOI: 10.1007/s40262-013-0076-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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