PHARMACODYNAMIC OF METFORMIN IN TYPE 2 DIABETES MELLITUS PATIENTS: REVIEW OF THE PRKAA2 AND SLC22A3 GENES
Main Article Content
Type 2 diabetes mellitus (type 2 DM) is a disease including on metabolic disorder that characterized by an increase in glucose levels above normal. This glucose increase is caused by reduced insulin function which can be in the form of abnormalities in insulin secretion, impaired insulin action in peripheral tissues, or both. Metformin is one of the recommended therapies for type 2 DM. AMPK is the main pathway of metformin's mechanism. AMPKa2 encoded by PRKAA2 gene is an AMPK subunit that plays an important role in AMPK activation. OCT3 encoded by SLC22A3 plays a role in the metformin transport mechanism. OCT3 is needed in the metformin pharmacokinetic like absorption and elimination, this process determines metformin bioavailability, clearance, and its pharmacological effects. Mutations in PRKAA2 and SLC22A3 cause variations in the pharmacodynamic effects and pharmacokinetic of metformin in individuals directly. These changes will ultimately affect the effectiveness of metformin in type 2 DM patients.
Keywords:
Diabetes mellitus type 2, metformin, mutation, PRKAA2, SLC22A3
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6. Chen EC, Liang X, Yee SW, Geier EG, Stocker SL, Chen L, et al. Targeted Disruption of Organic Cation Transporter 3 Attenuates the Pharmacologic Response to Metformin. Mol Pharmacol 2015;88:75–83. https://doi.org/10.1124/mol.114.096776.
7. Chen Y, Qiu F, Yu B, Chen Y, Zuo F, Zhu XY, et al. Metformin, an AMPK Activator, Inhibits Activation of FLSs but Promotes HAPLN1 Secretion. Mol Ther Methods Clin Dec. 2020;17:1202-1214. https://doi.org/10.1016/j.omtm.2020.05.008.
8. Clauss NJ, Koek W, Daws LC. Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice. Int J Mol Sci. 2021; 22(24): 13420. https://doi.org/10.3390/ijms222413420.
9. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45:2752-2786. https://doi.org/10.2337/dci22-0034.
10. De Paoli M, Zakharia A, Werstuck GH. The Role of Estrogen in Insulin Resistance A Review of Clinical and Preclinical Data. Am J Pathol. 2021;191:1490-1498. https://doi.org/10.1016/j.ajpath.2021.05.011.
11. EBF Lima J, Moreira NCS, Sakamoto-Hojo ET. Mechanisms underlying the pathophysiology of type 2 diabetes: from risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia. Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 2022;874-875:503437. https://doi.org/10.1016/j.mrgentox.2021.503437.
12. Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomedicine & Pharmacotherapy. 2022;146:112563. https://doi.org/10.1016/j.biopha.2021.112563.
13. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):6275. https://doi.org/10.3390/ijms21176275.
14. Garcia D, Shaw RJ. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Molecular Cell. 2017;66:789-800. https://doi.org/10.1016/j.molcel.2017.05.032.
15. Ghaffari-Cherati M, Mahrooz A, Hashemi-Soteh MB, Hosseyni-Talei SR, Alizadeh A, Nakhaei SM. Allele frequency and genotype distribution of a common variant in the 3 -untranslated region of the SLC22A3 gene in patients with type 2 diabetes: association with response to metformin. J Res Med Sci. 2016;21:92. https://doi.org/10.4103/1735-1995.192508.
16. Herman R, Kravos NA, Jensterle M, Janez A, Dolzan V. Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated
Glucose Transport. Int. J. Mol. Sci. 2022;23:1264. https://doi.org/10.3390/ ijms23031264.
17. Hosseyni-Talei SR, Mahrooz A, Hashemi-Soteh MB, Ghaffari-Cherati M, Alizadeh A. Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes. Iran J Basic Med Sci. 2017;20(3):250–255. https://doi.org/10.22038/IJBMS.2017.8351
18. Hu D, Hu D, Liu L, Barr D, Liu Y, Balderrabano-Saucedo N, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. EBioMedicine. 2020;54:102723. https://doi.org/10.1016/j.ebiom.2020.102723. Epub 2020.
19. Ke C, Venkat Narayan KM, Shah BR. Pathophysiology, Phenotypes and Management of Type 2 Diabetes mellitus in Indian and Chinese population. Nature Reviews Endocrinology. 2022;18:413-432. https://doi.org/10.1038/s41574-022-00669-4.
20. Kemenkes. Pedoman Nasional Pelayanan Kedokteran Tatalaksana Diabetes Mellitus tipe 2 Dewasa. Permenkes No HK.01.07/Menkes/603/2020.
21. Khayachi A, Abuzgaya M, Liu Y, Jiao C, Dejgaard K, Schorova L, et al. Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder. eBioMedicine. 2024;104:105161. https://doi.org/10. 1016/j.ebiom.2024.105161.
22. Kim M, Hunter RW, Garcia-Menendez L, Ghong G, Yang Y-Y, Kolwics Jr SC, et al. Mutation in the γ2-Subunit of AMP-Activated Protein Kinase Stimulates Cardiomyocyte Proliferation and Hypertrophy Independent of Glycogen Storage. Circulation Research. 2014;114(6):966-975. https://doi.org/10.1161/CIRCRESAHA.114.302364.
23. Koepsell H. Organic Cation Transporters in Health and Disease. Pharmacol Rev. 2020;72:253-319. https://doi.org/10.1124/pr.118.015578.
24. Lee N, Hebert MF, Wagner DJ, Easterling TR, Liang J, Rice K, et al. Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy. Mol Pharmacol. 2018;94(4):1125-1131.
25. Lemos C, Schulze VK, Baumgart SJ, Nevedomskaya E, Heinrich T, Lefranc J, et al. The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models. Cell Oncol. 2021;44(3):581-94. https://doi.org/ 10.1007/s13402-020-00584-8.
26. Li Z, Yuan X, Liu X, Yang Y, Huang L, Tan Q, et al. The Influence of SLC22A3 Genetic Polymorphisms on Susceptibility to Type 2 Diabetes Mellitus in Chinese Population. Diabetes Metab Syndr Obes. 2023;16:1775-1781. https://doi.org/ 10.2147/DMSO.S412857.
27. Ouyang Y, Gu Y, Zhang X, Huang Y, Wei X, Tang F, et al. AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma. BMC Cancer 2024; 24: 276. doi: 10.1186/s12885-024-12025-y.
28. Rena G, Hardia G, Perason ER. The mechanisms of action of metformin. Diabetologia. 2017; 60(9): 1577-1585. https://doi.org/ 10.1007/s00125-017-4342-z.
29. Ross FA, Hawley SA, Russell FM, Goodman N, Hardie DG. Frequent loss-of-function mutations in the AMPK- α2 catalytic subunit suggest a tumour suppressor role in human skin cancers. Biochemical Journal. 2023;480:1951-1968. https://doi.org/10.1042/BCJ20230380.
30. Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. The FEBS Journal. 2023;290:620–648. https://doi.org/10.1111/febs.16306.
31. Sharma A, Anand SKr, Singh N, Dwivedi UN. AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis. Experimental Cell Research. 2023;113614. https://doi.org/10.1016/j.yexcr.2023.113614.
32. Sheleme T. Clinical Pharmacokinetics of Metformin. Intechopen: Metformin - Pharmacology and Drug Interactions. Published: 15 December 2021. https://doi.org/10.5772/intechopen.99343.
33. Sukumaran A, Choi K, Dasgupta B. Insight on Transcriptional Regulation of the Energy Sensing AMPK and Biosynthetic mTOR Pathway Genes. Front Cell Dev Biol. 2020;8. https://doi.org/10.3389/fcell.2020.00671
34. Szymczak-Pajor I, Wenclewska S, Sliwi ́nska A. Metabolic Action of Metformin. Pharmaceuticals. 2022;15:810. https://doi.org/10.3390/
ph15070810
35. Tarasiuk O, Miceli M, Di Domizio A, Nicolini G. AMPK and Diseases: State of the Art Regulation by AMPK-Targeting Molecules. Biology. 2022;11(7): 1041. https://doi.org/10.3390/biology11071041.
36. Virginia DM, Dwiprahasto I, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. The Effect of PRKAA2 Variation on Type 2 Diabetes Mellitus in the Asian Population: A Systematic Review and Meta-Analysis. Malays J Med Sci. 2022;29(3):5–16. https://doi.org/10.21315/mjms2022.29.3.2.
37. Virginia DM, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. Association between Three Variants in the PRKAA2 gene, rs2796498, rs9803799, and rs2746342, with 10-year ASCVD Risk on Newly Diagnosed T2DM in Yogyakarta, Indonesia. Open Access Maced J Med Sci. 2021 Aug 14; 9(A):541-547. https://doi.org/10.3889/oamjms.2021.6213.
38. Virginia DM, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. Evaluation of PRKAA2 Genetic Variation on Metformin E cacy as an Initial Therapy Among Drug-Naïve Patients With Type II Diabetes Mellitus. Research Square November 24th, 2020. DOI: https://doi.org/10.21203/rs.3.rs-107043/v1.
39. Virginia DM, Petramurti C, Fenty, Setiawan CH, Julianus J, et al. Single Nucleotide Polymorphism in the 3’ Untranslated Region of PRKAA2 on Cardiometabolic Parameters in Type 2 Diabetes Mellitus Patients Who Received Metformin. Therapeutics and Clinical Risk Management 2022:18 349–357. https://doi.org/10/2147/TCRM.S349900.
40. Vollmar J, Kim YO, Marquardt JU, Becker D, Galle PR, Schuppan D, et al. Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGF. Am J Physiol Gastrointest Liver Physiol. 2019; 317: G195–G202. https://doi.org/10.1152/ajpgi.00088.2019.
41. Vollmar J, Lautem A, Closs E, Schuppan D, Kim YO, Grimm D, et al. Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis. Oncotarget, 2017, Vol. 8, (No. 70), pp: 115667-115680. https://doi.org/10.18632/oncotarget.23372.
42. Wahidin M, Achadi A, Besral B, Kosen S, Nadjib M, Nurwahyuni A, et al. Projection of diabetes morbidity and mortality till 2045 in Indonesia based on risk factors and NCD prevention and control programs. Scientific Reports. 2024;14: 5424. https://doi.org/10.1038/s41598-024-54563-2
43. World Health Organization. Diagnosis and management of type 2 diabetes (HEARTS-D). Geneva]: World Health Organization; 2020 (WHO/UCN/NCD/20.1). Licence: CC BY-NC-SA 3.0 IGO.
44. Xu Z, Pan Z, Jin Y, Gao Z, Jiang F, Fu H, et al. Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion. Autophagy 2024;20:2:416-436. https://doi.org/10.1080/15548627.2023.2259216.
45. Ye J, Wu Y, Yang S, Zhu D, Chen F, Chen J, et al. The global, regional and national burden of type 2 diabetes mellitus in the past, present and future: a systematic analysis of the Global Burden of Disease Study 2019. Front. Endocrinol. 2023;14: 1192629. https://doi.org/10.3389/fendo.2023.1192629.
46. Yuan P, Teng D, de Groot E, Li M, Trousil S. Shen C-H, et al. Loss of AMPKα2 promotes melanoma tumor growth and brain metastasis. iScience. 2023; 26(6): 106791. https://doi.org/10.1016/j.isci.2023.106791.
47. Ziegler N, Bader E, Epanchintshev A, Margerie D, Kannt A, Schmoll D. AMPKb1 and AMPKb2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification. J Biol Chem. 2020;295:51:17659–17671. https://doi.org/10.1074/jbc.RA120.013990.
2. Acar MB, Ayaz-Guner S, Gunaydin Z, Karakukcu M, Peluso G, Di Bernardo G, et al. Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells. Front. Bioeng. Biotechnol. 2021;9:1-10. https://doi.org/10.3389/fbioe.2021.730813.
3. AL-Eitan LN, Almomani BA, Nassar AM, Elsaqa BZ. Metformin Pharmacogenetics: Effects of SLC22A1, SLC22A2, and SLC22A3 Polymorphisms on Glycemic Control and HbA1c Levels. J. Pers. Med. 2019;9:17. https://doi.org/10.3390/jpm9010017.
4. American Diabetic Association (ADA). Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47 (Supplement_1):S158–S178. https://doi.org/10.2337/dc24-S009.
5. Banday MZ, Sameer AS, Nissar S. Pathophysiology of diabetes: An overview. Avicenna J Med. 2020;10:174-88. https://doi.org/10.4103/ajm.ajm_53_20.
6. Chen EC, Liang X, Yee SW, Geier EG, Stocker SL, Chen L, et al. Targeted Disruption of Organic Cation Transporter 3 Attenuates the Pharmacologic Response to Metformin. Mol Pharmacol 2015;88:75–83. https://doi.org/10.1124/mol.114.096776.
7. Chen Y, Qiu F, Yu B, Chen Y, Zuo F, Zhu XY, et al. Metformin, an AMPK Activator, Inhibits Activation of FLSs but Promotes HAPLN1 Secretion. Mol Ther Methods Clin Dec. 2020;17:1202-1214. https://doi.org/10.1016/j.omtm.2020.05.008.
8. Clauss NJ, Koek W, Daws LC. Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice. Int J Mol Sci. 2021; 22(24): 13420. https://doi.org/10.3390/ijms222413420.
9. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45:2752-2786. https://doi.org/10.2337/dci22-0034.
10. De Paoli M, Zakharia A, Werstuck GH. The Role of Estrogen in Insulin Resistance A Review of Clinical and Preclinical Data. Am J Pathol. 2021;191:1490-1498. https://doi.org/10.1016/j.ajpath.2021.05.011.
11. EBF Lima J, Moreira NCS, Sakamoto-Hojo ET. Mechanisms underlying the pathophysiology of type 2 diabetes: from risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia. Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 2022;874-875:503437. https://doi.org/10.1016/j.mrgentox.2021.503437.
12. Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomedicine & Pharmacotherapy. 2022;146:112563. https://doi.org/10.1016/j.biopha.2021.112563.
13. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):6275. https://doi.org/10.3390/ijms21176275.
14. Garcia D, Shaw RJ. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Molecular Cell. 2017;66:789-800. https://doi.org/10.1016/j.molcel.2017.05.032.
15. Ghaffari-Cherati M, Mahrooz A, Hashemi-Soteh MB, Hosseyni-Talei SR, Alizadeh A, Nakhaei SM. Allele frequency and genotype distribution of a common variant in the 3 -untranslated region of the SLC22A3 gene in patients with type 2 diabetes: association with response to metformin. J Res Med Sci. 2016;21:92. https://doi.org/10.4103/1735-1995.192508.
16. Herman R, Kravos NA, Jensterle M, Janez A, Dolzan V. Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated
Glucose Transport. Int. J. Mol. Sci. 2022;23:1264. https://doi.org/10.3390/ ijms23031264.
17. Hosseyni-Talei SR, Mahrooz A, Hashemi-Soteh MB, Ghaffari-Cherati M, Alizadeh A. Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes. Iran J Basic Med Sci. 2017;20(3):250–255. https://doi.org/10.22038/IJBMS.2017.8351
18. Hu D, Hu D, Liu L, Barr D, Liu Y, Balderrabano-Saucedo N, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. EBioMedicine. 2020;54:102723. https://doi.org/10.1016/j.ebiom.2020.102723. Epub 2020.
19. Ke C, Venkat Narayan KM, Shah BR. Pathophysiology, Phenotypes and Management of Type 2 Diabetes mellitus in Indian and Chinese population. Nature Reviews Endocrinology. 2022;18:413-432. https://doi.org/10.1038/s41574-022-00669-4.
20. Kemenkes. Pedoman Nasional Pelayanan Kedokteran Tatalaksana Diabetes Mellitus tipe 2 Dewasa. Permenkes No HK.01.07/Menkes/603/2020.
21. Khayachi A, Abuzgaya M, Liu Y, Jiao C, Dejgaard K, Schorova L, et al. Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder. eBioMedicine. 2024;104:105161. https://doi.org/10. 1016/j.ebiom.2024.105161.
22. Kim M, Hunter RW, Garcia-Menendez L, Ghong G, Yang Y-Y, Kolwics Jr SC, et al. Mutation in the γ2-Subunit of AMP-Activated Protein Kinase Stimulates Cardiomyocyte Proliferation and Hypertrophy Independent of Glycogen Storage. Circulation Research. 2014;114(6):966-975. https://doi.org/10.1161/CIRCRESAHA.114.302364.
23. Koepsell H. Organic Cation Transporters in Health and Disease. Pharmacol Rev. 2020;72:253-319. https://doi.org/10.1124/pr.118.015578.
24. Lee N, Hebert MF, Wagner DJ, Easterling TR, Liang J, Rice K, et al. Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy. Mol Pharmacol. 2018;94(4):1125-1131.
25. Lemos C, Schulze VK, Baumgart SJ, Nevedomskaya E, Heinrich T, Lefranc J, et al. The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models. Cell Oncol. 2021;44(3):581-94. https://doi.org/ 10.1007/s13402-020-00584-8.
26. Li Z, Yuan X, Liu X, Yang Y, Huang L, Tan Q, et al. The Influence of SLC22A3 Genetic Polymorphisms on Susceptibility to Type 2 Diabetes Mellitus in Chinese Population. Diabetes Metab Syndr Obes. 2023;16:1775-1781. https://doi.org/ 10.2147/DMSO.S412857.
27. Ouyang Y, Gu Y, Zhang X, Huang Y, Wei X, Tang F, et al. AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma. BMC Cancer 2024; 24: 276. doi: 10.1186/s12885-024-12025-y.
28. Rena G, Hardia G, Perason ER. The mechanisms of action of metformin. Diabetologia. 2017; 60(9): 1577-1585. https://doi.org/ 10.1007/s00125-017-4342-z.
29. Ross FA, Hawley SA, Russell FM, Goodman N, Hardie DG. Frequent loss-of-function mutations in the AMPK- α2 catalytic subunit suggest a tumour suppressor role in human skin cancers. Biochemical Journal. 2023;480:1951-1968. https://doi.org/10.1042/BCJ20230380.
30. Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. The FEBS Journal. 2023;290:620–648. https://doi.org/10.1111/febs.16306.
31. Sharma A, Anand SKr, Singh N, Dwivedi UN. AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis. Experimental Cell Research. 2023;113614. https://doi.org/10.1016/j.yexcr.2023.113614.
32. Sheleme T. Clinical Pharmacokinetics of Metformin. Intechopen: Metformin - Pharmacology and Drug Interactions. Published: 15 December 2021. https://doi.org/10.5772/intechopen.99343.
33. Sukumaran A, Choi K, Dasgupta B. Insight on Transcriptional Regulation of the Energy Sensing AMPK and Biosynthetic mTOR Pathway Genes. Front Cell Dev Biol. 2020;8. https://doi.org/10.3389/fcell.2020.00671
34. Szymczak-Pajor I, Wenclewska S, Sliwi ́nska A. Metabolic Action of Metformin. Pharmaceuticals. 2022;15:810. https://doi.org/10.3390/
ph15070810
35. Tarasiuk O, Miceli M, Di Domizio A, Nicolini G. AMPK and Diseases: State of the Art Regulation by AMPK-Targeting Molecules. Biology. 2022;11(7): 1041. https://doi.org/10.3390/biology11071041.
36. Virginia DM, Dwiprahasto I, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. The Effect of PRKAA2 Variation on Type 2 Diabetes Mellitus in the Asian Population: A Systematic Review and Meta-Analysis. Malays J Med Sci. 2022;29(3):5–16. https://doi.org/10.21315/mjms2022.29.3.2.
37. Virginia DM, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. Association between Three Variants in the PRKAA2 gene, rs2796498, rs9803799, and rs2746342, with 10-year ASCVD Risk on Newly Diagnosed T2DM in Yogyakarta, Indonesia. Open Access Maced J Med Sci. 2021 Aug 14; 9(A):541-547. https://doi.org/10.3889/oamjms.2021.6213.
38. Virginia DM, Hartati Wahyuningsih MS, Agung Nugrahaningsih DA. Evaluation of PRKAA2 Genetic Variation on Metformin E cacy as an Initial Therapy Among Drug-Naïve Patients With Type II Diabetes Mellitus. Research Square November 24th, 2020. DOI: https://doi.org/10.21203/rs.3.rs-107043/v1.
39. Virginia DM, Petramurti C, Fenty, Setiawan CH, Julianus J, et al. Single Nucleotide Polymorphism in the 3’ Untranslated Region of PRKAA2 on Cardiometabolic Parameters in Type 2 Diabetes Mellitus Patients Who Received Metformin. Therapeutics and Clinical Risk Management 2022:18 349–357. https://doi.org/10/2147/TCRM.S349900.
40. Vollmar J, Kim YO, Marquardt JU, Becker D, Galle PR, Schuppan D, et al. Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGF. Am J Physiol Gastrointest Liver Physiol. 2019; 317: G195–G202. https://doi.org/10.1152/ajpgi.00088.2019.
41. Vollmar J, Lautem A, Closs E, Schuppan D, Kim YO, Grimm D, et al. Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis. Oncotarget, 2017, Vol. 8, (No. 70), pp: 115667-115680. https://doi.org/10.18632/oncotarget.23372.
42. Wahidin M, Achadi A, Besral B, Kosen S, Nadjib M, Nurwahyuni A, et al. Projection of diabetes morbidity and mortality till 2045 in Indonesia based on risk factors and NCD prevention and control programs. Scientific Reports. 2024;14: 5424. https://doi.org/10.1038/s41598-024-54563-2
43. World Health Organization. Diagnosis and management of type 2 diabetes (HEARTS-D). Geneva]: World Health Organization; 2020 (WHO/UCN/NCD/20.1). Licence: CC BY-NC-SA 3.0 IGO.
44. Xu Z, Pan Z, Jin Y, Gao Z, Jiang F, Fu H, et al. Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion. Autophagy 2024;20:2:416-436. https://doi.org/10.1080/15548627.2023.2259216.
45. Ye J, Wu Y, Yang S, Zhu D, Chen F, Chen J, et al. The global, regional and national burden of type 2 diabetes mellitus in the past, present and future: a systematic analysis of the Global Burden of Disease Study 2019. Front. Endocrinol. 2023;14: 1192629. https://doi.org/10.3389/fendo.2023.1192629.
46. Yuan P, Teng D, de Groot E, Li M, Trousil S. Shen C-H, et al. Loss of AMPKα2 promotes melanoma tumor growth and brain metastasis. iScience. 2023; 26(6): 106791. https://doi.org/10.1016/j.isci.2023.106791.
47. Ziegler N, Bader E, Epanchintshev A, Margerie D, Kannt A, Schmoll D. AMPKb1 and AMPKb2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification. J Biol Chem. 2020;295:51:17659–17671. https://doi.org/10.1074/jbc.RA120.013990.
