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Sodium Glucose Transporter-2 Inhibitors (SGLT2Is)-TLRs Axis Modulates Diabetes

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Abstract

Diabetes affects millions of people worldwide and is mainly associated with impaired insulin function. To date, various oral anti-diabetic drugs have been developed, of which, the sodium glucose transporter-2 inhibitors (SGLT2Is) are of the most recent classes that have been introduced. They differ from other classes in terms of their novel mechanism of actions and unique beneficial effects rather than just lowering glucose levels. SGLT2Is can protect body against cardiovascular events and kidney diseases even in non-diabetic individuals. SGLT2Is participate in immune cell activation, oxidative stress reduction, and inflammation mediation, thereby, moderating diabetic complications. In addition, toll like receptors (TLRs) are the intermediators of the immune system and inflammatory process, thus it’s believed to play crucial roles in diabetic complications, particularly the ones that are related to inflammatory reactions. SGLT2Is are also effective against diabetic complications via their anti-inflammatory and oxidative properties. Given the anti-inflammatory properties of TLRs and SGLT2Is, this review investigates how SGLT2Is can affect the TLR pathway, and whether this could be favorable toward diabetes.

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Abbreviations

DM:

Diabetes

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

TLRs:

Toll-like receptors

TNF:

Tumor necrosis factor

NF-κB:

Nuclear factor kappa B

ROS:

Reactive oxygen species

ENOS:

Endothelial nitric oxide synthase

PP:

Pancreatic polypeptide

GLC:

Glucose

BMI:

Body mass index

PCOS:

Polycystic ovary syndrome

HDL:

High density lipoprotein

TZDs:

Thiazolidinediones

DPP-4:

Dipeptidyl peptidase IV

GLP-1:

Glucagon-like peptide-1

SGLT-2Is:

Sodium-glucose cotransporter-2 inhibitors

PAD:

Peripheral arterial disease

PPR:

Pattern recognition receptors

PAMPs:

Pathogen-associated molecular patterns

LPS:

Lipopolysaccharide

TM:

Transmembrane

LRR:

Leucine-rich repeat

MyD88:

Myeloid differentiation factor 88

MAL:

MyD88-adaptor-like protein

TRIF:

TIR-domain containing adaptor molecule

TRAM:

TRIF-related adaptor molecule

SARM:

sterile α- and armadillo-motif-containing

IFNs:

Interferons

I/R:

Ischemia/reperfusion

STAT:

Signal transducer and activator of transcription

iNOS:

Inducible nitric oxide synthase

NO:

Nitric oxide

CRP:

C-reactive protein

HMGB-1:

High mobility group box- 1

PPAR-γ:

Proliferator-activated receptor-γ

C-C motif:

Chemokine

CCL2:

ligand 2

NKAP:

Sodium/potassium adenosine triphosphatase Na/K ATPase pump

MI:

Myocardial infarction

SOD:

Superoxide dismutase

HO-1:

Heme oxygenase-1

MCP-1:

Macrophage chemoattractant protein-1

GPX:

Glutathione peroxidase

MDA:

Malondialdehyde

(NOX)-2:

Nicotinamide adenine dinucleotide phosphate oxidase

Nrf2:

Nuclear factor erythroid 2-related factor 2

PAH:

Pulmonary artery hypertension

UUO:

Unilateral ureteric obstruction

References

  1. Unnikrishnan, R., Anjana, R. M., & Mohan, V. (2016). Diabetes mellitus and its complications in India. Nature Reviews Endocrinology, 12(6), 357–370.

    PubMed  Google Scholar 

  2. Stedman, M., et al. (2020). Cost of hospital treatment of type 1 diabetes (T1DM) and type 2 diabetes (T2DM) compared to the non-diabetes population: a detailed economic evaluation. BMJ Open, 10(5), e033231.

    PubMed  PubMed Central  Google Scholar 

  3. Reid, L., Baxter, F., & Forbes, S. (2021). Effects of islet transplantation on microvascular and macrovascular complications in type 1 diabetes. Diabetic Medicine, 38(7), e14570.

    PubMed  Google Scholar 

  4. Azhar, A., et al. (2023). Prevalence of peripheral arterial disease in diabetic foot ulcer patients and its impact in limb salvage. The International Journal of Lower Extremity Wounds, 22, 518–523.

  5. Fowler, M. J. (2008). Microvascular and macrovascular complications of diabetes. Clinical diabetes, 26(2), 77–82.

    Google Scholar 

  6. Fowler, M. J. (2011). Microvascular and macrovascular complications of diabetes. Clinical diabetes, 29(3), 116–122.

    Google Scholar 

  7. Luc, K. et al. (2019). Oxidative stress and inflammatory markers in prediabetes and diabetes. J of Physiology and Pharmacology, 70(6), 809–824.

    CAS  Google Scholar 

  8. Zannad, F., et al. (2021). Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-reduced. Circulation, 143(4), 310–321.

    CAS  PubMed  Google Scholar 

  9. ElSayed, N. A., et al. (2023). Summary of revisions: standards of care in diabetes-2023. Diabetes Care, 46(Suppl 1), S5–s9.

    PubMed  Google Scholar 

  10. Saberzadeh-Ardestani, B., et al. (2018). Type 1 diabetes mellitus: cellular and molecular pathophysiology at a glance. Cell Journal, 20(3), 294.

    PubMed  PubMed Central  Google Scholar 

  11. Primavera, M., Giannini, C., & Chiarelli, F. (2020). Prediction and prevention of type 1 diabetes. Frontiers in Endocrinology, 11, 248.

    PubMed  PubMed Central  Google Scholar 

  12. Zorena, K., et al. (2022). Environmental factors and the risk of developing type 1 diabetes—old disease and new data. Biology, 11(4), 608.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gamboa, D., Vázquez, C. E., & Campos, P. J. (2020). Nonlinear analysis for a type-1 diabetes model with focus on t-cells and pancreatic β-cells behavior. Mathematical and Computational Applications, 25(2), 23.

    Google Scholar 

  14. Willcox, A., et al. (2009). Analysis of islet inflammation in human type 1 diabetes. Clinical & Experimental Immunology, 155(2), 173–181.

    CAS  Google Scholar 

  15. Bottazzo, G., Florin-Christensen, A., & Doniach, D. (1974). Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. The Lancet, 304(7892), 1279–1283.

    Google Scholar 

  16. Nathan, D. (2005). for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study research group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. The New England Journal of Medicine, 353, 2643–2653.

    PubMed  Google Scholar 

  17. Picardi, A., et al. (2006). Metabolic factors affecting residual beta cell function assessed by C-peptide secretion in patients with newly diagnosed type 1 diabetes. Hormone and Metabolic Research, 38(10), 668–672.

    CAS  PubMed  Google Scholar 

  18. Verdu, E. F., & Danska, J. S. (2018). Common ground: shared risk factors for type 1 diabetes and celiac disease. Nature Immunology, 19(7), 685–695.

    CAS  PubMed  Google Scholar 

  19. Yazdani, N. M., & Moghaddam, R. K. (2021). Blood glucose regulation in patients with type 1 diabetes by robust optimal safety critical control. Frontiers in Health Informatics, 10(1), 80.

    Google Scholar 

  20. Ghalwash, M., et al. (2022). Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study. The Lancet Diabetes & Endocrinology, 10(8), 589–596.

    CAS  Google Scholar 

  21. Patterson, C. C., et al. (2019). Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study. Diabetologia, 62(3), 408–417.

    PubMed  Google Scholar 

  22. Piffaretti, C., et al. (2019). Trends in childhood type 1 diabetes incidence in France, 2010–2015. Diabetes Research and Clinical Practice, 149, 200–207.

    PubMed  Google Scholar 

  23. DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018). Type 1 diabetes. The Lancet, 391(10138), 2449–2462.

    Google Scholar 

  24. Kyrou, I., et al. (2020). Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: a narrative review with emphasis on data from Europe. BMC endocrine disorders, 20(1), 1–13.

    Google Scholar 

  25. Yaghootkar, H., et al. (2020). Ethnic differences in adiposity and diabetes risk–insights from genetic studies. Journal of Internal Medicine, 288(3), 271–283.

    CAS  PubMed  Google Scholar 

  26. Martín Giménez, V. M., et al. (2020). Differences in RAAS/vitamin D linked to genetics and socioeconomic factors could explain the higher mortality rate in African Americans with COVID-19. Therapeutic Advances in Cardiovascular Disease, 14, 1753944720977715.

    PubMed  PubMed Central  Google Scholar 

  27. Kadayifci, F. Z., et al. (2019). Early-life programming of type 2 diabetes mellitus: understanding the association between epigenetics/genetics and environmental factors. Current Genomics, 20(6), 453–463.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Seneviratne, S. N., & Rajindrajith, S. (2022). Fetal programming of obesity and type 2 diabetes. World Journal of Diabetes, 13(7), 482–497.

    PubMed  PubMed Central  Google Scholar 

  29. Tian, M., et al. (2019). Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth. Journal of hypertension, 37(11), 2123–2134.

    CAS  PubMed  Google Scholar 

  30. Farruggia, M. C., & Small, D. M. (2019). Effects of adiposity and metabolic dysfunction on cognition: a review. Physiology & Behavior, 208, 112578.

    CAS  Google Scholar 

  31. Matsuo, A. R., et al. (2020). Tri-ponderal mass index as a tool for insulin resistance prediction in overweight adolescents: a cross-sectional study. Nutrition, 74, 110744.

    PubMed  Google Scholar 

  32. Lillioja, S., et al. (1988). Impaired glucose tolerance as a disorder of insulin action. New England Journal of Medicine, 318(19), 1217–1225.

    CAS  PubMed  Google Scholar 

  33. Saad, M., et al. (1989). Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. The Lancet, 333(8651), 1356–1359.

    Google Scholar 

  34. Jallut, D., et al. (1990). Impaired glucose tolerance and diabetes in obesity: A 6-year follow-up study of glucose metabolism. Metabolism, 39(10), 1068–1075.

    CAS  PubMed  Google Scholar 

  35. Straczkowski, M., et al. (2003). Insulin resistance in the first-degree relatives of persons with type 2 diabetes. Medical Science Monitor, 9(5), Cr186–Cr190.

    PubMed  Google Scholar 

  36. Carbone, S., et al. (2019). Obesity, risk of diabetes and role of physical activity, exercise training and cardiorespiratory fitness. Progress in Cardiovascular Diseases, 62(4), 327–333.

    PubMed  Google Scholar 

  37. Moyse, E., et al. (2019). Common pathological mechanisms and risk factors for Alzheimer’s disease and type-2 diabetes: focus on inflammation. Current Alzheimer Research, 16(11), 986–1006.

    CAS  PubMed  Google Scholar 

  38. Sharma, S., & Tripathi, P. (2019). Gut microbiome and type 2 diabetes: where we are and where to go?. Journal of Nutritional Biochemistry, 63, 101–108.

    CAS  PubMed  Google Scholar 

  39. Candler, T., et al. (2018). Continuing rise of type 2 diabetes incidence in children and young people in the UK. Diabetic Medicine, 35(6), 737–744.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun, H., et al. (2022). IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice, 183, 109119.

    PubMed  Google Scholar 

  41. Bekele, H., et al. (2020). Barriers and strategies to lifestyle and dietary pattern interventions for prevention and management of type-2 diabetes in Africa, systematic review. Journal of Diabetes Research, 2020, 7948712.

  42. Blaslov, K., et al. (2018). Treatment approach to type 2 diabetes: past, present and future. World Journal of Diabetes, 9(12), 209.

    PubMed  PubMed Central  Google Scholar 

  43. Jia, W., et al. (2019). Standards of medical care for type 2 diabetes in China 2019. Diabetes/Metabolism Research and Reviews, 35(6), e3158.

    PubMed  Google Scholar 

  44. Li, M., et al. (2009). The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Current Molecular Medicine, 9(3), 365–374.

    CAS  PubMed  Google Scholar 

  45. Arleevskaya, M. I., et al. (2020). Toll-like receptors, infections, and rheumatoid arthritis. Clinical Reviews in Allergy & Immunology, 58(2), 172–181.

    Google Scholar 

  46. Kaisho, T., & Akira, S. (2006). Toll-like receptor function and signaling. Journal of Allergy and Clinical Immunology, 117(5), 979–987.

    CAS  PubMed  Google Scholar 

  47. Thompson, A. J., & Locarnini, S. A. (2007). Toll‐like receptors, RIG‐I‐like RNA helicases and the antiviral innate immune response. Immunology and Cell Biology, 85(6), 435–445.

    CAS  PubMed  Google Scholar 

  48. Takeda, K., & Akira, S. (2001). Roles of Toll‐like receptors in innate immune responses. Genes to Cells, 6(9), 733–742.

    CAS  PubMed  Google Scholar 

  49. Muzio, M., et al. (2000). Toll‐like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. Journal of Leukocyte Biology, 67(4), 450–456.

    CAS  PubMed  Google Scholar 

  50. Akira, S., & Hemmi, H. (2003). Recognition of pathogen-associated molecular patterns by TLR family. Immunology Letters, 85(2), 85–95.

    CAS  PubMed  Google Scholar 

  51. Akira, S., & Takeda, K. (2004). Toll-like receptor signalling. Nature Reviews Immunology, 4(7), 499–511.

    CAS  PubMed  Google Scholar 

  52. Seki, E., & Brenner, D. A. (2008). Toll‐like receptors and adaptor molecules in liver disease: update. Hepatology, 48(1), 322–335.

    CAS  PubMed  Google Scholar 

  53. Nimma, S., et al. (2021). Structural evolution of TIR-domain signalosomes. Frontiers in Immunology, 12, 784484.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yamamoto, M., et al. (2003). Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 301(5633), 640–643.

    CAS  PubMed  Google Scholar 

  55. Gohda, J., Matsumura, T., & Inoue, J.-I. (2004). Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway in TLR signaling. The Journal of Immunology, 173(5), 2913–2917.

    CAS  PubMed  Google Scholar 

  56. Kolanowski, S. T., et al. (2014). TLR4-mediated pro-inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF. Innate Immunity, 20(4), 423–430.

    PubMed  Google Scholar 

  57. Yang, Y., et al. (2016). The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death & Disease, 7(5), e2234–e2234.

    CAS  Google Scholar 

  58. Zhao, X., et al. (2018). IRF3 negatively regulates toll-like receptor-mediated NF-κB signaling by targeting TRIF for degradation in teleost fish. Frontiers in Immunology, 9, 867.

    PubMed  PubMed Central  Google Scholar 

  59. Fitzgerald, K. A., & Kagan, J. C. (2020). Toll-like receptors and the control of immunity. Cell, 180(6), 1044–1066.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Fekonja, O., Avbelj, M., & Jerala, R. (2012). Suppression of TLR signaling by targeting TIR domain-containing proteins. Current Protein and Peptide Science, 13(8), 776–788.

    CAS  PubMed  Google Scholar 

  61. Cole, J. E., Georgiou, E. & Monaco, C. (2010). The expression and functions of toll-like receptors in atherosclerosis. Mediators of inflammation, 2010, ID 393946.

  62. Li, B., Xia, Y., & Hu, B. (2020). Infection and atherosclerosis: TLR-dependent pathways. Cellular and Molecular Life Sciences, 77(14), 2751–2769.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fresno, M., Alvarez, R., & Cuesta, N. (2011). Toll-like receptors, inflammation, metabolism and obesity. Archives of Physiology and Biochemistry, 117(3), 151–164.

    CAS  PubMed  Google Scholar 

  64. Fillatreau, S., Manfroi, B., & Dörner, T. (2021). Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nature Reviews Rheumatology, 17(2), 98–108.

    CAS  PubMed  Google Scholar 

  65. Spirig, R., Tsui, J. & Shaw, S. (2012). The emerging role of TLR and innate immunity in cardiovascular disease. Cardiology Research and Practice, 2012, 181394.

  66. Chedid, P., Salami, A. & El Shamieh, S. (2020). The association of rs1898830 in toll-like receptor 2 with lipids and blood pressure. Journal of Cardiovascular Development and Disease, 7(3) 24.

  67. Ashayeri Ahmadabad, R., et al. (2021). Toll-like receptor signaling pathways: novel therapeutic targets for cerebrovascular disorders. International Journal of Molecular Science, 22(11), 6153.

  68. Shi, H., et al. (2019). Role of Toll-like receptor mediated signaling in traumatic brain injury. Neuropharmacology, 145(Pt B), 259–267.

    CAS  PubMed  Google Scholar 

  69. Leitner, G. R., et al. (2019). Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders. Expert Opinion on Therapeutic Targets, 23(10), 865–882.

    PubMed  Google Scholar 

  70. Momtaz, S., et al. (2023). The Hydro-alcoholic Extract of Achillea wilhelmsii C. Koch Ameliorates Acetic Acid-induced Ulcerative Colitis through TLR-4. Proceedings of the National Academy of Sciences, India Section B: Biological Sciences, 93, 127–135.

  71. Lontchi-Yimagou, E., et al. (2013). Diabetes mellitus and inflammation. Current Diabetes Reports, 13(3), 435–444.

    CAS  PubMed  Google Scholar 

  72. King, G. L. (2008). The role of inflammatory cytokines in diabetes and its complications. Journal of Periodontology, 79, 1527–1534.

    CAS  PubMed  Google Scholar 

  73. Eizirik, D. L., Colli, M. L., & Ortis, F. (2009). The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nature Reviews Endocrinology, 5(4), 219–226.

    CAS  PubMed  Google Scholar 

  74. Eizirik, D. L., & Colli, M. L. (2020). Revisiting the role of inflammation in the loss of pancreatic β-cells in T1DM. Nature Reviews Endocrinology, 16(11), 611–612.

    PubMed  Google Scholar 

  75. Feuerer, M., et al. (2009). How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity, 31(4), 654–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Spranger, J., et al. (2003). Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes, 52(3), 812–817.

    CAS  PubMed  Google Scholar 

  77. Pradhan, A. D., et al. (2001). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 286(3), 327–334.

    CAS  PubMed  Google Scholar 

  78. Tilg, H., & Moschen, A. R. (2008). Inflammatory mechanisms in the regulation of insulin resistance. Molecular Medicine, 14(3), 222–231.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Westwell‐Roper, C., et al. (2014). Toll‐like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunology and Cell Biology, 92(4), 314–323.

    PubMed  Google Scholar 

  80. Jagannathan, M., et al. (2009). TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. The Journal of Immunology, 183(11), 7461–7470.

    CAS  PubMed  Google Scholar 

  81. Gupta, S., et al. (2017). Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications. Scientific Reports, 7(1), 1–10.

    Google Scholar 

  82. Dasu, M. R., et al. (2010). Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care, 33(4), 861–868.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mudaliar, H., et al. (2013). The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. American Journal of Physiology-Renal Physiology, 305(2), F143–F154.

    CAS  PubMed  Google Scholar 

  84. Devaraj, S., et al. (2008). Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. The Journal of Clinical Endocrinology & Metabolism, 93(2), 578–583.

    CAS  Google Scholar 

  85. Jagannathan, M., et al. (2010). Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia, 53(7), 1461–1471.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Karaali, Z. E., et al. (2019). Toll-like receptor 2 (TLR-2) gene polymorphisms in type 2 diabetes mellitus. Cell Journal, 20(4), 559.

    Google Scholar 

  87. Andrews, M., Soto, N., & Arredondo-Olguín, M. (2015). Association between ferritin and hepcidin levels and inflammatory status in patients with type 2 diabetes mellitus and obesity. Nutrition, 31(1), 51–57.

    CAS  PubMed  Google Scholar 

  88. Chen, G., et al. (2017). Maternal diabetes modulates offspring cell proliferation and apoptosis during odontogenesis via the TLR 4/NF‐κB signalling pathway. Cell Proliferation, 50(3), e12324.

    PubMed  Google Scholar 

  89. Devaraj, S., Tobias, P., & Jialal, I. (2011). Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine, 55(3), 441–445.

    CAS  PubMed  Google Scholar 

  90. Lin, M., et al. (2012). Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. Journal of the American Society of Nephrology, 23(1), 86–102.

    CAS  PubMed  Google Scholar 

  91. Yamazaki, Y., Harada, S., & Tokuyama, S. (2018). Sodium-glucose transporter as a novel therapeutic target in disease. Europeon Journal of Pharmacology, 822, 25–31.

    CAS  Google Scholar 

  92. Gyimesi, G., et al. (2020). Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application. Pflugers Archiv, 472(9), 1177–1206.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wright, E. M., Loo, D. D., & Hirayama, B. A. (2011). Biology of human sodium glucose transporters. Physiological Reviews, 91(2), 733–794.

    CAS  PubMed  Google Scholar 

  94. Ghezzi, C., Loo, D. D. F., & Wright, E. M. (2018). Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia, 61(10), 2087–2097.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hou, Y. C., et al. (2020). Molecular mechanisms of SGLT2 inhibitor on cardiorenal protection. Internaltional Journal of Molecular Science, 21(21) 7833.

  96. Vallon, V., & Verma, S. (2021). Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annual Review of Physiology, 83, 503–528.

    CAS  PubMed  Google Scholar 

  97. Giugliano, D., et al. (2021). Sodium-glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes. Cardiovascular Diabetology, 20(1), 17.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Suzuki, Y., et al. (2022). Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus. Cardiovascular Diabetology, 21(1), 67.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Dago, M., et al. (2022). Empagliflozin and dapagliflozin increase Na(+) and inward rectifier K(+) current densities in human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CMs). Cells, 11(23), 3707.

  100. Waugh, D. T. (2019). Fluoride exposure induces inhibition of sodium-and potassium-activated adenosine triphosphatase (Na(+), K(+)-ATPase) enzyme activity: molecular mechanisms and implications for public health. International Journal of Environmental Research and Public Health, 16(8), 1427.

  101. Fuller, W., et al. (2013). Regulation of the cardiac sodium pump. Cellular and Molecular Life Sciences, 70(8), 1357–1380.

    CAS  PubMed  Google Scholar 

  102. Askari, A. (2019). The sodium pump and digitalis drugs: Dogmas and fallacies. Pharmacology Research and Perspectives, 7(4), e00505.

    PubMed  PubMed Central  Google Scholar 

  103. Kowalska, K., et al. (2021) Empagliflozin-a new chance for patients with chronic heart failure. Pharmaceuticals, 15(1), 47, https://doi.org/10.3390/ph15010047.

  104. Refardt, J., et al. (2020). A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis. Journal of the American Society of Nephrology, 31(3), 615–624.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Feske, S., Wulff, H., & Skolnik, E. Y. (2015). Ion channels in innate and adaptive immunity. Annual Review of Immunology, 33, 291–353.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lees, G. J. (1991). Inhibition of sodium-potassium-ATPase: a potentially ubiquitous mechanism contributing to central nervous system neuropathology. Brain Research Reviews, 16(3), 283–300.

    CAS  PubMed  Google Scholar 

  107. Li, S., & Stys, P. K. (2001). Na(+)-K(+)-ATPase inhibition and depolarization induce glutamate release via reverse Na(+)-dependent transport in spinal cord white matter. Neuroscience, 107(4), 675–683.

    CAS  PubMed  Google Scholar 

  108. Stys, P. K. (2004). White matter injury mechanisms. Current Molecular Medicine, 4(2), 113–130.

    CAS  PubMed  Google Scholar 

  109. Kryvenko, V., & Vadász, I. (2021). Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19. American Journal of Physiology-Lung Cellular and Molecular Physiology, 320(6), L1186–l1193.

    PubMed  PubMed Central  Google Scholar 

  110. Kabel, A. M., Estfanous, R. S., & Alrobaian, M. M. (2020). Targeting oxidative stress, proinflammatory cytokines, apoptosis and toll like receptor 4 by empagliflozin to ameliorate bleomycin-induced lung fibrosis. Respiratory Physiology and Neurobiology, 273, 103316.

    CAS  PubMed  Google Scholar 

  111. Garibotto, G., et al. (2017). Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy. Journal of Nephrology, 30(6), 719–727.

    CAS  PubMed  Google Scholar 

  112. Ashrafi Jigheh, Z., et al. (2019). Empagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis. Iranian Journal of Basic Medical Sciences, 22(4), 384–390.

    PubMed  PubMed Central  Google Scholar 

  113. Zhang, Q. Q., et al. (2020). Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice. Therapeutic Advances in Chronic Disease, 11, 2040622320974833.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gangadharan Komala, M., et al. (2014). Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice. PLoS One, 9(11), e108994.

    PubMed  PubMed Central  Google Scholar 

  115. Al-Wakeel, D. E., El-Kashef, D. H., & Nader, M. A. (2022). Renoprotective effect of empagliflozin in cafeteria diet-induced insulin resistance in rats: Modulation of HMGB-1/TLR-4/NF-κB axis. Life Sciences, 301, 120633.

    CAS  PubMed  Google Scholar 

  116. Wang, C. Y., et al. (2020). TLR9 binding to beclin 1 and mitochondrial SIRT3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity. Biology, 9(11), 369, https://doi.org/10.3390/biology9110369.

  117. Lee, S. G., et al. (2020). Anti-inflammatory effect for atherosclerosis progression by sodium-glucose cotransporter 2 (SGLT-2) inhibitor in a normoglycemic rabbit model. Korean Circulation Journal, 50(5), 443–457.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Qin, T., et al. (2022). Protective effects of Dapagliflozin on the vulnerability of ventricular arrhythmia in rats with pulmonary artery hypertension induced by monocrotaline. Bioengineered, 13(2), 2697–2709.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Ko, S. F., et al. (2022). Combined therapy with dapagliflozin and entresto offers an additional benefit on improving the heart function in rat after ischemia-reperfusion injury. Biomedical Journal, 46, 100546.

  120. Refaie, M. M. M., et al. (2022). Dapagliflozin guards against cadmium-induced cardiotoxicity via modulation of IL6/STAT3 and TLR2/TNFα signaling pathways. Cardiovascular Toxicology, 22(10-11), 916–928.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhan, X., et al. (2022). Sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway. Frontiers in Cardiovascular Medicine, 9, 908037.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen, L., Klein, T., & Leung, P. S. (2012). Effects of combining linagliptin treatment with BI-38335, a novel SGLT2 inhibitor, on pancreatic islet function and inflammation in db/db mice. Current Molecular Medicine, 12(8), 995–1004.

    CAS  PubMed  Google Scholar 

  123. Nozu, T., et al. (2021). Phlorizin attenuates visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome. Biomedicine and Pharmacotherapy, 139, 111649.

    CAS  PubMed  Google Scholar 

  124. Kabel, A. M., & Salama, S. A. (2021). Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats. Human and Experimental Toxicology, 40(10), 1767–1780.

    CAS  PubMed  Google Scholar 

  125. Kimura, Y., et al. (2019). Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats. Journal of Diabetes Investigation, 10(4), 933–946.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Gong, Y., et al. (2022). Effect of sotagliflozin on ventricular arrhythmias in mice with myocardial infraction. European Journal of Pharmacology, 936, 175357.

    CAS  PubMed  Google Scholar 

  127. Abdollahi, E., et al. (2022). Dapagliflozin exerts anti-inflammatory effects via inhibition of LPS-induced TLR-4 overexpression and NF-κB activation in human endothelial cells and differentiated macrophages. European Journal of Pharmacology, 918, 174715.

    CAS  PubMed  Google Scholar 

  128. Panchapakesan, U., et al. (2013). Effects of SGLT2 inhibition in human kidney proximal tubular cells-renoprotection in diabetic nephropathy? PLoS One, 8(2), e54442.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Dean, H. J., & Sellers, E. A. (2007). Comorbidities and microvascular complications of type 2 diabetes in children and adolescents. Pediatric Diabetes, 8(Suppl 9), 35–41.

    PubMed  Google Scholar 

  130. Tomic, D., Shaw, J. E., & Magliano, D. J. (2022). The burden and risks of emerging complications of diabetes mellitus. Nature Reviews Endocrinology, 18(9), 525–539.

    PubMed  PubMed Central  Google Scholar 

  131. Kosiborod, M. N., et al. (2022). Effects of empagliflozin on symptoms, physical limitations, and quality of life in patients hospitalized for acute heart failure: results from the EMPULSE trial. Circulation, 146(4), 279–288.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Butler, J., et al. (2022). Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: the EMPEROR-preserved trial. Circulation, 145(3), 184–193.

    CAS  PubMed  Google Scholar 

  133. Kosiborod, M. N., et al. (2020). Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation, 141(2), 90–99.

    CAS  PubMed  Google Scholar 

  134. Sha, W., et al. (2020). The role of SGLT2 inhibitor on the treatment of diabetic retinopathy. Journal of Diabetes Research, 2020, 8867875.

    PubMed  PubMed Central  Google Scholar 

  135. Kaji, K., et al. (2018). Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. International Journal of Cancer, 142(8), 1712–1722.

    CAS  PubMed  Google Scholar 

  136. Cheng, Q., et al. (2019). SP434 renal tissue proteomics changes of the early tubulointerstitial injury in diabetic rats and the protective effects of sulodexide via toll-like receptor 2/4 pathways activation. Nephrology Dialysis Transplantation, 34(Supplement_1), gfz103 SP434.

    Google Scholar 

  137. Abbas, N. A. T., El Salem, A., & Awad, M. M. (2018). Empagliflozin, SGLT(2) inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: potential role of klotho expression. Naunyn-Schmiedeberg’s Archives of Pharmacology, 391(12), 1347–1360.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Amirhossein Niknejad, Yasamin Hosseini, Hedieh Sadat Shamsnia, Ayeh Sabbagh Kashani, Fatemeh Rostamian & Amir Hossein Abdolghaffari

  2. GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Amirhossein Niknejad, Yasamin Hosseini, Hedieh Sadat Shamsnia, Ayeh Sabbagh Kashani, Fatemeh Rostamian, Saeideh Momtaz & Amir Hossein Abdolghaffari

  3. Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran

    Saeideh Momtaz

  4. Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Saeideh Momtaz

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A.N., Y.H., H.S.S., A.S.K. and F.R. contributed in writing the original draft. A.N. contributed with development of figure. A.H.A. and S.M. supervised, reviewed and edited the draft. All authors read and approved the final manuscript.

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Niknejad, A., Hosseini, Y., Shamsnia, H.S. et al. Sodium Glucose Transporter-2 Inhibitors (SGLT2Is)-TLRs Axis Modulates Diabetes. Cell Biochem Biophys 81, 599–613 (2023). https://doi.org/10.1007/s12013-023-01164-x

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