BEYOND INSULIN: EXPLORING NON-HORMONAL THERAPEUTIC PATHWAYS FOR TYPE 1 DIABETES MANAGEMENT
Main Article Content
Keywords
Type 1 Diabetes, Immunomodulation, Beta-Cell Regeneration, Gut Microbiome, Artificial Pancreas
Abstract
Type 1 diabetes (T1DM) is an autoimmune disorder distinguished by the T cell-mediated destruction of pancreatic beta cells that produce insulin, which leads to inadequate insulin synthesis and hyperglycemia. Even though traditional insulin therapy is necessary, its drawbacks make it necessary to investigate non-hormonal therapeutic approaches.
This review aims to evaluate non-hormonal therapeutic approaches for T1D management, focusing on immunomodulatory strategies, beta-cell preservation and regeneration, the role of gut microbiota interventions, and emerging bioengineered pancreatic technologies.
This review synthesizes immunomodulatory strategies which may include T-cell modulation, cytokine targeting, and regulatory T-cell enhancement, suppressing autoimmunity while stabilizing residual beta-cell function. Among regenerative medicine tools will be stem cell therapy, gene therapy, and encapsulated islet transplantation in an attempt to restore endogenous insulin production. Although Probiotics, prebiotics, and intervening metabolomics will open new doors for T1D prevention through the natural involvement of the gut microbiome in immune modulation. Advances in bioengineered pancreas technologies involve combining artificial devices with cell-based therapies for improved glycemic control.
There are more adjunctive pharmacological agents such as SGLT2 inhibitors, metformin, and anti-inflammatories that can add to the benefits of insulin-free glucose regulation together with protection for beta cells. There is so much promise in development, yet it seems to be a long way off for these new therapies from becoming clinical realities.
Future research should be directed toward safety, efficacy, and integrating with existing treatment protocols. A multi-faceted immunomodulatory, regenerative medicine, and metabolic intervention approach may yet create the ultimate cure for T1D.
References
1. Grattoni, A., Korbutt, G., Tomei, A. A., García, A. J., Pepper, A. R., Stabler, C., & de Vos, P. (2024). Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead. Nature Reviews Endocrinology, 1-17. https://www.nature.com/articles/s41574-024-01029-0
2. Bluestone, J. A., Herold, K., & Eisenbarth, G. (2010). Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature, 464(7293), 1293-1300. https://www.nature.com/articles/nature08933
3. Hölzen, L., Schultes, B., Meyhöfer, S. M., & Meyhöfer, S. (2024). Hypoglycemia unawareness—a review on pathophysiology and clinical implications. Biomedicines, 12(2), 391. https://www.mdpi.com/2227-9059/12/2/391
4. Hirsch, I. B. (2016). Insulin in America: a right or a privilege? Diabetes Spectrum, 29(3), 130-132. https://diabetesjournals.org/spectrum/article-abstract/29/3/130/32812
5. Pociot, F., & Lernmark, Å. (2016). Genetic risk factors for type 1 diabetes. The Lancet, 387(10035), 2331-2339. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30582-7/abstract
6. Uniyal, P., Panwar, S., Bhatt, A., Marianesan, A. B., Kumar, R., Singh, T. G., & Kumar, B. (2025). An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them. Molecular Diversity, 1-27. https://link.springer.com/article/10.1007/s11030-025-11149-y
7. Herold, K. C., Delong, T., Perdigoto, A. L., Biru, N., Brusko, T. M., & Walker, L. S. (2024). The immunology of type 1 diabetes. Nature Reviews Immunology, 24(6), 435-451. https://www.nature.com/articles/s41577-023-00985-4
8. Lin, T. C., Lacorcia, M., & Mannering, S. I. (2025). Current and Emerging Assays for Measuring Human T-Cell Responses Against Beta-Cell Antigens in Type 1 Diabetes. Biomolecules, 15(3), 384. https://www.mdpi.com/2218-273X/15/3/384
9. Nagy, G., Szekely, T. E., Somogyi, A., Herold, M., & Herold, Z. (2022). New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World journal of diabetes, 13(10), 835. https://pmc.ncbi.nlm.nih.gov/articles/PMC9606789/
10. Zarei, M., Sheikholeslami, M. A., Mozaffari, M., & Mortada, Y. (2024). Innovative Immunotherapies and Emerging Treatments in Type 1 Diabetes Management. Diabetes Epidemiology and Management, 100247. https://www.sciencedirect.com/science/article/pii/S2666970624000519
11. Blok, L., Hanssen, N., Nieuwdorp, M., & Rampanelli, E. (2025). From microbes to metabolites: advances in gut Microbiome research in type 1 diabetes. Metabolites, 15(2), 138. https://www.mdpi.com/2218-1989/15/2/138
12. Calabrese, C. M., Valentini, A., & Calabrese, G. (2021). Gut microbiota and type 1 diabetes mellitus: The effect of Mediterranean diet. Frontiers in nutrition, 7, 612773. https://www.frontiersin.org/articles/10.3389/fnut.2020.612773/full
13. Fattah, H., & Vallon, V. (2018). The potential role of SGLT2 inhibitors in the treatment of type 1 diabetes mellitus. Drugs, 78, 717-726. https://link.springer.com/article/10.1007/s40265-018-0901-y
14. Donath, M. Y., Dinarello, C. A., & Mandrup-Poulsen, T. (2019). Targeting innate immune mediators in type 1 and type 2 diabetes. Nature Reviews Immunology, 19(12), 734-746.https://www.nature.com/articles/s41577-019-0213-9
15. Akil, A. A. S., Yassin, E., Al-Maraghi, A., Aliyev, E., Al-Malki, K., & Fakhro, K. A. (2021). Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. Journal of translational medicine, 19(1), 137. https://link.springer.com/article/10.1186/s12967-021-02778-6
16. DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018). Type 1 diabetes. The Lancet, 391(10138), 2449-2462. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31320-5/abstract
17. Hansen, M. S., Pokharel, P., Piganelli, J., & Sussel, L. (2024). The chicken or the egg dilemma: Understanding the interplay between the immune system and the β cell in type 1 diabetes. Cold Spring Harbor Perspectives in Medicine, a041591. https://perspectivesinmedicine.cshlp.org/content/early/2024/07/01/cshperspect.a041591.short
18. Blaine, J., Chonchol, M., & Levi, M. (2015). Renal control of calcium, phosphate, and magnesium homeostasis. Clinical Journal of the American Society of Nephrology, 10(7), 1257-1272. https://journals.lww.com/CJASN/fulltext/2015/07000/Renal_Control_of_Calcium,_Phosphate,_and_Magnesium.19.aspx
19. Alzhanuly, B., & Sharipov, K. (2024). Latest advancements in the development of new therapies for type 1 diabetes. Bratislava Medical Journal/Bratislavské Lekárske Listy, 125(8). https://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=00069248&AN=179221198&h=I9P3k0i1gA6cY8%2B3ntAzon3zxa9THvYz6bjzFJWeCyHxTnhO%2Fx7riaD7a7MSEl3R58ECdkSQnFnduK17GyAMAQ%3D%3D&crl=c
20. Devendra, D., Liu, E., & Eisenbarth, G. S. (2004). Type 1 diabetes: recent developments. Bmj, 328(7442), 750-754. https://www.bmj.com/content/328/7442/750.short
21. Al-Hawary, S. I. S., Jasim, S. A., Hjazi, A., Ullah, H., Bansal, P., Deorari, M., & Abosaoda, M. K. (2024). A new perspective on therapies involving B-cell depletion in autoimmune diseases. Molecular Biology Reports, 51(1), 629. https://link.springer.com/article/10.1007/s11033-024-09575-6
22. Gouirand, V., Habrylo, I., & Rosenblum, M. D. (2022). Regulatory T cells and inflammatory mediators in autoimmune disease. Journal of Investigative Dermatology, 142(3), 774-780. https://www.sciencedirect.com/science/article/pii/S0022202X21013038
23. Desai, T., & Shea, L. D. (2017). Advances in islet encapsulation technologies. Nature reviews Drug discovery, 16(5), 338-350. https://www.nature.com/articles/nrd.2016.232
24. Kreiner, F. F., von Scholten, B. J., Coppieters, K., & von Herrath, M. (2021). Current state of antigen-specific immunotherapy for type 1 diabetes. Current Opinion in Endocrinology, Diabetes and Obesity, 28(4), 411-418. https://journals.lww.com/co-endocrinology/fulltext/2021/08000/Current_state_of_antigen_specific_immunotherapy.13.aspx?context=LatestArticles
25. Hatipoglu, B., Benedetti, E., & Oberholzer, J. (2005). Islet transplantation: current status and future directions. Current Diabetes Reports, 5(4), 311-316. https://link.springer.com/article/10.1007/s11892-005-0029-9
26. Orban, T., Bundy, B., Becker, D. J., DiMeglio, L. A., Gitelman, S. E., Goland, R., & Skyler, J. S. (2011). Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. The Lancet, 378(9789), 412-419. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60886-6/fulltext?elq=ee57e9cf2dbb44439de1b398de11fe9f
27. Zhang, R., Zhao, Y., Chen, X., Zhuang, Z., Li, X., & Shen, E. (2024). Low-dose IL-2 therapy in autoimmune diseases: An update review. International Reviews of Immunology, 43(3), 113-137. https://www.tandfonline.com/doi/abs/10.1080/08830185.2023.2274574
28. Roep, B. O., Thomaidou, S., Van Tienhoven, R., & Zaldumbide, A. (2021). Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nature Reviews Endocrinology, 17(3), 150-161. https://www.nature.com/articles/s41574-020-00443-4
29. Wu, H., & Mahato, R. I. (2014). Mesenchymal stem cell-based therapy for type 1 diabetes. Discovery medicine, 17(93), 139-143. http://www.discoverymedicine.com/Hao-Wu/2014/03/07/mesenchymal-stem-cell-based-therapy-for-type-1-diabetes/
30. Vignali, D. A., Collison, L. W., & Workman, C. J. (2008). How regulatory T cells work. Nature reviews immunology, 8(7), 523-532. https://www.nature.com/articles/nri2343
31. Lo, K. B., Gul, F., Ram, P., Kluger, A. Y., Tecson, K. M., McCullough, P. A., & Rangaswami, J. (2020). The effects of SGLT2 inhibitors on cardiovascular and renal outcomes in diabetic patients: a systematic review and meta-analysis. Cardiorenal Medicine, 10(1), 1-10. https://karger.com/crm/article/10/1/1/86567
32. Bantounou, M. A., Sardellis, P., Thuemmler, R., Black Boada, D., Kaczmarek, J., Mahmood, R., & Philip, S. (2024). Effect of the dual sodium‐glucose co‐transporter‐1 and‐2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials. Diabetes, Obesity and Metabolism, 26(2), 710-720. https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.15364
33. El Masri, D., Ghosh, S., & Jaber, L. A. (2018). Safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 1 diabetes: A systematic review and meta-analysis. Diabetes Research and Clinical Practice, 137, 83-92. https://www.sciencedirect.com/science/article/pii/S016882271731344X
34. Nongthombam, G. S., Ahmed, S. A., Saikia, K., Gogoi, S., & Borah, J. C. (2025). Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors. RSC Medicinal Chemistry, 16(1), 296-311. https://pubs.rsc.org/en/content/articlehtml/2025/md/d4md00645c
35. Baker, C., Retzik-Stahr, C., Singh, V., Plomondon, R., Anderson, V., & Rasouli, N. (2021). Should metformin remain the first-line therapy for treatment of type 2 diabetes? Therapeutic Advances in Endocrinology and Metabolism, 12, 2042018820980225. https://journals.sagepub.com/doi/abs/10.1177/2042018820980225
36. Forner, P., Snaith, J., & Greenfield, J. R. (2024). Prescribing patterns of adjunctive therapy for the treatment of type 1 diabetes mellitus among Australian endocrinologists. Internal Medicine Journal, 54(5), 779-785. https://onlinelibrary.wiley.com/doi/abs/10.1111/imj.16312
37. Cree-Green, M., Bergman, B. C., Cengiz, E., Fox, L. A., Hannon, T. S., Miller, K., & Nadeau, K. J. (2019). Metformin improves peripheral insulin sensitivity in youth with type 1 diabetes. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3265-3278. https://academic.oup.com/jcem/article-abstract/104/8/3265/5423566
38. Abubaker, S. A., Alonazy, A. M., Abdulrahman, A., Abubaker, S., Alonazy, A., & Albasseet, A. (2022). Effect of alpha-lipoic acid in the treatment of diabetic neuropathy: A systematic review. Cureus, 14(6). https://www.cureus.com/articles/98939-effect-of-alpha-lipoic-acid-in-the-treatment-of-diabetic-neuropathy-a-systematic-review.pdf
39. Baumel-Alterzon, S., Katz, L. S., Lambertini, L., Tse, I., Heidery, F., Garcia-Ocaña, A., & Scott, D. K. (2024). NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function. Diabetologia, 67(3), 547-560. https://link.springer.com/article/10.1007/s00125-023-06071-7
40. dos Santos Haber, J. F., Barbalho, S. M., Sgarbi, J. A., de Argollo Haber, R. S., de Labio, R. W., Laurindo, L. F., ... & Payão, S. L. M. (2023). The relationship between type 1 diabetes mellitus, TNF-α, and IL-10 gene expression. Biomedicines, 11(4), 1120. https://www.mdpi.com/2227-9059/11/4/1120
41. Taneera, J., & Saber-Ayad, M. M. (2024). Preservation of β-cells as a therapeutic strategy for diabetes. Hormone and Metabolic Research, 56(04), 261-271. https://www.thieme-connect.com/products/ejournals/html/10.1055/a-2239-2668
42. Hunckler, M. D., & García, A. J. (2020). Engineered biomaterials for enhanced function of insulin‐secreting β‐cell organoids. Advanced Functional Materials, 30(48), 2000134. https://onlinelibrary.wiley.com/doi/abs/10.1002/adfm.202000134
43. Foster, N. C., Beck, R. W., Miller, K. M., Clements, M. A., Rickels, M. R., DiMeglio, L. A., ... & T1D Exchange Clinic Network. (2019). State of type 1 diabetes management and outcomes from the T1D exchange in 2016–2018. Diabetes Technology & Therapeutics, 21(2), 66-72. https://doi.org/10.1089/dia.2018.0384
44. Lehuen, A., Diana, J., Zaccone, P., & Cooke, A. (2019). Immune cell crosstalk in type 1 diabetes. Nature Reviews Immunology, 19(11), 734–747. https://doi.org/10.1038/s41577-019-0204-2
45. Sherr, J. L., Heinemann, L., & Fleming, G. A. (2022). Glycemic control with hybrid closed-loop insulin delivery: Systematic review. Diabetes Care, 45(2), 368–378. https://doi.org/10.2337/dci21-0024
46. ElSayed, N. A., Aleppo, G., Aroda, V. R., Bannuru, R. R., Brown, F. M., Bruemmer, D., & Gabbay, R. A. (2023). Introduction and methodology: standards of care in diabetes—2023. Diabetes Care, 46(Supplement_1), S1-S4. https://doi.org/10.2337/dc23-Sint
47. Insel, R. A., Dunne, J. L., Atkinson, M. A., Chiang, J. L., Dabelea, D., Gottlieb, P. A.,& Ziegler, A. G. (2015). Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care, 38(10), 1964-1974. https://doi.org/10.2337/dc15-1419
48. Zhao, L., Zhang, F., Ding, X., Wu, G., & Lam, K. S. (2021). Gut microbiota and diabetes: From mechanisms to clinical application. Nature Reviews Endocrinology, 17(10), 615–632. https://doi.org/10.1038/s41574-021-00507-0
49. Knip, M., & Simell, O. (2012). Environmental triggers of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine, 2(7), a007690. https://doi.org/10.1101/cshperspect.a007690
50. Van Belle, T. L., Coppieters, K. T., & von Herrath, M. G. (2011). Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiological Reviews, 91(1), 79–118. https://doi.org/10.1152/physrev.00003.2010
51. Wenzlau, J. M., Juhl, K., Yu, L., Moua, O., Sarkar, S. A., Gottlieb, P., & Hutton, J. C. (2007). The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proceedings of the National Academy of Sciences, 104(43), 17040–17045. https://doi.org/10.1073/pnas.0705894104
52. Herold, K. C., Gitelman, S. E., Ehlers, M. R., Gottlieb, P. A., Greenbaum, C. J., Hagopian, W., & Bluestone, J. A. (2019). Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in new-onset type 1 diabetes in a randomized controlled trial. Science Translational Medicine, 11(484), eaaw0681. https://doi.org/10.1126/scitranslmed.aaw0681
53. Long, S. A., Rieck, M., Sanda, S., Bollyky, P. L., Samuels, P. L., Goland, R., & Buckner, J. H. (2012). Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes, 61(9), 2340–2348. https://doi.org/10.2337/db12-0049
54. Fiorina, P., Vergani, A., Dada, S., Jurewicz, M., Wong, M., Law, K., & Sayegh, M. H. (2008). Targeting CD20+ B-cells restores T-cell homeostasis and insulin production in type 1 diabetes. Diabetes, 57(12), 3013–3024. https://doi.org/10.2337/db08-0332
55. Battaglia, M., Anderson, M. S., Buckner, J. H., Dotta, F., Ferrer, L., Piemonti, L., & Atkinson, M. A. (2017). Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetes, 66(5), 1153–1161. https://doi.org/10.2337/db16-1215
56. Ziegler, A. G., & Nepom, G. T. (2010). Prediction and pathogenesis in type 1 diabetes. Immunity, 32(4), 468–478. https://doi.org/10.1016/j.immuni.2010.03.018
57. Salama, R. A. A., Patni, M. A. M. F., Ba Hutair, S. N. M., Wadid, N. A., & Akikwala, M. S. (2024). Exploring novel treatment modalities for Type 1 diabetes mellitus: Potential and prospects. Healthcare, 12(15), Article 1485. https://doi.org/10.3390/healthcare12151485
58. Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., & Roep, B. O. (2001). Development of type 1 diabetes despite severe hereditary B-cell deficiency. New England Journal of Medicine, 345(14), 1036-1040. https://: doi.org/10.1056/NEJMoa010465
59. Garg, V. (2011). Noninsulin pharmacological management of Type 1 diabetes mellitus. Indian Journal of Endocrinology and Metabolism, 15(Suppl 1), S5–S11. https://doi.org/10.4103/2230-8210.83053
60. Wang, J., Shen, X., He, S., An, Y., Gong, Q., Li, H., & Li, G. (2019). Hypertriglyceridaemia predicts subsequent long‐term risk of cardiovascular events in Chinese adults: 23‐year follow‐up of the Daqing Diabetes Study. Diabetes/Metabolism Research and Reviews, 35(6), e3163.https://doi.org/10.1002/dmrr.3163
61. Lan, N. S., Hong, R. S., Ryan, C., Jenkins, A. J., & Fegan, P. G. (2023). Patient perceptions of cardiovascular risk, lipid management and statins in type 1 diabetes. Primary care diabetes, 17(5), 526-528.https://doi.org/10.1016/j.pcd.2023.07.005
62. Najafipour, M., Najafipour, F., Ostadrahimi, A., Ghavami, M., Razaghi, Z., Tutunchi, H., & Alamdari, N. M. (2024). The effects of empagliflozin in patients with type 1 diabetes: Results of a 12-week, double-blind, randomized, placebo-controlled clinical trial. Health Promotion Perspectives, 14(4), 380-387. https://doi.org/10.34172/hpp.42486
63. Liu, Y., Yang, S., Jiang, A., Zou, D., Chen, Z., & Su, N. (2025). Risk of diabetic ketoacidosis caused by sodium glucose cotransporter-2 inhibitors in patients with type 1 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Frontiers in Endocrinology, 15, 1453067. https://doi.org/10.3389/fendo.2024.1453067
64. Yau, C., & Danska, J. S. (2024). Cracking the type 1 diabetes code: Genes, microbes, immunity, and the early life environment. Immunological Reviews, 325(1), 23-45. https://doi.org/10.1111/imr.13362
65. Leão, I. S., Dantas, J. R., Araújo, D. B., Ramos, M. E. N., Silva, K. R., Batista, L. S., & Rodacki, M. (2024). Evaluation of type 1 diabetes’ partial clinical remission after three years of heterologous adipose tissue derived stromal/stem cells transplantation associated with vitamin D supplementation. Diabetology & Metabolic Syndrome, 16(1), 114. https://doi.org/10.1186/s13098-024-01302-2
66. Millman, J. R., Xie, C., Van Dervort, A., Gürtler, M., Pagliuca, F. W., & Melton, D. A. (2016). Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nature Communications, 7(1), 11463. https://doi.org/10.1038/ncomms11463
67. Hunault, L., & Hesselson, D. (2024). Finishing the odyssey to a stem cell cure for type 1 diabetes. Metabolic Health and Disease, 2(1), 9. https://doi.org/10.1038/s44324-024-00014-5
68. Wang, Y., Chen, Y., McGarrigle, J., Cook, J., Rios, P. D., La Monica, G., & Oberholzer, J. (2025). Cell Therapy for T1D Beyond BLA: Gearing Up Toward Clinical Practice. Diabetes Therapy, 1-14. https://doi.org/10.1007/s13300-025-01732-9
69. Murri, M., Leiva, I., Gomez-Zumaquero, J. M., Tinahones, F. J., Cardona, F., Soriguer, F., & Queipo-Ortuño, M. I. (2013). Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BioMed Central Medicine, 11, 1-12. https://doi.org/10.1186/1741-7015-11-46
70. Marino, E., Richards, J. L., McLeod, K. H., Stanley, D., Yap, Y. A., Knight, J., & Mackay, C. R. (2017). Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nature Immunology, 18(5), 552-562. https://doi.org/10.1038/ni.3713
71. Vatanen, T., Franzosa, E. A., Schwager, R., Tripathi, S., Arthur, T. D., Vehik, K., & Xavier, R. J. (2018). The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature, 562(7728), 589-594. https://doi.org/10.1038/s41586-018-0620-2
72. Wszoła, M., Nitarska, D., Cywoniuk, P., Gomółka, M., & Klak, M. (2021). Stem cells as a source of pancreatic cells for production of 3D bioprinted bionic pancreas in the treatment of type 1 diabetes. Cells, 10(6), 1544. https://doi.org/10.3390/cells10061544
73. Antonio-Villa, N. E., García-Tuomola, A., Almeda-Valdes, P., Vidrio-Velázquez, M., Islas-Ortega, L., Madrigal-Sanromán, J. R., & RENACED-DT1 Research Group. (2021). Glycemic control, treatment and complications in patients with type 1 diabetes amongst healthcare settings in Mexico. Diabetes Research and clinical practice, 180, 109038. https://doi.org/10.1016/j.diabres.2021.109038
74. Zhang, Q., Gonelle-Gispert, C., Li, Y., Geng, Z., Gerber-Lemaire, S., Wang, Y., & Buhler, L. (2022). Islet encapsulation: new developments for the treatment of type 1 diabetes. Frontiers in Immunology, 13, 869984. https://doi.org/10.3389/fimmu.2022.869984
75. Monami, M., Nreu, B., Zannoni, S., Lualdi, C., & Mannucci, E. (2017). Effects of SGLT-2 inhibitors on diabetic ketoacidosis: a meta-analysis of randomised controlled trials. Diabetes Research and Clinical Practice, 130, 53-60. https://doi.org/10.1016/j.diabres.2017.04.017
76. Mathieu, C., Rudofsky, G., Phillip, M., Araki, E., Lind, M., Arya, N., & Dandona, P. (2020). Long‐term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT‐2 study): 52‐week results from a randomized controlled trial. Diabetes, Obesity and Metabolism, 22(9), 1516-1526. https://doi.org/10.1111/dom.14060
77. Bjornstad, P., Schäfer, M., Truong, U., Cree-Green, M., Pyle, L., Baumgartner, A., & Nadeau, K. J. (2018). Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus: randomized controlled trial. Circulation, 138(25), 2895-2907. https://doi.org/10.1161/CIRCULATIONAHA.118.035525
78. Araki, E., Mathieu, C., Shiraiwa, T., Maeda, H., Ikeda, H., Thoren, F., & Iqbal, N. (2021). Long‐term (52‐week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT‐2 study. Diabetes, Obesity and Metabolism, 23(7), 1496-1504. https://doi.org/10.1111/dom.14362
79. Ma, J., Zhao, Y., Fan, H., & Liu, J. (2021). The efficacy of dapagliflozin for type 1 diabetes: a meta-analysis of randomized controlled studies. African Health Sciences, 21(1), 1–7. https://doi.org/10.4314/ahs.v21i1.2
80. Lund, S. S., Tarnow, L., Astrup, A. S., Hovind, P., Jacobsen, P. K., Alibegovic, A. C., Parving, I., Pietraszek, L., Frandsen, M., Rossing, P., Parving, H. H., & Vaag, A. A. (2008). Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. Public Library of Science ONE, 3(10), e3363. https://doi.org/10.1371/journal.pone.0003363
81. Lacigova, S., Rusavý, Z., Jankovec, Z., & Kyselova, P. (2001). Metformin in the treatment of type 1 diabetics--a placebo controlled study. Casopis Lekaru Ceskych, 140(10), 302-306. PMID: 11411059.
82. Scaramuzza, A., Giani, E., Redaelli, F., Ungheri, S., Macedoni, M., Giudici, V., Bosetti, A., Ferrari, M., & Zuccotti, G. V. (2015). Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial Dysfunction in Adolescents with Type 1 Diabetes: A Pilot Trial. Journal of Diabetes Research, 2015, 474561. https://doi.org/10.1155/2015/474561
83. Ding, Q., Sun, B., Wang, M., Li, T., Li, H., Han, Q., & Tang, Z. (2023). N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway. Life Sciences, 329, 121975. https://doi.org/10.1016/j.lfs.2023.121975
84. Musso, G., Sircana, A., Saba, F., Cassader, M., & Gambino, R. (2020). Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: a meta-analysis and meta-regression. Public Library of Science ONE medicine, 17(12), e1003461. https://doi.org/10.1371/journal.pmed.1003461
85. Danne, T., Garg, S., Peters, A. L., Buse, J. B., Mathieu, C., Pettus, J. H., & Phillip, M. (2019). International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium–glucose cotransporter (SGLT) inhibitors. Diabetes Care, 42(6), 1147-1154. https://doi.org/10.2337/dc18-2316
86. Holt, R. I., DeVries, J. H., Hess-Fischl, A., Hirsch, I. B., Kirkman, M. S., Klupa, T., & Peters, A. L. (2021). The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 44(11), 2589-2625. https://doi.org/10.2337/dci21-0043
87. Butrym, M., Byvald, F., Blanter, M., Ringqvist, E. E., Vasylovska, S., Marjomäki, V., & Flodström-Tullberg, M. (2024). Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells. Antiviral Research, 231, 106021. https://doi.org/10.1016/j.antiviral.2024.105527
88. Roy, S., Pokharel, P., & Piganelli, J. D. (2024). Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes. Molecular Metabolism, 101998. https://doi.org/10.1016/j.molmet.2024.101826
89. Collins, J., & Farnsworth, N. L. (2025). Active targeting of type 1 diabetes therapies to pancreatic beta cells using nanocarriers. Diabetologia, 1-12. https://doi.org/10.1007/s00125-024-06356-5
90. Keymeulen, B., van Maurik, A., Inman, D., Oliveira, J., McLaughlin, R., Gittelman, R. M., & Napolitano, A. (2021). A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes. Diabetologia, 64, 313-324. https://doi.org/10.1007/s00125-020-05317-y
91. Kokori, E., Olatunji, G., Ogieuhi, I. J., Aboje, J. E., Olatunji, D., Aremu, S. A., & Aderinto, N. (2024). Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus. Clinical Diabetes and Endocrinology, 10(1), 23. https://doi.org/10.1186/s40842-024-00181-w
92. Tauschmann, M., & Hovorka, R. (2018). Technology in the management of type 1 diabetes mellitus—current status and future prospects. Nature Reviews Endocrinology, 14(8), 464-475. https://doi.org/10.1038/s41574-018-0044-y
93. Santos, A. S., Cunha Neto, E., Fukui, R. T., Ferreira, L. R., & Silva, M. E. R. (2019). Increased expression of circulating microRNA 101-3p in type 1 diabetes patients: new insights into miRNA-regulated pathophysiological pathways for type 1 diabetes. Frontiers in Immunology, 10, 1637. https://doi.org/10.3389/fimmu.2019.01637
94. Cherney, D. Z., Perkins, B. A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., & von Eynatten, M. (2014). Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation, 129(5), 587-597. https://doi.org/10.1161/CIRCULATIONAHA.113.005081
95. Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023). Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell stem cell, 30(5), 530–548. https://doi.org/10.1016/j.stem.2023.04.002
96. Steffes, M. W., Chavers, B. M., Molitch, M. E., Cleary, P. A., Lachin, J. M., Genuth, S., & Nathan, D. M. (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA: Journal of the American Medical Association, 290(16). https://doi.org/10.1001/jama.290.16.2159
97. Atkinson, M. A., & Eisenbarth, G. S. (2001). Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet (London, England), 358(9277), 221–229. https://doi.org/10.1016/S0140-6736(01)05415-0
98. Boeder, S., & Edelman, S. V. (2019). Sodium‐glucose co‐transporter inhibitors as adjunctive treatment to insulin in type 1 diabetes: A review of randomized controlled trials. Diabetes, Obesity and Metabolism, 21, 62-77. https://doi.org/10.1111/dom.13749
99. Boeder, S. C., Thomas, R. L., Le Roux, M. J., Giovannetti, E. R., Gregory, J. M., & Pettus, J. H. (2025). Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial. Diabetes care, 48(1), 52–60. https://doi.org/10.2337/dc24-0212
100. Mesples, A., Majeed, N., Zhang, Y., & Hu, X. (2013). Early immunotherapy using autologous adult stem cells reversed the effect of anti-pancreatic islets in recently diagnosed type 1 diabetes mellitus: preliminary results. Medical science monitor: International Medical Journal of Experimental and Clinical Research, 19, 852–857. https://doi.org/10.12659/MSM.889525
101. Zhao, Y., Lin, B., Darflinger, R., Zhang, Y., Holterman, M. J., & Skidgel, R. A. (2009). Human cord blood stem cell-modulated regulatory T lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (NOD) mice. Public Library of Science ONE, 4(1), e4226. https://doi.org/10.1371/journal.pone.0004226
102. Gubitosi-Klug, R. A., Lachin, J. M., Backlund, J. Y. C., Lorenzi, G. M., Brillon, D. J., Orchard, T. J., & Diabetes Control and Complications Trial (DCCT. (2016). Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30-Year Follow-up. Diabetes Care, 39(5). https://doi.org/10.2337/dc15-1990
103. George, P., & 1 diabetes. McCrimmon, R. J. (2013). Potential role of non-insulin adjunct therapy in Type Diabetic medicin: A Journal of the British Diabetic Association, 30(2), 179–188. https://doi.org/10.1111/j.1464-5491.2012.03744.x
2. Bluestone, J. A., Herold, K., & Eisenbarth, G. (2010). Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature, 464(7293), 1293-1300. https://www.nature.com/articles/nature08933
3. Hölzen, L., Schultes, B., Meyhöfer, S. M., & Meyhöfer, S. (2024). Hypoglycemia unawareness—a review on pathophysiology and clinical implications. Biomedicines, 12(2), 391. https://www.mdpi.com/2227-9059/12/2/391
4. Hirsch, I. B. (2016). Insulin in America: a right or a privilege? Diabetes Spectrum, 29(3), 130-132. https://diabetesjournals.org/spectrum/article-abstract/29/3/130/32812
5. Pociot, F., & Lernmark, Å. (2016). Genetic risk factors for type 1 diabetes. The Lancet, 387(10035), 2331-2339. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30582-7/abstract
6. Uniyal, P., Panwar, S., Bhatt, A., Marianesan, A. B., Kumar, R., Singh, T. G., & Kumar, B. (2025). An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them. Molecular Diversity, 1-27. https://link.springer.com/article/10.1007/s11030-025-11149-y
7. Herold, K. C., Delong, T., Perdigoto, A. L., Biru, N., Brusko, T. M., & Walker, L. S. (2024). The immunology of type 1 diabetes. Nature Reviews Immunology, 24(6), 435-451. https://www.nature.com/articles/s41577-023-00985-4
8. Lin, T. C., Lacorcia, M., & Mannering, S. I. (2025). Current and Emerging Assays for Measuring Human T-Cell Responses Against Beta-Cell Antigens in Type 1 Diabetes. Biomolecules, 15(3), 384. https://www.mdpi.com/2218-273X/15/3/384
9. Nagy, G., Szekely, T. E., Somogyi, A., Herold, M., & Herold, Z. (2022). New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World journal of diabetes, 13(10), 835. https://pmc.ncbi.nlm.nih.gov/articles/PMC9606789/
10. Zarei, M., Sheikholeslami, M. A., Mozaffari, M., & Mortada, Y. (2024). Innovative Immunotherapies and Emerging Treatments in Type 1 Diabetes Management. Diabetes Epidemiology and Management, 100247. https://www.sciencedirect.com/science/article/pii/S2666970624000519
11. Blok, L., Hanssen, N., Nieuwdorp, M., & Rampanelli, E. (2025). From microbes to metabolites: advances in gut Microbiome research in type 1 diabetes. Metabolites, 15(2), 138. https://www.mdpi.com/2218-1989/15/2/138
12. Calabrese, C. M., Valentini, A., & Calabrese, G. (2021). Gut microbiota and type 1 diabetes mellitus: The effect of Mediterranean diet. Frontiers in nutrition, 7, 612773. https://www.frontiersin.org/articles/10.3389/fnut.2020.612773/full
13. Fattah, H., & Vallon, V. (2018). The potential role of SGLT2 inhibitors in the treatment of type 1 diabetes mellitus. Drugs, 78, 717-726. https://link.springer.com/article/10.1007/s40265-018-0901-y
14. Donath, M. Y., Dinarello, C. A., & Mandrup-Poulsen, T. (2019). Targeting innate immune mediators in type 1 and type 2 diabetes. Nature Reviews Immunology, 19(12), 734-746.https://www.nature.com/articles/s41577-019-0213-9
15. Akil, A. A. S., Yassin, E., Al-Maraghi, A., Aliyev, E., Al-Malki, K., & Fakhro, K. A. (2021). Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. Journal of translational medicine, 19(1), 137. https://link.springer.com/article/10.1186/s12967-021-02778-6
16. DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018). Type 1 diabetes. The Lancet, 391(10138), 2449-2462. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31320-5/abstract
17. Hansen, M. S., Pokharel, P., Piganelli, J., & Sussel, L. (2024). The chicken or the egg dilemma: Understanding the interplay between the immune system and the β cell in type 1 diabetes. Cold Spring Harbor Perspectives in Medicine, a041591. https://perspectivesinmedicine.cshlp.org/content/early/2024/07/01/cshperspect.a041591.short
18. Blaine, J., Chonchol, M., & Levi, M. (2015). Renal control of calcium, phosphate, and magnesium homeostasis. Clinical Journal of the American Society of Nephrology, 10(7), 1257-1272. https://journals.lww.com/CJASN/fulltext/2015/07000/Renal_Control_of_Calcium,_Phosphate,_and_Magnesium.19.aspx
19. Alzhanuly, B., & Sharipov, K. (2024). Latest advancements in the development of new therapies for type 1 diabetes. Bratislava Medical Journal/Bratislavské Lekárske Listy, 125(8). https://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=00069248&AN=179221198&h=I9P3k0i1gA6cY8%2B3ntAzon3zxa9THvYz6bjzFJWeCyHxTnhO%2Fx7riaD7a7MSEl3R58ECdkSQnFnduK17GyAMAQ%3D%3D&crl=c
20. Devendra, D., Liu, E., & Eisenbarth, G. S. (2004). Type 1 diabetes: recent developments. Bmj, 328(7442), 750-754. https://www.bmj.com/content/328/7442/750.short
21. Al-Hawary, S. I. S., Jasim, S. A., Hjazi, A., Ullah, H., Bansal, P., Deorari, M., & Abosaoda, M. K. (2024). A new perspective on therapies involving B-cell depletion in autoimmune diseases. Molecular Biology Reports, 51(1), 629. https://link.springer.com/article/10.1007/s11033-024-09575-6
22. Gouirand, V., Habrylo, I., & Rosenblum, M. D. (2022). Regulatory T cells and inflammatory mediators in autoimmune disease. Journal of Investigative Dermatology, 142(3), 774-780. https://www.sciencedirect.com/science/article/pii/S0022202X21013038
23. Desai, T., & Shea, L. D. (2017). Advances in islet encapsulation technologies. Nature reviews Drug discovery, 16(5), 338-350. https://www.nature.com/articles/nrd.2016.232
24. Kreiner, F. F., von Scholten, B. J., Coppieters, K., & von Herrath, M. (2021). Current state of antigen-specific immunotherapy for type 1 diabetes. Current Opinion in Endocrinology, Diabetes and Obesity, 28(4), 411-418. https://journals.lww.com/co-endocrinology/fulltext/2021/08000/Current_state_of_antigen_specific_immunotherapy.13.aspx?context=LatestArticles
25. Hatipoglu, B., Benedetti, E., & Oberholzer, J. (2005). Islet transplantation: current status and future directions. Current Diabetes Reports, 5(4), 311-316. https://link.springer.com/article/10.1007/s11892-005-0029-9
26. Orban, T., Bundy, B., Becker, D. J., DiMeglio, L. A., Gitelman, S. E., Goland, R., & Skyler, J. S. (2011). Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. The Lancet, 378(9789), 412-419. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60886-6/fulltext?elq=ee57e9cf2dbb44439de1b398de11fe9f
27. Zhang, R., Zhao, Y., Chen, X., Zhuang, Z., Li, X., & Shen, E. (2024). Low-dose IL-2 therapy in autoimmune diseases: An update review. International Reviews of Immunology, 43(3), 113-137. https://www.tandfonline.com/doi/abs/10.1080/08830185.2023.2274574
28. Roep, B. O., Thomaidou, S., Van Tienhoven, R., & Zaldumbide, A. (2021). Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nature Reviews Endocrinology, 17(3), 150-161. https://www.nature.com/articles/s41574-020-00443-4
29. Wu, H., & Mahato, R. I. (2014). Mesenchymal stem cell-based therapy for type 1 diabetes. Discovery medicine, 17(93), 139-143. http://www.discoverymedicine.com/Hao-Wu/2014/03/07/mesenchymal-stem-cell-based-therapy-for-type-1-diabetes/
30. Vignali, D. A., Collison, L. W., & Workman, C. J. (2008). How regulatory T cells work. Nature reviews immunology, 8(7), 523-532. https://www.nature.com/articles/nri2343
31. Lo, K. B., Gul, F., Ram, P., Kluger, A. Y., Tecson, K. M., McCullough, P. A., & Rangaswami, J. (2020). The effects of SGLT2 inhibitors on cardiovascular and renal outcomes in diabetic patients: a systematic review and meta-analysis. Cardiorenal Medicine, 10(1), 1-10. https://karger.com/crm/article/10/1/1/86567
32. Bantounou, M. A., Sardellis, P., Thuemmler, R., Black Boada, D., Kaczmarek, J., Mahmood, R., & Philip, S. (2024). Effect of the dual sodium‐glucose co‐transporter‐1 and‐2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials. Diabetes, Obesity and Metabolism, 26(2), 710-720. https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.15364
33. El Masri, D., Ghosh, S., & Jaber, L. A. (2018). Safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 1 diabetes: A systematic review and meta-analysis. Diabetes Research and Clinical Practice, 137, 83-92. https://www.sciencedirect.com/science/article/pii/S016882271731344X
34. Nongthombam, G. S., Ahmed, S. A., Saikia, K., Gogoi, S., & Borah, J. C. (2025). Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors. RSC Medicinal Chemistry, 16(1), 296-311. https://pubs.rsc.org/en/content/articlehtml/2025/md/d4md00645c
35. Baker, C., Retzik-Stahr, C., Singh, V., Plomondon, R., Anderson, V., & Rasouli, N. (2021). Should metformin remain the first-line therapy for treatment of type 2 diabetes? Therapeutic Advances in Endocrinology and Metabolism, 12, 2042018820980225. https://journals.sagepub.com/doi/abs/10.1177/2042018820980225
36. Forner, P., Snaith, J., & Greenfield, J. R. (2024). Prescribing patterns of adjunctive therapy for the treatment of type 1 diabetes mellitus among Australian endocrinologists. Internal Medicine Journal, 54(5), 779-785. https://onlinelibrary.wiley.com/doi/abs/10.1111/imj.16312
37. Cree-Green, M., Bergman, B. C., Cengiz, E., Fox, L. A., Hannon, T. S., Miller, K., & Nadeau, K. J. (2019). Metformin improves peripheral insulin sensitivity in youth with type 1 diabetes. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3265-3278. https://academic.oup.com/jcem/article-abstract/104/8/3265/5423566
38. Abubaker, S. A., Alonazy, A. M., Abdulrahman, A., Abubaker, S., Alonazy, A., & Albasseet, A. (2022). Effect of alpha-lipoic acid in the treatment of diabetic neuropathy: A systematic review. Cureus, 14(6). https://www.cureus.com/articles/98939-effect-of-alpha-lipoic-acid-in-the-treatment-of-diabetic-neuropathy-a-systematic-review.pdf
39. Baumel-Alterzon, S., Katz, L. S., Lambertini, L., Tse, I., Heidery, F., Garcia-Ocaña, A., & Scott, D. K. (2024). NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function. Diabetologia, 67(3), 547-560. https://link.springer.com/article/10.1007/s00125-023-06071-7
40. dos Santos Haber, J. F., Barbalho, S. M., Sgarbi, J. A., de Argollo Haber, R. S., de Labio, R. W., Laurindo, L. F., ... & Payão, S. L. M. (2023). The relationship between type 1 diabetes mellitus, TNF-α, and IL-10 gene expression. Biomedicines, 11(4), 1120. https://www.mdpi.com/2227-9059/11/4/1120
41. Taneera, J., & Saber-Ayad, M. M. (2024). Preservation of β-cells as a therapeutic strategy for diabetes. Hormone and Metabolic Research, 56(04), 261-271. https://www.thieme-connect.com/products/ejournals/html/10.1055/a-2239-2668
42. Hunckler, M. D., & García, A. J. (2020). Engineered biomaterials for enhanced function of insulin‐secreting β‐cell organoids. Advanced Functional Materials, 30(48), 2000134. https://onlinelibrary.wiley.com/doi/abs/10.1002/adfm.202000134
43. Foster, N. C., Beck, R. W., Miller, K. M., Clements, M. A., Rickels, M. R., DiMeglio, L. A., ... & T1D Exchange Clinic Network. (2019). State of type 1 diabetes management and outcomes from the T1D exchange in 2016–2018. Diabetes Technology & Therapeutics, 21(2), 66-72. https://doi.org/10.1089/dia.2018.0384
44. Lehuen, A., Diana, J., Zaccone, P., & Cooke, A. (2019). Immune cell crosstalk in type 1 diabetes. Nature Reviews Immunology, 19(11), 734–747. https://doi.org/10.1038/s41577-019-0204-2
45. Sherr, J. L., Heinemann, L., & Fleming, G. A. (2022). Glycemic control with hybrid closed-loop insulin delivery: Systematic review. Diabetes Care, 45(2), 368–378. https://doi.org/10.2337/dci21-0024
46. ElSayed, N. A., Aleppo, G., Aroda, V. R., Bannuru, R. R., Brown, F. M., Bruemmer, D., & Gabbay, R. A. (2023). Introduction and methodology: standards of care in diabetes—2023. Diabetes Care, 46(Supplement_1), S1-S4. https://doi.org/10.2337/dc23-Sint
47. Insel, R. A., Dunne, J. L., Atkinson, M. A., Chiang, J. L., Dabelea, D., Gottlieb, P. A.,& Ziegler, A. G. (2015). Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care, 38(10), 1964-1974. https://doi.org/10.2337/dc15-1419
48. Zhao, L., Zhang, F., Ding, X., Wu, G., & Lam, K. S. (2021). Gut microbiota and diabetes: From mechanisms to clinical application. Nature Reviews Endocrinology, 17(10), 615–632. https://doi.org/10.1038/s41574-021-00507-0
49. Knip, M., & Simell, O. (2012). Environmental triggers of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine, 2(7), a007690. https://doi.org/10.1101/cshperspect.a007690
50. Van Belle, T. L., Coppieters, K. T., & von Herrath, M. G. (2011). Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiological Reviews, 91(1), 79–118. https://doi.org/10.1152/physrev.00003.2010
51. Wenzlau, J. M., Juhl, K., Yu, L., Moua, O., Sarkar, S. A., Gottlieb, P., & Hutton, J. C. (2007). The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proceedings of the National Academy of Sciences, 104(43), 17040–17045. https://doi.org/10.1073/pnas.0705894104
52. Herold, K. C., Gitelman, S. E., Ehlers, M. R., Gottlieb, P. A., Greenbaum, C. J., Hagopian, W., & Bluestone, J. A. (2019). Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in new-onset type 1 diabetes in a randomized controlled trial. Science Translational Medicine, 11(484), eaaw0681. https://doi.org/10.1126/scitranslmed.aaw0681
53. Long, S. A., Rieck, M., Sanda, S., Bollyky, P. L., Samuels, P. L., Goland, R., & Buckner, J. H. (2012). Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes, 61(9), 2340–2348. https://doi.org/10.2337/db12-0049
54. Fiorina, P., Vergani, A., Dada, S., Jurewicz, M., Wong, M., Law, K., & Sayegh, M. H. (2008). Targeting CD20+ B-cells restores T-cell homeostasis and insulin production in type 1 diabetes. Diabetes, 57(12), 3013–3024. https://doi.org/10.2337/db08-0332
55. Battaglia, M., Anderson, M. S., Buckner, J. H., Dotta, F., Ferrer, L., Piemonti, L., & Atkinson, M. A. (2017). Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetes, 66(5), 1153–1161. https://doi.org/10.2337/db16-1215
56. Ziegler, A. G., & Nepom, G. T. (2010). Prediction and pathogenesis in type 1 diabetes. Immunity, 32(4), 468–478. https://doi.org/10.1016/j.immuni.2010.03.018
57. Salama, R. A. A., Patni, M. A. M. F., Ba Hutair, S. N. M., Wadid, N. A., & Akikwala, M. S. (2024). Exploring novel treatment modalities for Type 1 diabetes mellitus: Potential and prospects. Healthcare, 12(15), Article 1485. https://doi.org/10.3390/healthcare12151485
58. Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., & Roep, B. O. (2001). Development of type 1 diabetes despite severe hereditary B-cell deficiency. New England Journal of Medicine, 345(14), 1036-1040. https://: doi.org/10.1056/NEJMoa010465
59. Garg, V. (2011). Noninsulin pharmacological management of Type 1 diabetes mellitus. Indian Journal of Endocrinology and Metabolism, 15(Suppl 1), S5–S11. https://doi.org/10.4103/2230-8210.83053
60. Wang, J., Shen, X., He, S., An, Y., Gong, Q., Li, H., & Li, G. (2019). Hypertriglyceridaemia predicts subsequent long‐term risk of cardiovascular events in Chinese adults: 23‐year follow‐up of the Daqing Diabetes Study. Diabetes/Metabolism Research and Reviews, 35(6), e3163.https://doi.org/10.1002/dmrr.3163
61. Lan, N. S., Hong, R. S., Ryan, C., Jenkins, A. J., & Fegan, P. G. (2023). Patient perceptions of cardiovascular risk, lipid management and statins in type 1 diabetes. Primary care diabetes, 17(5), 526-528.https://doi.org/10.1016/j.pcd.2023.07.005
62. Najafipour, M., Najafipour, F., Ostadrahimi, A., Ghavami, M., Razaghi, Z., Tutunchi, H., & Alamdari, N. M. (2024). The effects of empagliflozin in patients with type 1 diabetes: Results of a 12-week, double-blind, randomized, placebo-controlled clinical trial. Health Promotion Perspectives, 14(4), 380-387. https://doi.org/10.34172/hpp.42486
63. Liu, Y., Yang, S., Jiang, A., Zou, D., Chen, Z., & Su, N. (2025). Risk of diabetic ketoacidosis caused by sodium glucose cotransporter-2 inhibitors in patients with type 1 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Frontiers in Endocrinology, 15, 1453067. https://doi.org/10.3389/fendo.2024.1453067
64. Yau, C., & Danska, J. S. (2024). Cracking the type 1 diabetes code: Genes, microbes, immunity, and the early life environment. Immunological Reviews, 325(1), 23-45. https://doi.org/10.1111/imr.13362
65. Leão, I. S., Dantas, J. R., Araújo, D. B., Ramos, M. E. N., Silva, K. R., Batista, L. S., & Rodacki, M. (2024). Evaluation of type 1 diabetes’ partial clinical remission after three years of heterologous adipose tissue derived stromal/stem cells transplantation associated with vitamin D supplementation. Diabetology & Metabolic Syndrome, 16(1), 114. https://doi.org/10.1186/s13098-024-01302-2
66. Millman, J. R., Xie, C., Van Dervort, A., Gürtler, M., Pagliuca, F. W., & Melton, D. A. (2016). Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nature Communications, 7(1), 11463. https://doi.org/10.1038/ncomms11463
67. Hunault, L., & Hesselson, D. (2024). Finishing the odyssey to a stem cell cure for type 1 diabetes. Metabolic Health and Disease, 2(1), 9. https://doi.org/10.1038/s44324-024-00014-5
68. Wang, Y., Chen, Y., McGarrigle, J., Cook, J., Rios, P. D., La Monica, G., & Oberholzer, J. (2025). Cell Therapy for T1D Beyond BLA: Gearing Up Toward Clinical Practice. Diabetes Therapy, 1-14. https://doi.org/10.1007/s13300-025-01732-9
69. Murri, M., Leiva, I., Gomez-Zumaquero, J. M., Tinahones, F. J., Cardona, F., Soriguer, F., & Queipo-Ortuño, M. I. (2013). Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BioMed Central Medicine, 11, 1-12. https://doi.org/10.1186/1741-7015-11-46
70. Marino, E., Richards, J. L., McLeod, K. H., Stanley, D., Yap, Y. A., Knight, J., & Mackay, C. R. (2017). Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nature Immunology, 18(5), 552-562. https://doi.org/10.1038/ni.3713
71. Vatanen, T., Franzosa, E. A., Schwager, R., Tripathi, S., Arthur, T. D., Vehik, K., & Xavier, R. J. (2018). The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature, 562(7728), 589-594. https://doi.org/10.1038/s41586-018-0620-2
72. Wszoła, M., Nitarska, D., Cywoniuk, P., Gomółka, M., & Klak, M. (2021). Stem cells as a source of pancreatic cells for production of 3D bioprinted bionic pancreas in the treatment of type 1 diabetes. Cells, 10(6), 1544. https://doi.org/10.3390/cells10061544
73. Antonio-Villa, N. E., García-Tuomola, A., Almeda-Valdes, P., Vidrio-Velázquez, M., Islas-Ortega, L., Madrigal-Sanromán, J. R., & RENACED-DT1 Research Group. (2021). Glycemic control, treatment and complications in patients with type 1 diabetes amongst healthcare settings in Mexico. Diabetes Research and clinical practice, 180, 109038. https://doi.org/10.1016/j.diabres.2021.109038
74. Zhang, Q., Gonelle-Gispert, C., Li, Y., Geng, Z., Gerber-Lemaire, S., Wang, Y., & Buhler, L. (2022). Islet encapsulation: new developments for the treatment of type 1 diabetes. Frontiers in Immunology, 13, 869984. https://doi.org/10.3389/fimmu.2022.869984
75. Monami, M., Nreu, B., Zannoni, S., Lualdi, C., & Mannucci, E. (2017). Effects of SGLT-2 inhibitors on diabetic ketoacidosis: a meta-analysis of randomised controlled trials. Diabetes Research and Clinical Practice, 130, 53-60. https://doi.org/10.1016/j.diabres.2017.04.017
76. Mathieu, C., Rudofsky, G., Phillip, M., Araki, E., Lind, M., Arya, N., & Dandona, P. (2020). Long‐term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT‐2 study): 52‐week results from a randomized controlled trial. Diabetes, Obesity and Metabolism, 22(9), 1516-1526. https://doi.org/10.1111/dom.14060
77. Bjornstad, P., Schäfer, M., Truong, U., Cree-Green, M., Pyle, L., Baumgartner, A., & Nadeau, K. J. (2018). Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus: randomized controlled trial. Circulation, 138(25), 2895-2907. https://doi.org/10.1161/CIRCULATIONAHA.118.035525
78. Araki, E., Mathieu, C., Shiraiwa, T., Maeda, H., Ikeda, H., Thoren, F., & Iqbal, N. (2021). Long‐term (52‐week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT‐2 study. Diabetes, Obesity and Metabolism, 23(7), 1496-1504. https://doi.org/10.1111/dom.14362
79. Ma, J., Zhao, Y., Fan, H., & Liu, J. (2021). The efficacy of dapagliflozin for type 1 diabetes: a meta-analysis of randomized controlled studies. African Health Sciences, 21(1), 1–7. https://doi.org/10.4314/ahs.v21i1.2
80. Lund, S. S., Tarnow, L., Astrup, A. S., Hovind, P., Jacobsen, P. K., Alibegovic, A. C., Parving, I., Pietraszek, L., Frandsen, M., Rossing, P., Parving, H. H., & Vaag, A. A. (2008). Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. Public Library of Science ONE, 3(10), e3363. https://doi.org/10.1371/journal.pone.0003363
81. Lacigova, S., Rusavý, Z., Jankovec, Z., & Kyselova, P. (2001). Metformin in the treatment of type 1 diabetics--a placebo controlled study. Casopis Lekaru Ceskych, 140(10), 302-306. PMID: 11411059.
82. Scaramuzza, A., Giani, E., Redaelli, F., Ungheri, S., Macedoni, M., Giudici, V., Bosetti, A., Ferrari, M., & Zuccotti, G. V. (2015). Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial Dysfunction in Adolescents with Type 1 Diabetes: A Pilot Trial. Journal of Diabetes Research, 2015, 474561. https://doi.org/10.1155/2015/474561
83. Ding, Q., Sun, B., Wang, M., Li, T., Li, H., Han, Q., & Tang, Z. (2023). N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway. Life Sciences, 329, 121975. https://doi.org/10.1016/j.lfs.2023.121975
84. Musso, G., Sircana, A., Saba, F., Cassader, M., & Gambino, R. (2020). Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: a meta-analysis and meta-regression. Public Library of Science ONE medicine, 17(12), e1003461. https://doi.org/10.1371/journal.pmed.1003461
85. Danne, T., Garg, S., Peters, A. L., Buse, J. B., Mathieu, C., Pettus, J. H., & Phillip, M. (2019). International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium–glucose cotransporter (SGLT) inhibitors. Diabetes Care, 42(6), 1147-1154. https://doi.org/10.2337/dc18-2316
86. Holt, R. I., DeVries, J. H., Hess-Fischl, A., Hirsch, I. B., Kirkman, M. S., Klupa, T., & Peters, A. L. (2021). The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 44(11), 2589-2625. https://doi.org/10.2337/dci21-0043
87. Butrym, M., Byvald, F., Blanter, M., Ringqvist, E. E., Vasylovska, S., Marjomäki, V., & Flodström-Tullberg, M. (2024). Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells. Antiviral Research, 231, 106021. https://doi.org/10.1016/j.antiviral.2024.105527
88. Roy, S., Pokharel, P., & Piganelli, J. D. (2024). Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes. Molecular Metabolism, 101998. https://doi.org/10.1016/j.molmet.2024.101826
89. Collins, J., & Farnsworth, N. L. (2025). Active targeting of type 1 diabetes therapies to pancreatic beta cells using nanocarriers. Diabetologia, 1-12. https://doi.org/10.1007/s00125-024-06356-5
90. Keymeulen, B., van Maurik, A., Inman, D., Oliveira, J., McLaughlin, R., Gittelman, R. M., & Napolitano, A. (2021). A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes. Diabetologia, 64, 313-324. https://doi.org/10.1007/s00125-020-05317-y
91. Kokori, E., Olatunji, G., Ogieuhi, I. J., Aboje, J. E., Olatunji, D., Aremu, S. A., & Aderinto, N. (2024). Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus. Clinical Diabetes and Endocrinology, 10(1), 23. https://doi.org/10.1186/s40842-024-00181-w
92. Tauschmann, M., & Hovorka, R. (2018). Technology in the management of type 1 diabetes mellitus—current status and future prospects. Nature Reviews Endocrinology, 14(8), 464-475. https://doi.org/10.1038/s41574-018-0044-y
93. Santos, A. S., Cunha Neto, E., Fukui, R. T., Ferreira, L. R., & Silva, M. E. R. (2019). Increased expression of circulating microRNA 101-3p in type 1 diabetes patients: new insights into miRNA-regulated pathophysiological pathways for type 1 diabetes. Frontiers in Immunology, 10, 1637. https://doi.org/10.3389/fimmu.2019.01637
94. Cherney, D. Z., Perkins, B. A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., & von Eynatten, M. (2014). Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation, 129(5), 587-597. https://doi.org/10.1161/CIRCULATIONAHA.113.005081
95. Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023). Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell stem cell, 30(5), 530–548. https://doi.org/10.1016/j.stem.2023.04.002
96. Steffes, M. W., Chavers, B. M., Molitch, M. E., Cleary, P. A., Lachin, J. M., Genuth, S., & Nathan, D. M. (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA: Journal of the American Medical Association, 290(16). https://doi.org/10.1001/jama.290.16.2159
97. Atkinson, M. A., & Eisenbarth, G. S. (2001). Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet (London, England), 358(9277), 221–229. https://doi.org/10.1016/S0140-6736(01)05415-0
98. Boeder, S., & Edelman, S. V. (2019). Sodium‐glucose co‐transporter inhibitors as adjunctive treatment to insulin in type 1 diabetes: A review of randomized controlled trials. Diabetes, Obesity and Metabolism, 21, 62-77. https://doi.org/10.1111/dom.13749
99. Boeder, S. C., Thomas, R. L., Le Roux, M. J., Giovannetti, E. R., Gregory, J. M., & Pettus, J. H. (2025). Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial. Diabetes care, 48(1), 52–60. https://doi.org/10.2337/dc24-0212
100. Mesples, A., Majeed, N., Zhang, Y., & Hu, X. (2013). Early immunotherapy using autologous adult stem cells reversed the effect of anti-pancreatic islets in recently diagnosed type 1 diabetes mellitus: preliminary results. Medical science monitor: International Medical Journal of Experimental and Clinical Research, 19, 852–857. https://doi.org/10.12659/MSM.889525
101. Zhao, Y., Lin, B., Darflinger, R., Zhang, Y., Holterman, M. J., & Skidgel, R. A. (2009). Human cord blood stem cell-modulated regulatory T lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (NOD) mice. Public Library of Science ONE, 4(1), e4226. https://doi.org/10.1371/journal.pone.0004226
102. Gubitosi-Klug, R. A., Lachin, J. M., Backlund, J. Y. C., Lorenzi, G. M., Brillon, D. J., Orchard, T. J., & Diabetes Control and Complications Trial (DCCT. (2016). Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30-Year Follow-up. Diabetes Care, 39(5). https://doi.org/10.2337/dc15-1990
103. George, P., & 1 diabetes. McCrimmon, R. J. (2013). Potential role of non-insulin adjunct therapy in Type Diabetic medicin: A Journal of the British Diabetic Association, 30(2), 179–188. https://doi.org/10.1111/j.1464-5491.2012.03744.x
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Sep 30, 2026
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Govind, Pooja Sinoriya, Aditya Mathur, Pooja, Arti Sinoria, & Tina Bhardwaj. (2026). BEYOND INSULIN: EXPLORING NON-HORMONAL THERAPEUTIC PATHWAYS FOR TYPE 1 DIABETES MANAGEMENT. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 2251-2275. https://doi.org/10.69980/3p1w7677
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Author Biographies
Govind
SGT College of Pharmacy, SGT University, Gurugram, Haryana 122505
Pooja Sinoriya
B.M. College of Pharmacy, Farukhnagar, Gurugram, Haryana 122506
Aditya Mathur
B.M. College of Pharmacy, Farukhnagar, Gurugram, Haryana 122506
Pooja
World College of Pharmaceutical Sciences, Girawar, Jhajjar, Haryana 124103
Arti Sinoria
Goel Institute of Pharmacy and Sciences, Lucknow, Uttar Pradesh 226028
Tina Bhardwaj
B.M. College of Pharmacy, Farukhnagar, Gurugram, Haryana 122506
How to Cite
Govind, Pooja Sinoriya, Aditya Mathur, Pooja, Arti Sinoria, & Tina Bhardwaj. (2026). BEYOND INSULIN: EXPLORING NON-HORMONAL THERAPEUTIC PATHWAYS FOR TYPE 1 DIABETES MANAGEMENT. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 2251-2275. https://doi.org/10.69980/3p1w7677
