Emerging therapeutic strategies for type 1 diabetes

Modern medical research identifies type 1 diabetes mellitus (T1D) as one of the most pressing global health challenges, with the incidence steadily increasing by up to 500,000 new cases annually. Current treatment approaches do not provide optimal glycemic control, as they are mainly aimed at compensating for endogenous insulin deficiency, which can significantly compromise patients’ quality of life. For a long time, researchers have sought a treatment strategy capable of achieving a rapid, safe, and reliable cure for T1D. Yet, due to the insufficient understanding of the mechanisms driving the autoimmune response underlying this condition, modern medicine has not been able to develop an etiotropic therapy that could ensure complete recovery. A wide range of therapeutic developments targeting different pathogenetic mechanisms of T1D are currently underway, all aimed at supporting optimal glucose metabolism. Their objectives include preventing or slowing disease progression (delaying the onset of the clinical stage) and facilitating glycemic control in affected patients. Despite substantial progress, none of these innovative strategies has yet reached widespread clinical application. The primary obstacles remain the lengthy timelines required to complete full cycles of clinical trials and the need to address limitations revealed during the research process. This review presents the leading modern approaches to T1DM therapy, with a focus on insulin therapy, immunotherapy, and cell-based strategies. Clinical trial data are analyzed, highlighting both advantages and limitations from practical and economic perspectives. The approaches discussed represent the most promising avenues and are expected to play a central role in future treatment of T1DM.

1. Taranushenko TE, Proskurina MV. A Modern View on the Issues of Epidemiology and Manifestation of Type 1 Diabetes Mellitus in Pediatrics. Doktor.Ru. 2024; 23 (3): 55–61. (In Russ.). doi: 10.31550/1727-2378-2024-23-3-55-61.

2. Dedov II, Shestakova MV, Vikulova OK, Zheleznyakova AV, Isakov MA, Sazonova DV, Mokrysheva NG. Diabetes mellitus in the Russian Federation: dynamics of epidemiological indicators according to the Federal Register of Diabetes Mellitus for the period 2010–2022. Diabetes mellitus. 2023; 26 (2): 104–123. doi: 10.14341/DM13035.

3. Diaz C JL, Colmegna P, Breton MD. Maximizing Glycemic Benefits of Using Faster Insulin Formulations in Type 1 Diabetes: In Silico Analysis Under Open- and Closed-Loop Conditions. Diabetes Technol Ther. 2023 Apr; 25 (4): 219–230. doi: 10.1089/dia.2022.0468.

4. Kjeldsen TB, Hubálek F, Hjørringgaard CU, Tagmose TM, Nishimura E, Stidsen CE et al. Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans. J Med Chem. 2021 Jul 8; 64 (13): 8942–8950. doi: 10.1021/acs.jmedchem.1c00257.

5. Philis-Tsimikas A, Bajaj HS, Begtrup K, Cailleteau R, Gowda A, Lingvay I et al. Rationale and design of the phase 3a development programme (ONWARDS 1–6 trials) investigating once-weekly insulin icodec in diabetes. Diabetes Obes Metab. 2023 Feb; 25 (2): 331–341. doi: 10.1111/dom.14871.

6. Bergenstal RM, Weinstock RS, Mathieu C, Onishi Y, Vijayanagaram V, Katz ML et al. Once-weekly insulin efsitora alfa versus once-daily insulin degludec in adults with type 1 diabetes (QWINT-5): a phase 3 randomised non-inferiority trial. Lancet. 2024 Sep 21; 404 (10458): 1132–1142. doi: 10.1016/S0140-6736(24)01804-X.

7. Hunt NJ, Lockwood GP, Heffernan SJ, Daymond J, Ngu M, Narayanan RK et al. Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia. Nat Nanotechnol. 2024 Apr; 19 (4): 534–544. doi: 10.1038/s41565-023-01565-2.

8. Ji K, Wei X, Kahkoska AR, Zhang J, Zhang Y, Xu J et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat Nanotechnol. 2024 Dec; 19 (12): 1880–1891. doi: 10.1038/s41565-024-01764-5.

9. Nwokolo M, Hovorka R. The Artificial Pancreas and Type 1 Diabetes. J Clin Endocrinol Metab. 2023 Jun 16; 108 (7): 1614–1623. doi: 10.1210/clinem/dgad068.

10. Schoelwer MJ, Kanapka LG, Wadwa RP, Breton MD, Ruedy KJ, Ekhlaspour L et al. Predictors of Time-inRange (70–180 mg/dL) Achieved Using a Closed-Loop Control System. Diabetes Technol Ther. 2021 Jul; 23 (7): 475–481. doi: 10.1089/dia.2020.0646.

11. Ametov AS, Pashkova EYu, Solovyeva UD, Mitchenko YuI. Natural hostages of artificial intelligence: clinical case of severe hypoglycemic state using an open source closed loop automated insulin delivery systems. Endokrinologiya: novosti, mneniya, obuchenie [Endocrinology: News, Opinions, Training]. 2024; 13 (4): 117–123. (In Russ.). doi: 10.33029/23049529-2024-13-4-117-123.

12. Jiao X, Shen Y, Chen Y. Better TIR, HbA1c, and less hypoglycemia in closed-loop insulin system in patients with type 1 diabetes: a meta-analysis. BMJ Open Diabetes Res Care. 2022 Apr; 10 (2): e002633. doi: 10.1136/bmjdrc-2021-002633.

13. Zeng B, Jia H, Gao L, Yang Q, Yu K, Sun F. Dual-hormone artificial pancreas for glucose control in type 1 diabetes: A meta-analysis. Diabetes Obes Metab. 2022 Oct; 24 (10): 1967–1975. doi: 10.1111/dom.14781.

14. Kurkin DV, Bakulin DA, Robertus AI, Kolosov YuA, Krysanov IS, Morkovin EI et al. Evolution of insulin therapy: past, present, future. Problems of Endocrinology. 2023; 69 (6): 86–101. [In Russ.]. doi: 10.14341/probl13251.

15. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y et al. An ingestible selforienting system for oral delivery of macromolecules. Science. 2019 Feb 8; 363 (6427): 611–615. doi: 10.1126/science.aau2277.

16. McGill JB, Weiss D, Grant M, Jones MC, Kendall DM, Hoogwerf BJ. Understanding inhaled Technosphere Insulin: Results of an early randomized trial in type 1 diabetes mellitus. J Diabetes. 2021 Feb; 13 (2): 164–172. doi: 10.1111/1753-0407.13099.

17. Hirsch IB, Beck RW, Marak MC, Calhoun P, Mottalib A, Salhin A et al. A Randomized Comparison of Postprandial Glucose Excursion Using Inhaled Insulin Versus Rapid-Acting Analog Insulin in Adults With Type 1 Diabetes Using Multiple Daily Injections of Insulin or Automated Insulin Delivery. Diabetes Care. 2024 Sep 1; 47 (9): 1682–1687. doi: 10.2337/dc24-0838.

18. Kaiserman KB, Christiansen M, Bhavsar S, Ulloa J, Santogatta B, Hanna J, Bailey TS. Reduction in Postprandial Peak Glucose With Increased Technosphere Insulin Dosage. J Diabetes Sci Technol. 2024 Mar; 18 (2): 397–401. doi: 10.1177/19322968221110622.

19. Hua S. Advances in nanoparticulate drug delivery approaches for sublingual and buccal administration. Front Pharmacol. 2019 Nov 5; 10: 1328. doi: 10.3389/fphar.2019.01328.

20. Limenh LW, Worku NK, Melese M, Esubalew D, Fenta ET, Hailu M et al. Effectiveness, safety, and preference of transdermal insulin compared to subcutaneous insulin in the treatment of diabetes patients: a systematic review of clinical trials. Diabetol Metab Syndr. 2024 Aug 17; 16 (1): 197. doi: 10.1186/s13098-024-01442-5.

21. Xue J, Shi Y, Li C, Xu X, Xu S, Cao M. Methylcellulose and polyacrylate binary hydrogels used as rectal suppository to prevent type I diabetes. Colloids Surfaces B Biointerfaces. 2018 Dec 1; 172: 37–42. doi: 10.1016/j.colsurfb.2018.08.021.

22. Matsumoto A, Murakami K, Watanabe C, Murakami M. Improved systemic delivery of insulin by condensed drug loading in a dimpled suppository. Drug Discov Ther. 2017; 11 (6): 293–299. doi: 10.5582/ddt.2017.01072.

23. Edgerton DS, Scott M, Farmer B, Williams PE, Madsen P, Kjeldsen T et al. Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery. JCI Insight. 2019 Feb 26; 5 (7): e126974. doi: 10.1172/jci.insight.126974.

24. Bode BW, Weinstock RS, Gard SK, Klonoff DC, Singh KK, Muchmore DB et al. 111-LB: Hepatic Insulin Delivery to Minimize Hypoglycemic Events in Persons with Type 1 Diabetes: The OPTI-1 Study. Diabetes. 2020 Jun 1; 69 (Suppl 1): 111-LB. doi: 10.2337/db20-111-LB.

25. Laptev DN, Dedov II. Towards prevention of type 1 diabetes: FDA approved first drug with potential to delay clinical stage of disease. Diabetes mellitus. 2022; 25 (6): 576–579. [In Russ.]. doi: 10.14341/DM12988.

26. Harsunen M, Haukka J, Harjutsalo V, Mars N, Syreeni A, Härkönen T et al. Residual insulin secretion in individuals with type 1 diabetes in Finland: longitudinal and cross-sectional analyses. Lancet Diabetes Endocrinol. 2023 Jul; 11 (7): 465–473. doi: 10.1016/S22138587(23)00123-7.

27. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+) CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005 Jan; 54 (1): 92–99. doi: 10.2337/diabetes.54.1.924.

28. Volfson-Sedletsky V, Jones A IV, Hernandez-Escalante J, Dooms H. Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes. Front Immunol. 2021 Mar 18; 12: 635767. doi: 10.3389/fimmu.2021.635767.

29. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25; 7 (315): 315ra189. doi: 10.1126/scitranslmed.aad4134.

30. Marek-Trzonkowska N, Myśliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juścińska J et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up. Clin Immunol. 2014 Jul; 153 (1): 23–30. doi: 10.1016/j.clim.2014.03.016.

31. Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH et al. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021 Sep 22; 6 (18): e147474. doi: 10.1172/jci.insight.147474.

32. Pharmaceutical-technology.com [Internet]. EASD 2024: PolTREG’s T-cell therapy shows long-term remission in type 1 diabetes. Available from: https://www.pharmaceutical-technology.com/news/easd2024-poltregs-tcell-therapy-shows-long-term-remission-in-type-1-diabetes/.

33. Mathew JM, Voss JH, McEwen ST, Konieczna I, Chakraborty A, Huang X et al. Generation and Characterization of Alloantigen-Specific Regulatory T Cells For Clinical Transplant Tolerance. Sci Rep. 2018 Jan 18; 8 (1): 1136. doi: 10.1038/s41598-018-19621-6.

34. De Geest BG. Engineering the immune system with particles, step-by-step. Mol Immunol. 2018 Jun; 98: 25–27. doi: 10.1016/j.molimm.2018.02.015.

35. Dul M, Nikolic T, Stefanidou M, McAteer MA, Williams P, Mous J et al. Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen speci fi c immunotherapy. Int J Pharm. 2019 May 1; 562: 303–312. doi: 10.1016/j.ijpharm.2019.03.041.

36. Takiishi T, Cook DP, Korf H, Sebastiani G, Mancarella F, Cunha JP et al. Reversal of Diabetes in NOD Mice by Clinical-Grade Proinsulin and IL-10 – Secreting Lactococcus lactis in Combination With Low-Dose Anti-CD3 Depends on the Induction of Foxp3-Positive T Cells. Diabetes. 2017 Feb; 66 (2): 448–459. doi: 10.2337/db151625.

37. Mathieu C, Wiedeman A, Cerosaletti K, Long SA, Serti E, Cooney L et al. AG019-T1D-101 Trial Investigators. A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab. Diabetologia. 2024 Jan; 67 (1): 27–41. doi: 10.1007/s00125-023-06014-2.

38. Nowak C, Lind M, Sumnik Z, Pelikanova T, NatteroChavez L, Lundberg E et al. Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. J Clin Endocrinol Metab. 2022 Aug 18; 107 (9): 2644–2651. doi: 10.1210/clinem/dgac343.

39. Casas R, Dietrich F, Puente-Marin S, Barcenilla H, Tavira B, Wahlberg J et al. Intra-lymphatic administration of GAD-alum in type 1 diabetes: long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial). Acta Diabetol. 2022 May; 59 (5): 687–696. doi: 10.1007/s00592-022-01852-9.

40. Van Rampelbergh J, Achenbach P, Leslie RD, Kindermans M, Parmentier F, Carlier V et al. First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes: an exploratory analysis of immune biomarkers. BMC Med. 2024 Jun 21; 22 (1): 259. doi: 10.1186/s12916024-03476-y.

41. Van Rampelbergh J, Achenbach P, Leslie R, Ali MA, Dayan C, Keymeulen B et al. First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes. BMC Med. 2023 May 24; 21 (1): 190. doi: 10.1186/s12916-02302900-z.

42. Ramos EL, Dayan CM, Chatenoud L, Sumnik Z, Simmons KM, Szypowska A et al. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med. 2023 Dec 7; 389 (23): 2151–2161. doi: 10.1056/NEJMoa2308743.

43. Long SA, Thorpe J, DeBerg HA, Gersuk V, Eddy J, Harris KM et al. Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes. Sci Immunol. 2016 Nov; 1 (5): eaai7793. doi: 10.1126/sciimmunol.aai7793.

44. Herold KC, Gitelman SE, Gottlieb PA, Knecht LA, Raymond R, Ramos EL. Teplizumab: A Disease-Modifying Therapy for Type 1 Diabetes That Preserves β-Cell Function. Diabetes Care. 2023 Oct 1; 46 (10): 1848–1856. doi: 10.2337/dc23-0675.

45. Zagainov VЕ, Meleshina AV, Korneva КG, Vasenin SА, Zagaynova EV. Transplantation technologies for treatment of carbohydrate metabolism disorders. Russian Journal of Transplantology and Artificial Organs. 2020; 22 (1): 184–195. doi: 10.15825/19951191-2020-1-184-195.

46. Wang S, Du Y, Zhang B, Meng G, Liu Z, Liew SY et al. Transplantation of chemically induced pluripotent stemcell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell. 2024 Oct 31; 187 (22): 6152–6164.e18. doi: 10.1016/j.cell.2024.09.004.

47. Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature. 2022 May; 605 (7909): 325–331. doi: 10.1038/s41586-022-04593-5.

48. Wu J, Li T, Guo M, Ji J, Meng X, Fu T et al. Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue. Cell Discov. 2024 Apr 30; 10 (1): 45. doi: 10.1038/s41421-024-00662-3.

49. Reichman TW, Ricordi C, Naji A, Markmann JF, Perkins BA, Wijkstrom M et al. 836-P: Glucose-Dependent Insulin Production and Insulin-Independence in Type 1 Diabetes from Stem Cell–Derived, Fully Differentiated Islet Cells – Updated Data from the VX-880 Clinical Trial. Diabetes. 2023 Jun 23; 72 (Suppl 1): 836-P. doi: 10.2337/db23-836-P.

50. Ermakova PS, Cherkasova EI, Lenshina NA, Konev AN, Batenkin MA, Chesnokov SA et al. Modern pancreatic islet encapsulation technologies for the treatment of type 1 diabetes. Russian Journal of Transplantology and Artificial Organs. 2021; 23 (4): 95–109. doi: 10.15825/19951191-2021-4-95-109.

51. Ermakova P, Vasilchikova E, Baten’kin M, Bogomolova A, Konev A, Anisimova N et al. Probing of New Polymer-Based Microcapsules for Islet Cell Immunoisolation. Polymers (Basel). 2024 Aug 30; 16 (17): 2479. doi: 10.3390/polym16172479.

52. Sernova.com [Internet]. Sernova Announces New Positive Data from Phase I/II Trial Regarding Islet Survival and Function. Available from: https://sernova.com/press_releases/sernova-announces-new-positive-datafrom-phase-i-ii-trial-regarding-islet-survival-and-function/.

53. Sernova.com [Internet]. Sernova Announces New Advancements of Conformal Coating Technology in Combination with the Cell Pouch System™ at the 2023 IPITA-IXA-CTRMS Joint Congress. Available from: https://sernova.com/press_releases/sernova-announcesnew-advancements-of-conformal-coating-technologyin-combination-with-the-cell-pouch-system-at-the2023-ipita-ixa-ctrms-joint-congress/.

54. Diatribe.org [Internet]. Vertex Releases New Data on Potential Cure for Type 1 Diabetes. Available from: https://diatribe.org/diabetes-medications/vertex-releases-newdata-potential-cure-type-1-diabetes.

55. Diatribe.org [Internet]. Deal Boosts Gene-Editing Technology Aiming to Cure Type 1 Diabetes. Available from: https://diatribe.org/diabetes-research/deal-boosts-geneediting-technology-aiming-cure-type-1-diabetes.

56. Diatribe.org [Internet]. ViaCyte and CRISPR Introduce New Stem Cell Therapy for Type 1 Diabetes. Available from: https://diatribe.org/diabetes-research/viacyte-andcrispr-introduce-new-stem-cell-therapy-type-1-diabetes.

57. Hu X, White K, Young C, Olroyd AG, Kievit P, Connolly AJ et al. Hypoimmune islets achieve insulin independence after allogeneic transplantation in a fully immunocompetent non-human primate. Cell Stem Cell. 2024 Mar 7; 31 (3): 334–340.e5. doi: 10.1016/j.stem.2024.02.001.

58. Ir.sana.com [Internet]. Sana Biotechnology Announces Positive Clinical Results from Type 1 Diabetes Study of Islet Cell Transplantation Without Immunosuppression. Available from: https://ir.sana.com/news-releases/newsrelease-details/sana-biotechnology-announces-positiveclinical-results-type-1.

59. Diabetesvoice.org [Internet]. Can nanosensor technology and stem cell transplants revolutionise type 1 diabetes treatment? Available from: https://diabetesvoice.org/en/caring-for-diabetes/nanosensor-technology-and-stemcell-transplants/.

60. Soetedjo AAP, Lee JM, Lau HH, Goh GL, An J, Koh Y et al. Tissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes. Trends Endocrinol Metab. 2021 Aug; 32 (8): 609–622. doi: 10.1016/j.tem.2021.05.007.

61. Klak M, Łojszczyk I, Berman A, Tymicki G, AdamiokOstrowska A, Sierakowski M et al. Impact of Porcine Pancreas Decellularization Conditions on the Quality of Obtained dECM. Int J Mol Sci. 2021 Jun 29; 22 (13): 7005. doi: 10.3390/ijms22137005.

62. Ponomareva AS, Kirsanova LA, Baranova NV, Surguchenko VA, Bubentsova GN, Basok YuB et al. Decellularization of donor pancreatic fragment to obtain a tissue-specific matrix scaffold. Russian Journal of Transplantology and Artificial Organs. 2020; 22 (1): 123–133. doi: 10.15825/1995-1191-20201-123-133.

63. Skaletskaya GN, Skaletskiy NN, Kirsanova LA, Bubentsova GN, Sevastianov VI. Intrasplenic implantation of tissue-engineered pancreatic construct in experimental diabetic rats. Russian Journal of Transplantology and Artificial Organs. 2020; 22 (1): 134–141. doi: 10.15825/1995-1191-2020-1-134-141.

64. Baranova NV, Ponomareva AS, Kirsanova LA, Nikolskaya AO, Bubentsova GN, Basok YuB, Sevastianov VI. Functional efficiency of pancreatic cell-engineered construct in an animal experimental model for type I diabetes. Russian Journal of Transplantology and Artificial Organs. 2024; 26 (2): 94–104. doi: 10.15825/1995-1191-2024-2-94-104.

65. Eledon.com [Internet]. TEGOPRUBART’s Multiple Mechanisms of Action Could Help Effectively Manage Immune Response. Available from: https://eledon.com/science/mechanism-of-action/.

66. Breakthrought1d.org [Internet]. Eledon Pharmaceuticals Announces Positive Initial Data from Subjects with Type 1 Diabetes Treated with Tegoprubart as Part of an Immunosuppression Regimen Following Islet Transplantation in Investigator-Initiated Trial at UChicago Medicine. Available from: https://www.breakthrought1d.org/for-the-media/press-releases/eledon-pharmaceuticalsannounces-positive-initial-data-from-subjects-withtype-1-diabetes-treated-with-tegoprubart-as-part-of-animmunosuppression-regimen-following/.