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2000
Volume 1, Issue 1
  • ISSN: 2949-902X
  • E-ISSN: 2949-9011

Abstract

In autoimmune diabetes, the body's immune system attacks and destroys pancreatic beta cells, leading to a complete loss of insulin production. As a result, individuals with this condition require lifelong external insulin therapy. Recent advancements in diabetes treatment have focused on strategies to preserve and regenerate beta cell mass, making this an important area for research. Beyond its role in insulin biosynthesis, C-peptide has gained attention for its physiological effects, which extend beyond simply being a byproduct of insulin production. This review explores the structure and function of C-peptide, its potential impact on autoimmune processes in Type 1 diabetes, and its ability to stimulate beta cell regeneration. Additionally, we discuss the mechanisms by which C-peptide protects beta cell function, counteracts the harmful effects of pro-inflammatory cytokines, and modulates immune responses. Clinical trials have provided promising evidence that C-peptide supplementation can lead to improved clinical outcomes, including enhanced insulin secretion, better beta cell function, and a reduction in diabetes-related complications. This article also examines the potential for C-peptide therapy to become a standard treatment option for autoimmune diabetes, either as a standalone therapy or in combination with other treatments aimed at modulating the immune system and promoting beta cell regeneration. By providing insights into the multiple therapeutic roles of C-peptide, this review aims to help readers understand its potential as a valuable tool in diabetes management and its broader implications for controlling autoimmune diabetes.

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2025-08-07
2025-12-31
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References

  1. LiuJ. TingJ.P. Al-AzzamS. DingY. AfsharS. Therapeutic advances in diabetes, autoimmune, and neurological diseases.Int. J. Mol. Sci.2021226280510.3390/ijms2206280533802091
    [Google Scholar]
  2. HedeskovC.J. Mechanism of glucose-induced insulin secretion.Physiol. Rev.198060244250910.1152/physrev.1980.60.2.4426247727
    [Google Scholar]
  3. SzablewskiL. Role of immune system in type 1 diabetes mellitus pathogenesis.Int. Immunopharmacol.201422118219110.1016/j.intimp.2014.06.03324993340
    [Google Scholar]
  4. BolliG.B. FanelliC.G. Physiology of glucose counterregulation to hypoglycemia.Endocrinol. Metab. Clin. North Am.199928346749310.1016/S0889‑8529(05)70083‑910500926
    [Google Scholar]
  5. AnnicchiaricoA. BarileB. BuccolieroC. NicchiaG.P. BrunettiG. Alternative therapeutic strategies in diabetes management.World J. Diabetes20241561142116110.4239/wjd.v15.i6.114238983831
    [Google Scholar]
  6. MaddaloniE. BolliG.B. FrierB.M. LittleR.R. LeslieR.D. PozzilliP. BuzzettiR. C‐peptide determination in the diagnosis of type of diabetes and its management: A clinical perspective.Diabetes Obes. Metab.202224101912192610.1111/dom.1478535676794
    [Google Scholar]
  7. WahrenJ. EkbergK. JörnvallH. C-peptide is a bioactive peptide.Diabetologia200750350350910.1007/s00125‑006‑0559‑y17235526
    [Google Scholar]
  8. SimB.C. KangY.E. YouS.K. LeeS.E. NgaH.T. LeeH.Y. NguyenT.L. MoonJ.S. TianJ. JangH.J. LeeJ.E. YiH.S. Hepatic T-cell senescence and exhaustion are implicated in the progression of fatty liver disease in patients with type 2 diabetes and mouse model with nonalcoholic steatohepatitis.Cell Death Dis.202314961810.1038/s41419‑023‑06146‑837735474
    [Google Scholar]
  9. JonesA.G. HattersleyA.T. The clinical utility of C‐peptide measurement in the care of patients with diabetes.Diabet. Med.201330780381710.1111/dme.1215923413806
    [Google Scholar]
  10. SteinerD.F. The proinsulin C-peptide--A multirole model.Exp. Diabesity Res.20045171410.1080/1543860049042438915198367
    [Google Scholar]
  11. MayerJ.P. ZhangF. DiMarchiR.D. Insulin structure and function.Biopolymers200788568771310.1002/bip.2073417410596
    [Google Scholar]
  12. LuziL. ZerbiniG. CaumoA. C-peptide: A redundant relative of insulin?Diabetologia200750350050210.1007/s00125‑006‑0576‑x17225123
    [Google Scholar]
  13. SimmondsM.J. DetterichJ.A. ConnesP. DetterichJ.A. ConnesP. Nitric oxide, vasodilation and the red blood cell.Biorheology2014512-312113410.3233/BIR‑14065324819865
    [Google Scholar]
  14. BrandenburgD. History and diagnostic significance of C-peptide.J. Diabetes Res.20082008157686210.1155/2008/57686218509495
    [Google Scholar]
  15. RoepB.O. ThomaidouS. van TienhovenR. ZaldumbideA. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?).Nat. Rev. Endocrinol.202117315016110.1038/s41574‑020‑00443‑433293704
    [Google Scholar]
  16. GanM.J. Albanese-O’NeillA. HallerM.J. Type 1 diabetes: Current concepts in epidemiology, pathophysiology, clinical care, and research.Curr. Probl. Pediatr. Adolesc. Health Care2012421026929110.1016/j.cppeds.2012.07.00223046732
    [Google Scholar]
  17. TruccoM. Regeneration of the pancreatic β cell.J. Clin. Invest.2005115151210.1172/JCI20052393515630433
    [Google Scholar]
  18. ChistyakovaO.V. Signaling pathway of insulin and insulin-like growth factor 1 (IGF-1) as a potential regulator of lifespan.J. Evol. Biochem. Physiol.200844111110.1134/S0022093008010015
    [Google Scholar]
  19. MillmanJ.R. PagliucaF.W. Autologous pluripotent stem cell–derived β-like cells for diabetes cellular therapy.Diabetes20176651111112010.2337/db16‑140628507211
    [Google Scholar]
  20. FiorinaP. VoltarelliJ. ZavazavaN. Immunological applications of stem cells in type 1 diabetes.Endocr. Rev.201132672575410.1210/er.2011‑000821862682
    [Google Scholar]
  21. BouwensL. RoomanI. Regulation of pancreatic beta-cell mass.Physiol. Rev.20058541255127010.1152/physrev.00025.200416183912
    [Google Scholar]
  22. NewsholmeP. KeaneK.N. CarlessiR. CruzatV. Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: Importance to cell metabolism, function, and dysfunction.Am. J. Physiol. Cell Physiol.20193173C420C43310.1152/ajpcell.00141.201931216193
    [Google Scholar]
  23. LuppiP. DrainP. C‐peptide antioxidant adaptive pathways in β cells and diabetes.J. Intern. Med.2017281172410.1111/joim.1252227251308
    [Google Scholar]
  24. LiuY. Delivery of a pancreatic beta cell-derived hormone to erythrocytes by albumin and downstream cellular effects.Michigan State University2015
    [Google Scholar]
  25. LuppiP. CifarelliV. TseH. PiganelliJ. TruccoM. Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-κB pathway.Diabetologia20085181534154310.1007/s00125‑008‑1032‑x18493738
    [Google Scholar]
  26. ShpakovA.O. Mechanisms of action and therapeutic potential of proinsulin C-peptide.J. Evol. Biochem. Physiol.201753318019010.1134/S0022093017030024
    [Google Scholar]
  27. MziautH. HennigerG. GanssK. HempelS. WolkS. McChordJ. ChowdhuryK. RavassardP. KnochK.P. KrautzC. WeitzJ. GrützmannR. PilarskyC. SolimenaM. KerstingS. MiR-132 controls pancreatic beta cell proliferation and survival through Pten/AKT/Foxo3 signaling.Mol. Metab.20203115016210.1016/j.molmet.2019.11.01231918917
    [Google Scholar]
  28. PinheiroM.M. PinheiroF.M.M. DinizS.N. FabbriA. InfanteM. Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes.Int. Immunopharmacol.20219510751810.1016/j.intimp.2021.10751833756226
    [Google Scholar]
  29. BurrackA.L. MartinovT. FifeB.T. T cell-mediated beta cell destruction: Autoimmunity and alloimmunity in the context of type 1 diabetes.Front. Endocrinol.2017834310.3389/fendo.2017.0034329259578
    [Google Scholar]
  30. ChanJ. S.; Steiner, D.F. Insulin through the ages: Phylogeny of a growth promoting and metabolic regulatory hormone.Am. Zool.200040221322210.1093/icb/40.2.213
    [Google Scholar]
  31. LewittM.S. BoydG.W. Role of the insulin-like growth factor system in neurodegenerative disease.Int. J. Mol. Sci.2024258451210.3390/ijms2508451238674097
    [Google Scholar]
  32. LuoJ. JiangJ. HuangH. JiangF. XuZ. ZhouZ. ZhuH. C-peptide ameliorates high glucose-induced podocyte dysfunction through the regulation of the Notch and TGF-β signaling pathways.Peptides202114217055710.1016/j.peptides.2021.17055733901627
    [Google Scholar]
  33. AlmaçaJ. CaicedoA. LandsmanL. Beta cell dysfunction in diabetes: The islet microenvironment as an unusual suspect.Diabetologia202063102076208510.1007/s00125‑020‑05186‑532894318
    [Google Scholar]
  34. DruckerD.J. Glucagon-like peptide-1 and the islet β-cell: Augmentation of cell proliferation and inhibition of apoptosis.Endocrinology2003144125145514810.1210/en.2003‑114714645210
    [Google Scholar]
  35. DerkachK.V. BakhtyukovA.A. BasovaN.E. ZorinaI.I. ShpakovA.O. The restorative effect of combined insulin and C-peptide intranasal administration on hormonal status and hypothalamic signaling in the male rat model of severe short-term streptozotocin-induced diabetes.J. Evol. Biochem. Physiol.202258367769110.1134/S002209302203005X
    [Google Scholar]
  36. FuZ. GilbertE.R. LiuD. Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes.Curr. Diabetes Rev.201391255310.2174/15733991380414322522974359
    [Google Scholar]
  37. ZhangY. GaoY. WangJ. GaoR. SuQ. ZhangJ. JiangL. ZhangC. HuangP. WangW. FengZ. Bioenergetic metabolism modulatory peptide hydrogel for cardiac protection and repair after myocardial infarction.Adv. Funct. Mater.20243424231277210.1002/adfm.202312772
    [Google Scholar]
  38. GhaniM.W. YeL. YiZ. GhaniH. BirmaniM.W. NawabA. CunL.G. BinL. MeiX. Pancreatic β-cell replacement: Advances in protocols used for differentiation of pancreatic progenitors to β-like cells.Folia Histochem. Cytobiol.201957310111531396945
    [Google Scholar]
  39. HaidetJ. CifarelliV. TruccoM. LuppiP. Anti-inflammatory properties of C-Peptide.Rev. Diabet. Stud.20096316817910.1900/RDS.2009.6.16820039006
    [Google Scholar]
  40. YostenG.L.C. Maric-BilkanC. LuppiP. WahrenJ. Physiological effects and therapeutic potential of proinsulin C-peptide.Am. J. Physiol. Endocrinol. Metab.201430711E955E96810.1152/ajpendo.00130.201425249503
    [Google Scholar]
  41. PathakV. PathakN.M. O’NeillC.L. Guduric-FuchsJ. MedinaR.J. Therapies for type 1 diabetes: Current scenario and future perspectives.Clin. Med. Insights Endocrinol. Diabetes201912117955141984452110.1177/117955141984452131105434
    [Google Scholar]
  42. BasileG. QadirM.M.F. Mauvais-JarvisF. VetereA. ShobaV. ModellA.E. PastoriR.L. RussH.A. WagnerB.K. Dominguez-BendalaJ. Emerging diabetes therapies: Bringing back the β-cells.Mol. Metab.20226010147710.1016/j.molmet.2022.10147735331962
    [Google Scholar]
  43. CnopM. WelshN. JonasJ.C. JörnsA. LenzenS. EizirikD.L. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities.Diabetes200554S97S10710.2337/diabetes.54.suppl_2.S9716306347
    [Google Scholar]
  44. LiY. SunF. YueT.T. WangF.X. YangC.L. LuoJ.H. RongS.J. XiongF. ZhangS. WangC.Y. Revisiting the antigen-presenting function of β cells in T1D pathogenesis.Front. Immunol.20211269078310.3389/fimmu.2021.69078334335595
    [Google Scholar]
  45. HuangQ. ZhuJ. Regulatory T cell-based therapy in type 1 diabetes: Latest breakthroughs and evidence.Int. Immunopharmacol.202414011272410.1016/j.intimp.2024.11272439098233
    [Google Scholar]
  46. VerhaegheJ. LoosR. VlietinckR. Van HerckE. Van BreeR. De SchutterA.M. C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in cord serum of twins: Genetic versus environmental regulation.Int. J. Gynaecol. Obstet.199756330830910.1016/S0020‑7292(97)83416‑9
    [Google Scholar]
  47. CifarelliV. TruccoM. LuppiP. Anti-inflammatory effects of C-peptide prevent endothelial dysfunction in type 1 diabetes.Immunol. Endocr. Metab. Agents Med. Chem.20111115970
    [Google Scholar]
  48. LuppiP. DrainP. Autocrine C‐peptide mechanism underlying INS1 beta cell adaptation to oxidative stress.Diabetes Metab. Res. Rev.201430759960910.1002/dmrr.252824459093
    [Google Scholar]
  49. Marek-TrzonkowskaN. MyśliwecM. SiebertJ. TrzonkowskiP. Clinical application of regulatory T cells in type 1 diabetes.Pediatr. Diabetes201314532233210.1111/pedi.1202923627860
    [Google Scholar]
  50. PhamM.N. KolbH. BattelinoT. LudvigssonJ. PozzilliP. ZiveheF. RodenM. Mandrup-PoulsenT. SchlootN.C. Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes.Diabetologia20135661356136310.1007/s00125‑013‑2883‑323494449
    [Google Scholar]
  51. ChenJ. HuangY. LiuC. ChiJ. WangY. XuL. The role of C-peptide in diabetes and its complications: An updated review.Front. Endocrinol.202314125609310.3389/fendo.2023.125609337745697
    [Google Scholar]
  52. KondělkováK. VokurkováD. KrejsekJ. BorskáL. FialaZ. AndrýsC. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders.Acta Med.2010532737710.14712/18059694.2016.6320672742
    [Google Scholar]
  53. EizirikD.L. SzymczakF. MalloneR. Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?Nat. Rev. Endocrinol.202319742543410.1038/s41574‑023‑00826‑337072614
    [Google Scholar]
  54. SmithT.J. Insulin-like growth factor-I regulation of immune function: A potential therapeutic target in autoimmune diseases?Pharmacol. Rev.201062219923610.1124/pr.109.00246920392809
    [Google Scholar]
  55. BoS. GentileL. CastiglioneA. PrandiV. CanilS. GhigoE. CicconeG. C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: A retrospective cohort study after a 14-year follow-up.Eur. J. Endocrinol.2012167217318010.1530/EJE‑12‑008522577110
    [Google Scholar]
  56. KwiatkowskiA.J. StewartJ.M. ChoJ.J. AvramD. KeselowskyB.G. Nano and microparticle emerging strategies for treatment of autoimmune diseases: multiple sclerosis and type 1 diabetes.Adv. Healthc. Mater.2020911200016410.1002/adhm.20200016432519501
    [Google Scholar]
  57. MuscogiuriG. CaporussoM. CarusoP. PoggiC.D. VitaleM. ZurruA. ColaoA. Current evidence on gender-related risk factors for type 1 diabetes, type 2 diabetes and prediabetes: A reappraisal of the Italian study group on gender difference in endocrine diseases.J. Endocrinol. Invest.202448357358510.1007/s40618‑024‑02491‑339570488
    [Google Scholar]
  58. NilssonB. TeramuraY. EkdahlK.N. The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies.Mol. Immunol.201461218519010.1016/j.molimm.2014.06.00924998801
    [Google Scholar]
  59. SchuerweghA.J. DombrechtE.J. StevensW.J. Van OffelJ.F. BridtsC.H. De ClerckL.S. Influence of pro-inflammatory (IL-1α, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4) cytokines on chondrocyte function.Osteoarthritis Cartilage200311968168710.1016/S1063‑4584(03)00156‑012954239
    [Google Scholar]
  60. KhodabandehlooH. Gorgani-FiruzjaeeS. PanahiG. MeshkaniR. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction.Transl. Res.2016167122825610.1016/j.trsl.2015.08.01126408801
    [Google Scholar]
  61. PoteryaevaO.N. UsyninI.F. Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review). Biochem.Moscow Suppl Ser B202115273910.1134/S1990750821010066
    [Google Scholar]
  62. WashburnR.L. MuellerK. KaurG. MorenoT. Moustaid-MoussaN. RamalingamL. DufourJ.M. C-peptide as a therapy for type 1 diabetes mellitus.Biomedicines20219327010.3390/biomedicines903027033800470
    [Google Scholar]
  63. HaidetJ CifarelliV GengX TruccoM LuppiP. C-peptide: a new molecule with anti-inflammatory properties.201211112710.1007/978‑1‑61779‑391‑2_10
    [Google Scholar]
  64. SaishoY. Postprandial C-peptide to glucose ratio as a marker of β cell function: Implication for the management of type 2 diabetes.Int. J. Mol. Sci.201617574410.3390/ijms1705074427196896
    [Google Scholar]
  65. Jamiołkowska-SztabkowskaM. Głowińska-OlszewskaB. BossowskiA. C-peptide and residual β-cell function in pediatric diabetes – state of the art.Pediatr. Endocrinol. Diabetes Metab.202127212313310.5114/pedm.2021.10716534514768
    [Google Scholar]
  66. DobretsovM. RomanovskyD. StimersJ.R. Early diabetic neuropathy: Triggers and mechanisms.World J. Gastroenterol.200713217519110.3748/wjg.v13.i2.17517226897
    [Google Scholar]
  67. JohanssonB.L. KernellA. SjöbergS. WahrenJ. Influence of combined C-peptide and insulin administration on renal function and metabolic control in diabetes type 1.J. Clin. Endocrinol. Metab.19937749769818408474
    [Google Scholar]
  68. LinK.J. WangT.J. ChenS.D. LinK.L. LiouC.W. LanM.Y. ChuangY.C. ChuangJ.H. WangP.W. LeeJ.J. WangF.S. LinH.Y. LinT.K. Two birds one stone: The neuroprotective effect of antidiabetic agents on Parkinson disease—focus on sodium-glucose cotransporter 2 (SGLT2) inhibitors.Antioxidants20211012193510.3390/antiox1012193534943038
    [Google Scholar]
  69. LachinJ.M. McGeeP. PalmerJ.P. Impact of C-peptide preservation on metabolic and clinical outcomes in the diabetes control and complications trial.Diabetes201463273974810.2337/db13‑088124089509
    [Google Scholar]
  70. BhattacharyaS. ParaskarG. JhaM. GuptaG.L. PrajapatiB.G. Deciphering regulatory T-cell dynamics in cancer immunotherapy: Mechanisms, implications, and therapeutic innovations.ACS Pharmacol. Transl. Sci.2024782215223610.1021/acsptsci.4c0015639144553
    [Google Scholar]
  71. PolonskyK.S. Lilly lecture 1994. The β-cell in diabetes: From molecular genetics to clinical research.Diabetes199544670571710.2337/diab.44.6.7057789637
    [Google Scholar]
  72. Nordin-JohanssonA. AsplundK. Randomized controlled trials and consensus as a basis for interventions in internal medicine.J. Intern. Med.200024719410410.1046/j.1365‑2796.2000.00583.x10672136
    [Google Scholar]
  73. WahrenJ. KallasÅ. SimaA.A. The clinical potential of C-peptide replacement in type 1 diabetes.Diabetes2012614761772
    [Google Scholar]
  74. SjöbergL. PitkäniemiJ. HaapalaL. KaajaR. TuomilehtoJ. Fertility in people with childhood-onset type 1 diabetes.Diabetologia2013561788110.1007/s00125‑012‑2731‑x23011355
    [Google Scholar]
  75. ZieglerR. HeidtmannB. HilgardD. HoferS. RosenbauerJ. HollR. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes.Pediatr. Diabetes2011121111710.1111/j.1399‑5448.2010.00650.x20337978
    [Google Scholar]
  76. ForstT. HanefeldM. JacobS. MoeserG. SchwenkG. PfütznerA. HauptA. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: A systematic review and meta-analysis of observational studies.Diab. Vasc. Dis. Res.201310430231410.1177/147916411246544223291340
    [Google Scholar]
  77. WahrenJ. LarssonC. C-peptide: New findings and therapeutic possibilities.Diabetes Res. Clin. Pract.2015107330931910.1016/j.diabres.2015.01.01625648391
    [Google Scholar]
  78. CarlbomL. EspesD. LubberinkM. ErikssonO. JohanssonL. JanssonL. KorsgrenO. AhlströmH. CarlssonP.O. Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes.Diabetologia20165991968197210.1007/s00125‑016‑4016‑227306617
    [Google Scholar]
  79. TianJ. DangH. O’LacoK.A. SongM. TiuB.C. GillesS. ZakarianC. KaufmanD.L. Homotaurine treatment enhances CD4+ and CD8+ regulatory T cell responses and synergizes with low-dose anti-CD3 to enhance diabetes remission in type 1 diabetic mice.Immunohorizons201931049851010.4049/immunohorizons.190001931636084
    [Google Scholar]
  80. GibbF.W. McKnightJ.A. ClarkeC. StrachanM.W.J. Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash glucose monitoring in adults with type 1 diabetes.Diabetologia202063590691410.1007/s00125‑020‑05099‑332034440
    [Google Scholar]
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  • Article Type:
    Review Article
Keyword(s): autoimmune diabetes; beta cells; C-peptide; glucose; hyperglycemia; insulin
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