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Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes

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Abstract

Aims/hypothesis

Notwithstanding the irreversible beta cell failure seen in type 1 diabetes, some individuals may experience a special phase named ‘partial remission’ or ‘the honeymoon period’, in which there is a transient recovery of beta cell function. Importantly, this stage of partial remission shows spontaneous immune downregulation, although the exact mechanisms are unclear. Intracellular energy metabolism is crucial for the differentiation and function of T cells, and provides promising targets for immunometabolic intervention strategies, but its role during partial remission is unknown. In this study, we aim to investigate the association between T cell intracellular glucose and fatty acid metabolism and the partial remission phase.

Methods

This is a cross-sectional study with a follow-up component. Intracellular uptake of glucose and fatty acids by T cells was detected in participants with either new-onset type 1 diabetes or type 1 diabetes that was already in partial remission, and compared with heathy individuals and participants with type 2 diabetes. Subsequently, the participants with new-onset type 1 diabetes were followed up to determine whether they experienced a partial remission (remitters) or not (non-remitters). The trajectory of changes in T cell glucose metabolism was observed in remitters and non-remitters. Expression of programmed cell death-1 (PD-1) was also analysed to investigate possible mechanisms driving altered glucose metabolism. Partial remission was defined when patients had convalescent fasting or 2 h postprandial C-peptide >300 pmol/l after insulin treatment.

Results

Compared with participants with new-onset type 1 diabetes, intracellular glucose uptake by T cells decreased significantly in individuals with partial remission. The trajectory of these changes during follow-up showed that intracelluar glucose uptake in T cells fluctuated during different disease stages, with a decreased uptake during partial remission that rebounded after remission. This dynamic in T cell glucose uptake was only detected in remitters and not in non-remitters. Further analysis demonstrated that changes of intracellular glucose uptake were found in subsets of CD4+ and CD8+ T cells, including Th17, Th1, CD8+ naive T cells (Tn) and CD8+ terminally differentiated effector memory T cells (Temra). Moreover, glucose uptake in CD8+ T cells was negatively related to PD-1 expression. The intracellular metabolism of fatty acids was not found to be different between new-onset participants and those in partial remission.

Conclusions/interpretation

Intracellular glucose uptake in T cells was specifically decreased during partial remission in type 1 diabetes and may be related to PD-1 upregulation, which may be involved in the down-modulation of immune responses during partial remission. This study suggests that altered immune metabolism could be a target for interventions at the point of diagnosis of type 1 diabetes.

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Abbreviations

2h-CP:

2 hour C-peptide

2NBDG:

2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose

BODIPY:

4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-hexadecanoic acid

CCR:

C-C chemokine receptor

CPT1A:

Carnitine palmitoyltransferase 1A

FCP:

Fasting C-peptide

GADA:

GAD antibody

IA-2A:

Protein tyrosine phosphatase autoantibody

MMTT:

Mixed meal tolerance test

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed cell death-1

PR:

Partial remission

Tcm:

Central memory T cells

Tem:

Effector memory T cells

Temra:

Terminally differentiated effector memory T cells

Tn:

Naive T cells

Treg:

Regulatory T cells

ZnT8:

Zinc transporter 8 autoantibody

References

  1. Syed FZ (2022) Type 1 diabetes mellitus. Ann Intern Med 175(3):Itc33-itc48. https://doi.org/10.7326/aitc202203150

    Article  PubMed  Google Scholar 

  2. Zhong T, Tang R, Gong S, Li J, Li X, Zhou Z (2020) The remission phase in type 1 diabetes: changing epidemiology, definitions, and emerging immuno-metabolic mechanisms. Diabetes Metab Res Rev 36(2):e3207. https://doi.org/10.1002/dmrr.3207

    Article  PubMed  Google Scholar 

  3. Aly H, Gottlieb P (2009) The honeymoon phase: intersection of metabolism and immunology. Curr Opin Endocrinol Diabetes Obes 16(4):286–292. https://doi.org/10.1097/MED.0b013e32832e0693

    Article  CAS  PubMed  Google Scholar 

  4. Fonolleda M, Murillo M, Vázquez F, Bel J, Vives-Pi M (2017) Remission phase in paediatric type 1 diabetes: new understanding and emerging biomarkers. Horm Res Paediatr 88(5):307–315. https://doi.org/10.1159/000479030

    Article  CAS  PubMed  Google Scholar 

  5. Villalba A, Fonolleda M, Murillo M et al (2019) Partial remission and early stages of pediatric type 1 diabetes display immunoregulatory changes. A pilot study. Transl Res 210:8–25. https://doi.org/10.1016/j.trsl.2019.03.002

    Article  PubMed  Google Scholar 

  6. Tang R, Zhong T, Wu C, Zhou Z, Li X (2019) The remission phase in type 1 diabetes: role of hyperglycemia rectification in immune modulation. Front Endocrinol (Lausanne) 10:824. https://doi.org/10.3389/fendo.2019.00824

    Article  PubMed  Google Scholar 

  7. Gomez-Muñoz L, Perna-Barrull D, Villalba A et al (2020) NK cell subsets changes in partial remission and early stages of pediatric type 1 diabetes. Front Immunol 11:611522. https://doi.org/10.3389/fimmu.2020.611522

    Article  CAS  PubMed  Google Scholar 

  8. Li X, Zhong T, Tang R et al (2020) PD-1 and PD-L1 expression in peripheral CD4/CD8+ T cells is restored in the partial remission phase in type 1 diabetes. J Clin Endocrinol Metab 105(6):dgaa130. https://doi.org/10.1210/clinem/dgaa130

    Article  PubMed  Google Scholar 

  9. Marchingo JM, Cantrell DA (2022) Protein synthesis, degradation, and energy metabolism in T cell immunity. Cell Mol Immunol 19(3):303–315. https://doi.org/10.1038/s41423-021-00792-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Diskin C, Ryan TAJ, O’Neill LAJ (2021) Modification of proteins by metabolites in immunity. Immunity 54(1):19–31. https://doi.org/10.1016/j.immuni.2020.09.014

    Article  CAS  PubMed  Google Scholar 

  11. Chapman NM, Chi H (2022) Metabolic adaptation of lymphocytes in immunity and disease. Immunity 55(1):14–30. https://doi.org/10.1016/j.immuni.2021.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Møller SH, Hsueh PC, Yu YR, Zhang L, Ho PC (2022) Metabolic programs tailor T cell immunity in viral infection, cancer, and aging. Cell Metab 34(3):378–395. https://doi.org/10.1016/j.cmet.2022.02.003

    Article  CAS  PubMed  Google Scholar 

  13. Qiu J, Wu B, Goodman SB, Berry GJ, Goronzy JJ, Weyand CM (2021) Metabolic control of autoimmunity and tissue inflammation in rheumatoid arthritis. Front Immunol 12:652771. https://doi.org/10.3389/fimmu.2021.652771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kunkl M, Sambucci M, Ruggieri S et al (2019) CD28 autonomous signaling up-regulates C-myc expression and promotes glycolysis enabling inflammatory T cell responses in multiple sclerosis. Cells 8(6):575. https://doi.org/10.3390/cells8060575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Galgani M, De Rosa V, Matarese G (2015) T cell metabolism and susceptibility to autoimmune diseases. Mol Immunol 68(2 Pt C):558–563. https://doi.org/10.1016/j.molimm.2015.07.035

    Article  CAS  PubMed  Google Scholar 

  16. Zhang M, Zhou Y, Xie Z et al (2022) New developments in T cell immunometabolism and therapeutic implications for type 1 diabetes. Front Endocrinol (Lausanne) 13:914136. https://doi.org/10.3389/fendo.2022.914136

    Article  PubMed  Google Scholar 

  17. Tang R, Zhong T, Fan L, Xie Y, Li J, Li X (2022) Enhanced T cell glucose uptake is associated with progression of beta-cell function in type 1 diabetes. Front Immunol 13:897047. https://doi.org/10.3389/fimmu.2022.897047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kong BS, Min SH, Lee C, Cho YM (2021) Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes. Cell Rep 36(4):109447. https://doi.org/10.1016/j.celrep.2021.109447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vignali D, Cantarelli E, Bordignon C et al (2018) Detection and characterization of CD8(+) autoreactive memory stem T cells in patients with type 1 diabetes. Diabetes 67(5):936–945. https://doi.org/10.2337/db17-1390

    Article  CAS  PubMed  Google Scholar 

  20. Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553. https://doi.org/10.1002/(sici)1096-9136(199807)15:7%3c539::Aid-dia668%3e3.0.Co;2-s

    Article  CAS  PubMed  Google Scholar 

  21. Zhong T, Tang R, Xie Y, Liu F, Li X, Zhou Z (2020) Frequency, clinical characteristics, and determinants of partial remission in type 1 diabetes: different patterns in children and adults. J Diabetes 12(10):761–768. https://doi.org/10.1111/1753-0407.13044

    Article  CAS  PubMed  Google Scholar 

  22. Shi M, Xie Y, Tang R, Zhong T, Zhou Z, Li X (2021) Three-phasic pattern of C-peptide decline in type 1 diabetes patients with partial remission. Diabetes Metab Res Rev 37(8):e3461. https://doi.org/10.1002/dmrr.3461

    Article  CAS  PubMed  Google Scholar 

  23. Li X, Campbell-Thompson M, Wasserfall CH et al (2017) Serum trypsinogen levels in type 1 diabetes. Diabetes Care 40(4):577–582. https://doi.org/10.2337/dc16-1774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang G, Yin M, Xiang Y et al (2016) Persistence of glutamic acid decarboxylase antibody (GADA) is associated with clinical characteristics of latent autoimmune diabetes in adults: a prospective study with 3-year follow-up. Diabetes Metab Res Rev 32(6):615–622. https://doi.org/10.1002/dmrr.2779

    Article  CAS  PubMed  Google Scholar 

  25. Shi X, Huang G, Wang Y et al (2019) Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA. Diabetologia 62(3):399–407. https://doi.org/10.1007/s00125-018-4799-4

    Article  CAS  PubMed  Google Scholar 

  26. Xiang Y, Huang G, Zhu Y et al (2019) Identification of autoimmune type 1 diabetes and multiple organ-specific autoantibodies in adult-onset non-insulin-requiring diabetes in China: a population-based multicentre nationwide survey. Diabetes Obes Metab 21(4):893–902. https://doi.org/10.1111/dom.13595

    Article  CAS  PubMed  Google Scholar 

  27. Watson MJ, Vignali PDA, Mullett SJ et al (2021) Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591(7851):645–651. https://doi.org/10.1038/s41586-020-03045-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koga T, Sato T, Furukawa K et al (2019) Promotion of calcium/calmodulin-dependent protein kinase 4 by GLUT1-dependent glycolysis in systemic lupus erythematosus. Arthritis Rheumatol 71(5):766–772. https://doi.org/10.1002/art.40785

    Article  CAS  PubMed  Google Scholar 

  29. Lau EYM, Carroll EC, Callender LA et al (2019) Type 2 diabetes is associated with the accumulation of senescent T cells. Clin Exp Immunol 197(2):205–213. https://doi.org/10.1111/cei.13344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Atkinson MA, Roep BO, Posgai A, Wheeler DCS, Peakman M (2019) The challenge of modulating β-cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol 7(1):52–64. https://doi.org/10.1016/s2213-8587(18)30112-8

    Article  CAS  PubMed  Google Scholar 

  31. Bluestone JA, Buckner JH, Herold KC (2021) Immunotherapy: building a bridge to a cure for type 1 diabetes. Science 373(6554):510–516. https://doi.org/10.1126/science.abh1654

    Article  CAS  PubMed  Google Scholar 

  32. Garyu JW, Uduman M, Stewart A et al (2016) Characterization of diabetogenic CD8+ T cells: immune therapy with metabolic blockade. J Biol Chem 291(21):11230–11240. https://doi.org/10.1074/jbc.M115.713362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Geltink RIK, Kyle RL, Pearce EL (2018) Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol 36:461–488. https://doi.org/10.1146/annurev-immunol-042617-053019

    Article  CAS  PubMed  Google Scholar 

  34. Granados HM, Draghi A 2nd, Tsurutani N et al (2017) Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes. PLoS One 12(9):e0183887. https://doi.org/10.1371/journal.pone.0183887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shields BM, McDonald TJ, Oram R et al (2018) C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care 41(7):1486–1492. https://doi.org/10.2337/dc18-0465

    Article  CAS  PubMed  Google Scholar 

  36. Greenbaum CJ, Beam CA, Boulware D et al (2012) Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite type 1 diabetes TrialNet data. Diabetes 61(8):2066–2073. https://doi.org/10.2337/db11-1538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martins CP, New LA, O’Connor EC et al (2021) Glycolysis inhibition induces functional and metabolic exhaustion of CD4(+) T cells in type 1 diabetes. Front Immunol 12:669456. https://doi.org/10.3389/fimmu.2021.669456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Previte DM, O’Connor EC, Novak EA, Martins CP, Mollen KP, Piganelli JD (2017) Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLoS One 12(4):e0175549. https://doi.org/10.1371/journal.pone.0175549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee YS, Kim D, Lee EK, Kim S, Choi CS, Jun HS (2015) Sodium meta-arsenite prevents the development of autoimmune diabetes in NOD mice. Toxicol Appl Pharmacol 284(2):254–261. https://doi.org/10.1016/j.taap.2014.12.016

    Article  CAS  PubMed  Google Scholar 

  40. Patsoukis N, Bardhan K, Chatterjee P et al (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6:6692. https://doi.org/10.1038/ncomms7692

    Article  CAS  PubMed  Google Scholar 

  41. Tan CL, Kuchroo JR, Sage PT et al (2021) PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med 218(1):e20182232. https://doi.org/10.1084/jem.20182232

    Article  CAS  PubMed  Google Scholar 

  42. Sen P, Dickens AM, López-Bascón MA et al (2020) Metabolic alterations in immune cells associate with progression to type 1 diabetes. Diabetologia 63(5):1017–1031. https://doi.org/10.1007/s00125-020-05107-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

    Rong Tang, Ting Zhong, Kang Lei, Xiaoxi Lin & Xia Li

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Correspondence to Xia Li.

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Acknowledgements

We thank all participants of the study. The authors would like to express gratitude to Professor Xilin Yang (Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China) for his assistance with statistical analysis, and Professor R. David Leslie (Department of Diabetes and Metabolic Medicine, Blizard Institute, London, UK) for his generous help with language editing, which greatly contributed to the clarity and precision of this manuscript.

Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 82070812), the science and technology innovation Program of Hunan Province (2020RC4044). The funder was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

XLi, RT and TZ designed the study, analysed and interpreted data, and drafted and revised the manuscript. RT, KL and XLin conducted the experiments, acquired and analysed data, discussed the results and revised the manuscript. All authors have reviewed and approved the final version. XLi is the guarantor of this work.

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Tang, R., Zhong, T., Lei, K. et al. Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes. Diabetologia 66, 1532–1543 (2023). https://doi.org/10.1007/s00125-023-05938-z

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