Autoreactive T cells have a pivotal pathogenic role in the autoimmune process of beta-cell destruction in type 1 diabetes (T1D), making them ideal targets for immunotherapy strategies aiming to prevent or delay the disease (1, 2). However, clinical evidence witnessed refractory results to standard immunomodulatory and immunosuppressive strategies (3–5). In this sense, the identification and characterization of novel target pathways to control the T cell response to beta cells is still a strong demand (6).

There is a growing appreciation that the function and response of T cells are tightly linked to their bio-energetic metabolism (7). Resting T cells import small amounts of glucose to maintain basal energy and biosynthesis. However, immediately upon activation, T cells strongly upregulate the anabolic process of glycolysis even in the presence of oxygen (Warburg effect) (8, 9). Moreover, it should be noted that the function and metabolism of T cells are bidirectional. On the one hand, T cells with different functions have different intracellular energy metabolism (10); On the other hand, abnormal metabolism of T cells also affects their function (11, 12). In recent years, accumulating evidence demonstrated that abnormal metabolism of T cells is involved in the pathological mechanism of various diseases by regulating immune function (13–15), especially in some autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (16, 17). Further, a few limited animal studies indicated that metabolic inhibition is an effective strategy to weaken the T cell effect in preclinical models of autoimmunity (18–20). Especially, the use of glucose uptake pathway inhibitors can alleviate effectively insulitis in NOD mice (21–23). However, the role of T cell metabolism in T1D patients remains unclear. The possibility of intracellular metabolism of T cells as innovative targets for T1D intervention would be strengthened if the status of intracellular glucose uptake in T cells is well researched. So, we aimed to investigate the intracellular metabolism of T cells and its association with beta-cell function in clinical settings.

In this study, we showed that intracellular glucose uptake of CD4⁺/CD8⁺ T cells is abnormally enhanced in T1D and the status of glucose uptake in T cells is associated with beta-cell function and progression. To the best of our knowledge, this is the first study focusing on the association of T cell glucose uptake with clinical indicators and disease progression in T1D, providing new insights into the mechanism and intervention targets in the field of immunometabolism. It is well recognized that metabolism and the immunological state are inextricably linked (34). With the arising studies focusing on the intrinsic metabolic pathways of immune cells themselves such as glycolysis and Krebs cycle (35–37), immunometabolism has emerged as a major mechanism central to immune regulation. In this way, the metabolic signaling of immune cells drives cell fate. Considering the effect of the microenvironment on cell metabolism, immune cells can adopt programs specific for the tissues where they infiltrate and reside, highlighting opportunities of immunometabolism findings for clinical translation (38, 39).

However, puzzlingly, in the field of T1D where T cells are the primary mechanism, whether intra-T cellular metabolism is involved in the pathological process of T1D remains unclear. Through our T1D cohort study, we found the glucose uptake in T cells was significantly increased in T1D, which was mainly reflected as increased expression of GLUT1, a key transporter in the glucose metabolism pathway, and uptake of 2NBDG. Also, our results showed the abnormality of T cell glucose uptake was significantly correlated with islet function progression and glycemic control trajectory. Although no previous data has been reported about the association of intra-T cellular metabolism with beta-cell function progression, a few cross-sectional studies reported the status of T cell metabolism in T1D patients. Our results are similar to Kong BS’ research in 2021 which found that patients with T1D had enhanced CD4⁺ T cell glycolysis and decreased oxidative phosphorylation (40). Likewise, in NOD mice, increased 2NBDG uptake was also detected in NRP-V7-reactive T cells (a sort of diabetes pathogenic T cell) (21). A study by Vignali D found that GLUT1 was overexpressed in specific stem memory T cells by investigating the metabolic signature of naïve precursors stimulated with GAD65. And the similar metabolic signature was also found in influenza-specific T cells, indicating that this metabolic profile is not confined to autoreactive T cells (23). However, in this study, the 2NBDG uptake and mitochondrial mass and activity were similar among circulating CD8⁺ T cell subsets and no significant changes were found in T1D, indicating that the metabolic dysregulation of T1D not directly impact the basal metabolism of resting circulating T cell (23), which is not consistent with our results. It should be noted that the cells examined in the above studies were different. Upregulation of glucose metabolism was detected in pathogenic T cell populations with a specific antigen (NRP-V7 specific, GAD65, or influenza), but it is not uniformly in the circulating cells, which most will be of naïve phenotype, just as glucose metabolism is upregulated in CD4⁺ T cells (in the Kong BS study) but not in a subset of CD8⁺ T cells with different phenotypes (in the Vignali D study). We detected increased T cell glucose uptake in circulating CD4⁺ and CD8⁺ T cells from individuals with a large sample size with regular follow-up data, which might provide some solid information. Most importantly, our finding that abnormal glucose uptake of T cells is significantly correlated with beta-cell function and its progression. It offers potential markers for evaluating disease prognosis and suggests that the presence of a population of T cells characterized by elevated glucose metabolism enhances the immune attack on beta cells in T1D.

The causes of increased glucose uptake in T cells in T1D are unclear. Our primary consideration is hyperglycemia in the peripheral circulation of diabetes. However, there is little evidence of the relationship between hyperglycemia and the energy metabolism of immune cells. A study in a mouse model of autoimmune colitis with high glucose uptake found that hyperglycemia did not affect intracellular CD4⁺ T cell metabolism (41). However, it has also been reported that hyperglycemia can lead to increased glycolysis in activated T cells, resulting in increased IFN-γ production and non-antigen specific inflammation (42). Recent studies found T cell glucose metabolism decreased in patients with type 2 diabetes (33, 43) which may provide strong evidence that hyperglycemia is not the cause of changes in T cell glucose metabolism. In our study, the differential glucose uptake persists in beta-cell function progression after correction for glycation. Thus, the role of hyperglycemia may be limited. On the other hand, we consider that the enhanced glucose metabolism in T cells may be caused by susceptibility mediated by signaling pathways, oxidative stress, or immunomodulatory molecules. Enhanced T cell glucose metabolism has also been found in other autoimmune diseases including Systemic lupus erythematosus, Rheumatoid Arthritis, and Multiple Sclerosis (44–46). The metabolic abnormalities of T cells may be related to the production of autoantibodies to metabolic enzymes or the activation of the phosphoinositide 3-kinase (PI3K)-Akt and mammalian target of rapamycin (mTOR) pathway, which mediates susceptibility to immunometabolism abnormality in autoimmune diseases including T1D (16, 18). Oxidative stress and mitochondrial dysfunction have also been shown to play an important role in abnormal T cell metabolism in autoimmune diseases (47). In addition, the immune molecule programmed death 1 (PD-1) is a key regulator of T cell metabolic reprogramming, which has been found to be involved in the pathogenesis of T1D (30, 48, 49) and a study found that knocking out PD-1 on Treg cells in NOD mice significantly reduced the incidence of NOD mice by regulating intracellular metabolism (50).

Enhanced T cell metabolism was also detected in NOD mice and when prediabetic NOD mice were treated with 2-deoxyglucose to block aerobic glycolysis, islet antigen-specific T cell frequency and islet infiltrating lymphocytes decreased, beta-cell degranulation was improved (21). Similarly, in the adoptive transfer model of T1D, a competitive inhibitor of the glycolytic rate-limiting enzyme of CD4⁺ T cells reduced T cell responses to β cell antigen in vitro, thus reducing the immunopathological parameters associated with disease onset as 57% of animals remaining euglycemic at the end of the study period (22). Other studies also found that there are some potential immunotherapy drugs for T1D by inhibiting the T cell glucose metabolism pathway (51–53). These evidences, to some extent, suggest that T cell metabolism is an initiating factor in the pathogenesis of T1D. However, since the association between T cell metabolism and disease progression in T1D patients is poorly defined, our study provides human pathophysiological evidence for T cell glucose metabolism as a potential target.

Although the relationship between tissue infiltration and circulating immune cells is not fully understood, some evidence supports the hypothesis that effector cells migrate to the pancreas and that this autoimmune process persists in disease (54–56). The results of enhanced glucose metabolism in circulating T cells in T1D are consistent with the pathogenicity of T1D primarily caused by Th1 and Th17 and cytotoxic CD8⁺ T cells (54), as these cells require extensive glycolysis for energy during activation and differentiation. Furthermore, we found that changes in T cell glucose metabolism were correlated with beta-cell function progression within 36 months follow-up, suggesting that similar intracellular metabolic changes may also exist in T cells in islet infiltration. Anyway, further research will have to sort this out more completely.

Our study has some limitations, the most important of which is the failure to utilize the seahorse XF equipment to detection of intracellular glycolysis and aerobic phosphorylation pathways directly due to the limited number of cells. And the follow-up data on T cell metabolism is lacking to explore its mechanism during disease progression. Further, the intracellular glucose uptake is detected in bulk CD4⁺ and CD8⁺ T cells rather than pathogenic T cells with specific antigenic targets such as glucose-6-phosphatase catalytic subunit-related protein (IGRP) or GAD that can be detected by MHC tetramer technology as in other studies (21, 23), which is also one of our limitatons.

Overall, the association between intra-T cellular glucose uptake and progression of beta-cell function in T1D provides a promising possibility of T cell metabolism as biomarkers and potential targets. While there are trials focusing on immune intervention in T1D, the translation to specific T cell metabolism might provide a new and effective therapeutic strategy for T1D.

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

The studies involving human participants were reviewed and approved by The Second Xiangya Hospital of Central South University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

RT and TZ performed experiments and analyzed the data. RT wrote the manuscript. YX and XL reviewed and edited the manuscript. LF and JL contributed to the data collection and discussion. XL designed the study. All authors contributed to manuscript revision, read, and approved the submitted version.

This work was supported by National Natural Science Foundation of China (Grant No 82070812), the science and technology innovation Program of Hunan Province (2020RC4044), and DMRFP_I_04 from SHMHDF.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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