INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance, and progressive β-cell dysfunction, leading to severe long-term complications and significant global health and economic burdens[1,2]. Central to the regulation of systemic glucose balance is the pancreas-liver axis, in which the liver serves as the principal site for glycogen storage and release, while insulin secreted from pancreatic β cells acts as the dominant hormonal signal driving glycogen synthesis and glucose utilization[3-5]. This classical framework has underpinned decades of metabolic research, establishing insulin as the cornerstone of interorgan communication between the pancreas and liver.
However, this insulin-centric view provides an incomplete picture of the molecular crosstalk governing glucose metabolism. Increasing evidence suggests that additional regulatory signals may be critical for modulating hepatic glucose handling. In addition to hormones and metabolites, extracellular vesicles, particularly exosomes, have emerged as pivotal mediators of intercellular communication by transferring proteins, lipids, and regulatory RNAs between cells and across tissues[6-10]. In metabolic diseases, exosomal miRNAs have been increasingly associated with systemic metabolic regulation, with reported roles in insulin responsiveness and hepatic glucose handling[9,11], lipid homeostasis[12], and β-cell/islet function[10], thereby adding an additional layer of complexity to whole-body metabolic control[9-13].
Among these regulatory miRNAs, miR-375-3p is highly enriched in pancreatic islets and has long been recognized as a critical modulator of β-cell development, function, and stress responses[14-16]. Circulating miR-375 has also been proposed as a biomarker of β-cell injury in both type 1 diabetes mellitus and T2DM[17-19]. Despite these insights, whether β-cell-derived exosomal miR-375 can directly influence hepatic glucose metabolism has not been established.
In this context, Xu et al[20] recently published a study in World Journal of Diabetes demonstrating that under glucotoxicity stress, pancreatic β cells secrete exosomes enriched with miR-375-3p, which are subsequently taken up by hepatocytes. Within hepatocytes, miR-375-3p represses the transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ), leading to impaired protein kinase B (AKT)/glycogen synthase kinase (GSK) signaling and diminished glycogen storage, thereby linking β-cell stress to impaired hepatic insulin signaling through an exosomal pathway[20]. This groundbreaking finding expands the classical insulin-glycogen paradigm to include an “exosome-miRNA axis” as an additional dimension of pancreas-liver communication.
In this editorial, we aim to critically evaluate the conceptual and mechanistic significance of the exosomal miR-375-3p-mediated pancreas-liver axis proposed by Xu et al[20]. Specifically, we discuss the key mechanistic advances that extend the classical insulin-centered view of interorgan glucose regulation, highlight the major strengths and current limitations of the study, and outline future research directions required to validate this pathway as a clinically relevant biomarker and therapeutic target in T2DM. Through this structured discussion, we seek to provide readers with a clear and coherent framework for understanding how each section contributes to the central thesis of exosome-mediated metabolic communication in glucotoxicity states.
ADVANCING EXOSOME-MIRNA RESEARCH: MECHANISMS, LIMITATIONS, AND FUTURE DIRECTIONS
To guide the reader through the implications of this newly proposed exosome-miRNA axis, the following discussion is structured to first highlight the key mechanistic advances of the study, then critically evaluate its strengths and limitations, and finally outline future research directions that may advance both mechanistic understanding and clinical translation.
Newly discovered pathogenic mechanism
At the core of the study by Xu et al[20] was the identification of a previously unrecognized exosome-mediated pathogenic mechanism linking β-cell glucotoxic stress to hepatic insulin resistance and impaired hepatic glycogen storage. Under conditions of chronic hyperglycemia, pancreatic β cells undergo functional stress that promotes the release of extracellular vesicles enriched with regulatory miRNAs, most notably miR-375-3p, which function as interorgan signals that mediate pancreas-liver metabolic communication. This mechanistic framework enables a critical evaluation of the pathway’s conceptual importance, strengths, limitations, and translational relevance in T2DM. Notably, this observation is consistent with previous reports demonstrating the selective enrichment of miR-375 in pancreatic islets and its release into the extracellular milieu during β-cell dysfunction[16,18,19].
Xu et al[20] reported that these β-cell-derived exosomes are internalized by hepatocytes, where miR-375-3p directly represses RBPJ expression. RBPJ, a central transcriptional mediator of Notch signaling, has been implicated in hepatic metabolic regulation, in part through indirect modulation of the AKT/GSK pathway[21]. By targeting RBPJ, exosomal miR-375-3p attenuates AKT activation and disrupts downstream GSK activity, thereby reducing the glycogen storage capacity of the liver[11]. This finding aligns with prior reports showing that islet-derived miRNAs can target nodes of the AKT pathway[22] and that other miRNAs (e.g., miR-143) similarly inhibit insulin-stimulated AKT activation to impair glucose metabolism[23].
This sequence of events provides a plausible mechanistic bridge between β-cell glucotoxicity and the progressive development of hepatic insulin resistance, underscoring the importance of small RNA cargo as a mediator of interorgan metabolic communication[11]. This finding extends a growing body of literature suggesting that stressed pancreatic β cells actively communicate with distant metabolic tissues via exosomal miRNA cargo[24,25] and situates the pancreas-liver dialogue within a broader exosome-mediated network[6,7,9,13].
Key strengths of the study
In this section, we briefly summarize the key strengths of the study by Xu et al[20] and discuss the implications of the proposed exosomal miR-375-3p-mediated pancreas-liver axis. From a conceptual perspective, one of the major strengths of this study is that it provides a coherent mechanistic framework supporting the proposed exosomal miR-375-3p-mediated pancreas-liver axis[20]. Rather than identifying correlative associations alone, the investigators delineated a causal pathway in which exosomal miR-375-3p, which is secreted under glucotoxicity conditions, exerts a direct effect on hepatocyte signaling. This mechanistic framework integrates three critical levels of evidence: The vesicular carrier (exosome), the molecular effector (miRNA), and the downstream signaling cascade (RBPJ-AKT/GSK), thereby providing a comprehensive model of pancreas-liver communication that extends beyond conventional insulin action[6,21,26].
Another strength is the robustness of the experimental evidence. The study employed both in vitro hepatocyte culture models and in vivo mouse experiments, ensuring that the proposed mechanism was not confined to a single system. By demonstrating consistent effects across cellular and animal models, the authors significantly reinforced the validity of their findings. This dual-level evidence is particularly important in metabolic research, where results derived from reductionist models often fail to capture the complexity of interorgan interactions[7,13,26].
Importantly, this study establishes a direct link between β-cell stress induced by glucotoxicity and hepatic metabolic dysfunction. Previous studies have documented the release of islet-derived miRNAs into the circulation under β-cell injury[16,18,19], but Xu et al[20] extended this paradigm by demonstrating that such miRNA cargo, specifically miR-375-3p, can actively reprogram hepatocyte glycogen metabolism[26]. This connection between pancreatic stress and hepatic insulin resistance provides a coherent pathogenic model that may explain, at least in part, the progression from hyperglycemia to systemic metabolic deterioration in T2DM patients.
Collectively, these strengths highlight the conceptual and methodological rigor of the study, establishing exosomal miR-375-3p as a credible candidate for mediating pathological pancreas-liver crosstalk in glucotoxicity states[26].
Discussion - limitations and gaps
Despite its conceptual novelty, several limitations must be addressed before this exosome-miRNA axis can be fully integrated into the current understanding of T2DM pathogenesis or considered for clinical translation.
Lack of human data: A major limitation of the study by Xu et al[20] is the absence of validation in human subjects. All of the experimental evidence was derived from hepatocyte cell culture and murine models of glucotoxicity, which, although informative, cannot fully capture the complexity of human T2DM. It is well established that interspecies differences exist in pancreatic β-cell biology, miRNA expression patterns, and exosome biodistribution[3,4,19,27]. For example, murine β cells display distinct transcriptional networks and stress responses compared with their human counterparts, and hepatic glycogen metabolism in mice is more dynamic because of differences in feeding patterns and metabolic rates. These variations raise caution when extrapolating results directly to clinical settings. Furthermore, circulating miRNA profiles in humans are influenced by genetic heterogeneity, environmental exposure, and comorbid conditions, factors that cannot be accounted for in highly controlled animal experiments[18,28]. In the absence of validation in human serum, plasma, or liver tissue, it remains uncertain whether exosomal miR-375-3p is consistently elevated across different stages of prediabetes and T2DM. Thus, while Xu et al[20] provided strong mechanistic evidence in preclinical systems, the translational value of their findings depends on rigorous validation in well-characterized human cohorts, including longitudinal studies that assess temporal changes in circulating exosomal miR-375-3p across different stages of disease progression.
Challenges in liver-specific targeting of natural exosomes: Another significant gap lies in the inherent limitations of the use of natural exosomes as delivery vehicles. Owing to their biological nature, exosomes are released into the circulation and are distributed broadly across multiple organs. Although Xu et al[20] demonstrated uptake by hepatocytes, the efficiency and specificity of this process in vivo remain unclear. Prior studies have shown that exosome biodistribution is influenced by vesicle size, membrane composition, and the recipient tissue microenvironment, resulting in variable and often unpredictable targeting[6,7,29]. From a translational standpoint, this poses challenges for both mechanistic interpretation and therapeutic application[30]. If only a fraction of β-cell-derived exosomes reach the liver, the physiological impact of miR-375-3p transfer could be less pronounced than suggested by experimental models. Moreover, the systemic distribution of exosomes raises concerns regarding off-target effects, particularly if therapeutic strategies aim to harness or block this pathway. Achieving hepatocyte-specific delivery will likely require engineered exosomes or synthetic vesicle platforms, which are approaches that are still in development and face technical and regulatory hurdles[31]. Until such targeting strategies are refined, the natural biodistribution of exosomes remains a significant obstacle to interpreting their physiological role and therapeutic potential in T2DM.
Uncertainty regarding tissue specificity: The question of tissue specificity represents another unresolved limitation. While Xu et al[20] focused on the liver as the recipient organ of β-cell exosomal miR-375-3p, it is highly plausible that other insulin-sensitive tissues, including skeletal muscle and adipose tissue, also internalize these vesicles[31,32]. Previous studies have emphasized the systemic roles of exosomal miRNAs in mediating interorgan communication across metabolic tissues[13,33,34]. For example, exosomal cargo derived from adipocytes has been shown to modulate insulin sensitivity in muscle and liver, underscoring the bidirectional nature of vesicle-mediated signaling[9,25,35]. Without a comprehensive biodistribution map, it cannot be assumed that the liver is the exclusive, or even the dominant, target of β-cell-derived exosomal miR-375-3p. This uncertainty has important mechanistic and therapeutic implications. If exosomal miR-375-3p acts in multiple tissues simultaneously, its pathogenic role may be more complex than that of a single pancreas-liver axis, potentially influencing systemic insulin resistance through multiorgan pathways. Conversely, if tissue uptake varies according to disease stage or metabolic status, the functional relevance of miR-375-3p could shift over time. These considerations highlight the necessity of systematic in vivo tracking studies, ideally using labeled exosomes or tissue-specific knockout models, to delineate the true spectrum of target organs involved in this newly proposed signaling axis.
Ambiguity between physiological and pathological roles: Another conceptual gap relates to the uncertainty of whether exosomal miR-375-3p functions primarily as a pathological mediator or as part of an adaptive physiological response. Xu et al[20] interpreted its release under glucotoxicity conditions as pathogenic, contributing to hepatic insulin resistance. However, alternative interpretations are plausible. It is conceivable that exosomal miR-375-3p secretion represents an adaptive compensatory response aimed at redistributing regulatory signals during metabolic stress, thereby promoting homeostasis. In this context, parallels can be drawn to the dual role of autophagy in cancer and metabolic diseases, where the same process may exert protective or deleterious effects depending on context[16,18,24,26,36]. Without longitudinal data or models that distinguish between adaptive and maladaptive responses, the current interpretation risks oversimplification. This ambiguity has important implications for therapeutic targeting. If exosomal miR-375-3p has been shown to have protective functions in early disease stages, interventions aimed at inhibiting its release or blocking its hepatic uptake could inadvertently worsen metabolic outcomes. On the other hand, if its effects are consistently deleterious across contexts, targeting this pathway may hold therapeutic promise. Clarifying this distinction will require experimental designs that probe temporal dynamics, stress thresholds, and compensatory feedback mechanisms within the pancreas-liver axis.
Uncertainty regarding the utility of clinical biomarkers: Finally, the potential of exosomal miR-375-3p as a clinical biomarker remains unclear. Previous studies have suggested that circulating miR-375 levels reflect β-cell injury in both type 1 diabetes mellitus and T2DM[18,19,27]. However, it remains unclear whether exosomal miR-375-3p increases early enough in the disease trajectory to serve as a predictive biomarker or whether it simply reflects late-stage β-cell dysfunction[17]. Sensitivity and specificity are additional concerns, as circulating miRNA profiles can be influenced by numerous confounding factors, including age, obesity, inflammation, and medication use[28,33]. Moreover, the technical variability in the isolation and quantification of exosomal miRNAs from blood samples poses further barriers to clinical translation[20,33]. Establishing biomarker validity will require longitudinal cohort studies with standardized methodologies, as well as head-to-head comparisons with existing indicators of β-cell stress and hepatic insulin resistance. Only with such data can the field determine whether exosomal miR-375-3p is suitable as a diagnostic or prognostic biomarker or whether its value lies primarily in mechanistic insight rather than in clinical application.
Future directions and promising approaches
The identification of exosomal miR-375-3p as a mediator of pancreas-liver communication provides a new framework for understanding glucotoxicity and hepatic insulin resistance. Several key avenues warrant further investigation.
Clinical validation in humans: Longitudinal studies are needed to assess whether circulating exosomal miR-375-3p levels reflect β-cell stress and correlate with hepatic glycogen storage and insulin resistance across different stages of T2DM. Standardized exosome isolation and quantification methods are critical to ensure reproducibility and clinical relevance.
Mechanistic studies in vivo: Further research should clarify the tissue specificity and uptake dynamics of β-cell-derived exosomes, including potential effects on skeletal muscle and adipose tissue. Animal models and advanced imaging or labeling techniques could help map the systemic distribution and functional impact of miR-375-3p in metabolic tissues.
Therapeutic exploration: Modulating the exosome-miR-375-3p-RBPJ axis offers a potential strategy to improve hepatic glucose metabolism. Preclinical interventions targeting exosome release, miRNA inhibition, or the restoration of RBPJ activity could establish a proof-of-concept for novel therapies for diabetes.
Integration into multiorgan networks: Understanding how pancreatic exosomal miRNAs interact with other organs may provide a broader perspective on systemic glucose regulation and reveal additional therapeutic targets.
Collectively, these directions aim to bridge preclinical findings with clinical application, advancing both mechanistic understanding and potential interventions for T2DM. These proposed directions, which extend the exosomal miR-375-3p-mediated pancreas-liver axis from mechanistic discovery toward multiorgan integration and clinical translation, are summarized schematically in Figure 1.
Figure 1 Possible future directions of exosomal miR-375-3p-mediated pancreas-liver communication in type 2 diabetes.
Conceptual model summarizing current experimental observations, key unresolved questions, and hypothesized future implications of exosomal miR-375-3p-mediated pancreas-liver communication in type 2 diabetes. While mechanistic insights have been obtained in preclinical models, the relevance of this pathway in humans and its potential clinical significance remain to be determined.
