Exploring Sex-Specific Mechanisms in Type 2 Diabetes Mellitus by Single-Cell Analysis in Pancreatic Islets

Pancreatic beta-cell dysfunction is a central feature of type 2 diabetes mellitus (T2DM), yet the influence of biological sex on beta-cell pathophysiology remains underexplored [1,2]. Epidemiological studies consistently demonstrate sex differences in T2DM risk profiles, complications, and therapeutic responses; however, the mechanistic basis underlying these disparities is not fully understood [3,4]. In particular, sex differences at the level of pancreatic beta-cell biology have not been investigated in depth.

The study by Van Anh et al. [5] represents an important advance in understanding sex differences in T2DM by elucidating sex-specific transcriptomic signatures in pancreatic beta-cells. Through integrated single-cell RNA sequencing datasets, the authors identified a male-enriched beta-cell cluster characterized by downregulation of protein metabolism and insulin synthesis pathways, altered vesicle transport, and distinct ligand–receptor signaling networks. These findings highlight the need to incorporate sex-disaggregated analyses not only in clinical trials but also in basic and translational research.

The advent of single-cell transcriptomics has revolutionized diabetes research by providing unprecedented resolution of islet heterogeneity [5,6]. Xin et al. [7] build upon earlier reports of functional sex differences by describing a male-enriched beta-cell subpopulation associated with endoplasmic reticulum stress pathways and immune-modulatory ligand–receptor interactions, including TNFSF18–TNFRSF18 and NGF–NTRK1. These molecular cues suggest that male islets may be particularly vulnerable to dysfunction and apoptosis. In this cluster, genes such as VAMP4, CDC7, and PIGR were upregulated. The authors further validated their findings using independent public bulk RNA-seq datasets from pancreatic islets of male and female donors. In addition, trajectory inference and gene set enrichment analysis revealed that male beta-cells are not merely quantitatively reduced or functionally inferior but are transcriptionally distinct in stress responses and intercellular communication.

These findings bring the field closer to precision medicine by providing a molecular evidence basis which may potentially explain the observed sexual differences in T2DM outcomes. Notably, the identification of novel ligand–receptor pairs (e.g., NPPA–NPR1, CD160–TNFRSF14) suggests a novel therapeutic targets or biomarkers for T2DM development or progression.

The precise mechanisms underlying these sex differences remain uncertain. Because VAMP4, CDC7, and PIGR are located on chromosome 1 rather than sex chromosomes, these transcriptomic differences may arise from environmental or hormonal influences (e.g., estrogen or testosterone) rather than inherent genetic determinants. Previous studies, including our own, have demonstrated that sex-specific exposures such as pregnancy or testosterone treatment can modulate beta-cell characteristics [5,8,9].

Importantly, Van Anh et al. [5] also showed that sex-specific beta-cell subpopulations in T2DM exhibit altered ligand–receptor landscapes, affecting communication with neighboring endocrine and stromal cells. Recent studies emphasize the critical role of intercellular communication in beta-cell function within the islet microenvironment. At the beta–alpha cell interface, Tong et al. [10] demonstrated that beta-cells adjacent to alpha-cells express glucagon-like peptide-1 receptor nanodomains, which are pre-internalized under low-glucose conditions and allow for earlier, amplified insulin responses upon glucose elevation. Similarly, Pourhosseinzadeh et al. [11] described heterogeneity in beta–delta cell communication, mediated by Cx36 gap junctions and beta-cell–derived paracrine signals, which synchronize delta-cell calcium oscillations with beta-cell activity. Furthermore, Basile et al. [12] showed that in T2DM, aberrant deposition of exocrine-derived elastase (CELA3B) within the islet niche impairs beta-cell viability and insulin secretion by disrupting mechanosignaling and PAR2 pathways; notably, this pathological acinar–beta-cell communication was reversible with targeted elastase inhibition. Within this framework, Van Anh et al. [5] proposed NPPA–NPR1 signaling as a male-specific beta–delta cell interaction and CD160–TNFRSF14 signaling as a male-specific pathway involving beta–alpha or beta–acinar cells. Functional studies to validate these mechanisms will be critical for determining whether sex-specific intercellular signaling contributes to beta-cell vulnerability.

Although bulk RNA sequencing provided validation, limitations remain. The relatively small number of beta-cells analyzed and reliance on publicly available datasets warrant cautious interpretation. Moreover, functional studies are required to confirm whether modulation of candidate genes (e.g., VAMP4, CDC7, and PIGR) can enhance beta-cell survival or insulin secretion in a sex-dependent manner. Future work integrating proteomic, epigenomic, and spatial transcriptomic approaches in sex-stratified, prospective cohorts will be important to fully clarify the implications of these subpopulations.

In summary, the work by Van Anh et al. [5] highlights a previously unrecognized dimension of beta-cell biology, demonstrating that sex differences in T2DM extend to the single-cell, transcriptomic level. These insights challenge to conventional approaches to diabetes care and establish the foundation for sex-dependent strategies in beta-cell protection and therapeutic development, thereby advancing the field toward precision medicine.