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

Joonyub Lee

doi:10.3803/EnM.2025.2678

Articles

Page Path: HOME > Endocrinol Metab > Volume 40(5); 2025 > Article

Editorial Diabetes, obesity and metabolism Exploring Sex-Specific Mechanisms in Type 2 Diabetes Mellitus by Single-Cell Analysis in Pancreatic Islets: Joonyub Lee; Endocrinology and Metabolism 2025;40(5):699-701.
DOI: https://doi.org/10.3803/EnM.2025.2678
Published online: October 29, 2025

Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author: Joonyub Lee. Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6005, Fax: +82-2-3147-9566, E-mail: likeasisay@empal.com

• Received: September 20, 2025 • Accepted: October 2, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2,207 Views
40 Download

prev next

Full Article

Download PDF

Article information
References

ⓘ

See the Original "Exploring Sex Differences in Type 2 Diabetes via a Male-Dominant Beta-Cell Cluster from Single-Cell Pancreatic Sequencing of Public Datasets" on page 706.

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.

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

1. Lee J, Yoon KH. β Cell replacement therapy for the cure of diabetes. J Diabetes Investig 2022;13:1798–802.Article PubMed PMC PDF
2. Lee J, Yoon KH. Evolving characteristics of type 2 diabetes mellitus in East Asia. Endocrinol Metab (Seoul) 2025;40:57–63.Article PubMed PMC PDF
3. Hu G; DECODE Study Group. Gender difference in all-cause and cardiovascular mortality related to hyperglycaemia and newly-diagnosed diabetes. Diabetologia 2003;46:608–17.Article PubMed PDF
4. Kautzky-Willer A, Leutner M, Harreiter J. Sex differences in type 2 diabetes. Diabetologia 2023;66:986–1002.Article PubMed PMC PDF
5. Van Anh N, Gil HW, Park S, Ryu S. Exploring sex differences in type 2 diabetes via a male-dominant beta-cell cluster from single-cell pancreatic sequencing of public datasets. Endocrinol Metab (Seoul) 2025;40:706–17.Article PubMed PMC PDF
6. Moon JH, Lee J, Kim KH, Kim HJ, Kim H, Cha HN, et al. Multiparity increases the risk of diabetes by impairing the proliferative capacity of pancreatic β cells. Exp Mol Med 2023;55:2269–80.Article PubMed PMC PDF
7. Xin Y, Kim J, Okamoto H, Ni M, Wei Y, Adler C, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab 2016;24:608–15.Article PubMed
8. Makkar G, Shrivastava V, Hlavay B, Pretorius M, Kyle BD, Braun AP, et al. Lrrc55 is a novel prosurvival factor in pancreatic islets. Am J Physiol Endocrinol Metab 2019;317:E794–804.Article PubMed PMC
9. Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G, et al. Extranuclear actions of the androgen receptor enhance glucose-stimulated insulin secretion in the male. Cell Metab 2016;23:837–51.Article PubMed PMC
10. Tong JCL, Frazer-Morris C, Shilleh AH, Viloria K, de Bray A, Nair AM, et al. Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication. Cell Metab 2025;37:1698–714.e5.Article PubMed PMC
11. Pourhosseinzadeh MS, Huang JL, Shin D, Hart RG, Framroze LY, Guillen JV, et al. Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low-density Cx36 gap junctions. Proc Natl Acad Sci U S A 2025;122:e2504151122.Article PubMed PMC
12. Basile G, Vetere A, Hu J, Ijaduola O, Zhang Y, Liu KC, et al. Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways. Cell Metab 2023;35:1242–60.e9.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite

Cite: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

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

Endocrinol Metab. 2025;40(5):699-701. Published online October 29, 2025

DOI: https://doi.org/10.3803/EnM.2025.2678

XML Download

Related articles

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