Single-Cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells
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Abstract
Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.
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In male mice, specific upregulated DEGs were associated with mitochondrial function, which is known to affect the process of insulin secretion.
“In male mice, specific upregulated DEGs were associated with mitochondrial function, which is known to affect the process of insulin secretion.”
From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [84]
In Results (‘Extensive sex-dependent T2D gene expression alterations in mouse β cells’; page unavailable), the paper identifies the mitochondrial-function genes Cox4i1 and Ndufb7 as down-regulated in β cells of male T2D mice, contrary to the claim that they were upregulated. The same passage does associate mitochondrial function with insulin secretion capacity. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn females, some of these DEGs were associated with impaired endoplasmic reticulum stress responses.
“In females, some of these DEGs were associated with impaired endoplasmic reticulum stress responses.”
From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [84]
The Results section on sex-dependent T2D gene expression (page unavailable in our copy) reports that two genes up-regulated in female diabetic mouse β cells, Serp1 and Ero1lb, encode ER stress-associated proteins. It suggests differences in ER stress responses, but does not establish that those responses were impaired. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe two sexes share some aspects of the disease pathogenesis since sex-independent DEGs involving several disease-specific processes were also demonstrated.
“However, the two sexes share some aspects of the disease pathogenesis since sex-independent DEGs involving several disease-specific processes were also demonstrated [84].”
From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [84]
In diabetic mice, other T2D sex-specific DEGs were identified in comparison with healthy mice, some showing female superiority, while others being expressed to a greater extent in male mice.
“In the same study, other T2D sex-specific DEGs were identified in diabetic mice in comparison with healthy mice, some showing female superiority, while others being expressed to a greater extent in male mice.”
From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [84]
The insulin II gene appeared to have a more pronounced expression in male compared to female β-cells of healthy mice.
“With regard to sex-specific DEGs, the insulin II gene may serve as an example since it appeared to have a more pronounced expression in male compared to female β-cells of healthy mice.”
From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [84]
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- Authors
- Liu, G., Li, Y., Zhang, T., Li, M., Li, S., He, Q., Liu, S., Xu, M., Xiao, T., Shao, Z., Shi, W., & Li, W.
- Affiliations
- Tongji University (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Pennsylvania State University (US)
- Ocean University of China (CN)
- Corresponding author
- Shao, Zhen
- Shi, Weiyang
- Li, Weida
- ORCID
- Venue
- Genomics, Proteomics & Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-06-01
- Volume
- 19
- Issue
- 3
- Pages
- 408-422
- ISSN
- 1672-0229 (ISSN-L)
- 2210-3244
- PMC
- PMC8864195
- OpenAlex
- W3201663978
- Cited by
- 30
- References
- 71
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 1
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Genomics Proteomics & Bioinformatics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Key R&D Program of China (2016YFA0102200, 2017YFA0106500, 2018YFA0107102, 2020YFA0112500 awarded to WL, 2018YFA0107602 awarded to ZS, 2018YFD0900604 awarded to WS)
- Key Project of the Science and Technology Commission of Shanghai Municipality, China (19JC1415300 awarded to WL)
- National Natural Science Foundation of China (41676119, 41476120 awarded to WS)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- type 2 diabetes, sex differences, pancreatic beta cells, high-fat diet-induced diabetes, islet transplantation, glucose tolerance, diabetes susceptibility
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Male, Sequence Analysis, RNA, Insulin-Secreting Cells, Mice, Transcriptome
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