Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome
Open accessAbstract
Elucidating the pathophysiology and molecular attributes of common disorders as well as developing targeted and effective treatments hinges on the study of the relevant cell type and tissues. Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. We perform the first comparison of gene expression profiles between beta cells, whole islets, and beta cell depleted islet preparations, revealing thus beta-cell–specific expression and splicing signatures. Further, we demonstrate that genes with consistent increased expression in beta cells have neuronal-like properties, a signal previously hypothesized. Finally, we find evidence for extensive allelic imbalance in expression and uncover genetic regulatory variants (eQTLs) active in beta cells. This first molecular blueprint of the human beta cell offers biological insight into its differentiated function, including expression of key genes associated with both major types of diabetes.
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In contrast to mouse β-cells, the delayed rectifying K+ current in human β-cells is carried principally by Kv2.2 (KCNB2) and Kv1.6 (KCNA6) channels.
“In contrast to mouse β-cells, the delayed rectifying K+ current in human β-cells is carried principally by Kv2.2 (KCNB2) and Kv1.6 (KCNA6) channels (Appendix Figure 5A), which are expressed at high levels in the human β-cell and encode inactivating TEA-sensitive voltage-gated K+ channels (68, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results (page unavailable) describe gene-expression differences among human β-cells, islets, and non-β-cells, but do not identify which channels carry the delayed rectifying K+ current. Searches for KCNB2, KCNA6, the channel names, and a human–mouse comparison found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHuman β-cells mainly express SCN8A (Nav1.6), accounting for 40% of Na+ channel transcripts, with the remainder being SCN9A (Nav1.7), SCN3A (Nav1.3) and SCN2A (Nav1.2).
“Whereas mouse β-cells mainly express Scn9a (Nav1.7), SCN8A (Nav1.6) accounts for 40% of Na+ channel transcripts in human β-cells (68, 475) with the remainder being SCN9A (Nav1.7), SCN3A (Nav1.3) and SCN2A (Nav1.2) (see Appendix Figure 4).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results passages in our copy (page not provided) describe human β-cell transcript profiles but do not give a breakdown of sodium-channel transcripts. Searches for SCN8A, SCN9A, Nav1.6, and the claimed 40% figure found no passage addressing the claim. (LLM, conf=0.75)
Experimental — accuracy not yet measuredLike their mouse counterparts, human β-cells predominantly express SK3 (KCNN3), with other SKs being expressed at 10-fold lower levels.
“Like their mouse counterparts, human β-cells predominantly express SK3 (KCNN3) with other SKs being expressed at 10-fold lower levels (68, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe gene-expression profiles of human β-cells, but the passages in our copy do not compare SK-channel expression. Searches for KCNN3, SK3, and related channel terms found no passage establishing that SK3 predominates or that other SKs are expressed at 10-fold lower levels. (LLM, conf=0.75)
Experimental — accuracy not yet measuredIn human β-cells, ITPR3 is expressed at particularly high levels, approximately 10-fold greater than ITPR1 or ITPR2.
“In human β-cells, ITPR3 is expressed at particularly high levels (≈10-fold greater than ITPR1 or ITPR2) (68, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe gene expression in human β-cells, but the passages in our copy do not report expression of ITPR3 relative to ITPR1 or ITPR2. Searches for the gene names, inositol trisphosphate receptors, and a tenfold comparison found no passage addressing the claim; page numbers were not available. (LLM, conf=0.72)
Experimental — accuracy not yet measuredSLC17A9 expression in human β-cells is almost undetectable.
“Although SLC17A9 expression in human β-cells is almost undetectable (68, 475), stimulation of insulin secretion is still associated with ATP release (347).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe RNA sequencing of purified human β-cells and comparisons of gene expression, but the passages in our copy do not report SLC17A9 expression. Searches for SLC17A9 and its transporter name, VNUT, found no passage establishing that its expression is almost undetectable. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Expression of GABAA receptor β-subunits in human β-cells is much higher than α-subunits and is entirely accounted for by GABRB3.
“Expression of the β-subunits is much higher (Appendix Figure 18B) and is entirely accounted for by GABRB3 (68, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results and Discussion passages describe human beta-cell transcriptomes but do not compare GABAA receptor α- and β-subunit expression. Searches for GABRB3 and GABA receptor subunits found no passage establishing that GABRB3 accounts for all β-subunit expression. (LLM, conf=0.75)
Experimental — accuracy not yet measuredGABA transporters GAT1-3 are only expressed at low levels in mouse and human β-cells.
“However, these are only expressed at low levels in mouse and human β-cells alike (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe transcript expression in purified human β-cells, but the passages found do not report expression levels for GAT1–3 or their gene names. Searches for GABA transporters, SLC6A1/SLC6A12/SLC6A13, and mouse and human β-cells found no passage addressing the claimed low expression in both species. (LLM, conf=0.72)
Experimental — accuracy not yet measuredGlycine is cleared from interstitium by plasmalemmal glycine transporter GlyT1 (SLC6A9), which cotransports Na+.
“Following its release, glycine is cleared from the interstitium by the plasmalemmal glycine transporter GlyT1 (SLC6A9) (68, 475), which cotransports Na+.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results passages concern gene expression in human pancreatic beta cells, not glycine clearance from the interstitium. Searches for GlyT1, SLC6A9, glycine uptake, and sodium cotransport found no passage addressing the claim in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredBoth human and mouse β-cells express Slc6a17/SLC6a17, which encodes a synaptic vesicle glycine transporter.
“Both human and mouse β-cells also express Slc6a17/SLC6a17 (3, 68, 146, 475) that encodes a synaptic vesicle glycine transporter (502).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe transcriptomes of human β-cells and list selected expressed genes, but the passages found for SLC6A17/Slc6a17 do not mention that gene. The paper also does not establish its expression in mouse β-cells. I searched for the gene name and the synaptic-vesicle glycine-transporter description; neither yielded a passage supporting the attributed claim. (LLM, conf=0.72)
Experimental — accuracy not yet measuredExpression of functional GABAA receptors is very low in human α-cells.
“However, it should be noted that the expression of functional GABAA receptors is very low in human α-cells (89), an observation confirmed at the mRNA level (68, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results describe RNA expression differences between beta cells, islets, and nonbeta cells, but do not report GABAA-receptor transcript levels specifically in human α-cells. Searches for GABA, GABAA-receptor subunits, and gamma-aminobutyric acid found no passage confirming the claimed low expression at the mRNA level. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIAPP (amylin) is expressed at levels 1% and 10% of that of insulin in human and mouse β-cells, respectively.
“IAPP (amylin) is expressed at levels 1% and 10% of that of insulin in human (68, 475) and mouse β-cells, respectively (Appendix Figure 1A).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [475]
The Results report that INS accounts for approximately 38% of the human beta-cell transcriptome, but do not give IAPP expression or an IAPP-to-insulin ratio. Searches for IAPP, amylin, and the claimed 1% ratio found no passage supporting the human figure attributed to this paper. The mouse figure is attributed to the citing paper’s appendix, not this source. (LLM, conf=0.72)
Experimental — accuracy not yet measuredTop-attention genes included reported markers of specific cell types, such as LOXL4 for alpha cell and ADCYAP1 for beta cell.
“The top-attention genes included reported markers of specific cell types (i.e., LOXL4 for alpha cell and ADCYAP1 for beta cell 40 )(Extended Data Figure 6a).”
From scBERT as a Large-scale Pretrained Deep Language Model for Cell Type Annotation of Single-cell RNA-seq Data (2021) · cites this paper as [40]
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References 44 · Cited by 189
- Authors
- Nica, A. C., Ongen, H., Irminger, J.-C., Bosco, D., Berney, T., Antonarakis, S. E., Halban, P. A., & Dermitzakis, E. T.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Halban, Philippe A.
- Dermitzakis, Emmanouil T.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-05-28
- Volume
- 23
- Issue
- 9
- Pages
- 1554-1562
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3759730
- OpenAlex
- W2114055879
- Cited by
- 189
- References
- 44
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 20 · 2022: 12 · 2021: 10 · 2020: 13 · 2019: 15 · 2018: 17 · 2017: 18 · 2016: 24 · 2015: 26 · 2014: 15 · 2013: 4
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Louis-Jeantet Foundation
- Innovative Medicines Initiative (115317)
- 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
- pancreatic beta cells, pancreatic islets, beta cell differentiation, allelic imbalance, expression quantitative trait loci, type 1 diabetes, type 2 diabetes, single-cell RNA sequencing
- MeSH terms
- Alleles, Humans, Organ Specificity, Quantitative Trait Loci, Insulin-Secreting Cells, Gene Regulatory Networks, Transcriptome
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