Biology subjects

Korsgren, O.

Publications and source records attributed to Korsgren, O..

8 recordsLinked to original sources

bioRxiv2026

Spatial and functional mapping of the human pancreas reveals endocrine and exocrine cell states in health and metabolic disease

The human pancreas contains diverse endocrine and exocrine cell populations whose spatial organization is essential for tissue physiology. While single-cell and spatial transcriptomics revealed molecular heterogeneity across pancreatic cell types, linking these states to physiological activity in situ has remained challenging. Here, we combined single-nucleus RNA sequencing, spatial transcriptomics, and functional calcium imaging across pancreatic samples in health and metabolic disease. We identified heterogeneous endocrine and exocrine cell states associated with obesity and diabetes, including inflammatory remodeling of acinar and ductal populations. To directly couple tissue physiology with molecular state, we developed Slice-seq, which integrates calcium imaging with spatial transcriptomics in acute pancreatic slices. Slice-seq linked local endocrine composition and transcriptional programs with {beta} cell activity and identified extra-islet {beta} cells with reduced glucose responsiveness and mitochondrial oxidative metabolism. Together, our study provides a framework for linking pancreatic cell states to tissue organization and physiological activity in health and disease.

genomics↗

bioRxiv2025

Single-cell proteomics of pancreatic islet cells reveals type 1 diabetes and donor-specific features

Type 1 diabetes mellitus (T1DM) is the most common severe chronic disease in children and adolescents and requires life-long exogenous insulin treatment. Investigating key differences between the pancreas of healthy and T1DM patients is key to help uncover new treatments. Here we performed a single-cell proteomic (SCP) analysis of purified pancreatic islets from several healthy and T1DM donors at a depth of > 4000 protein quantified. We employed tools designed for single-cell mRNA sequencing (scRNAseq) for cell type annotation highlighting discrepancies between mRNA and protein markers. Subsequently, we defined a subset of markers useful for future proteomics analyses of pancreatic islets. This marker list was employed to refine the annotations of our combined dataset, which we exploited with a machine learning approach to successfully transfer annotations into a new islet dataset. Lastly, we showcase the applicability and value of SCP in a clinical context by providing novel insights into cell type-specific differences between healthy and T1DM islets as well as between healthy islets of different donors. Our study is the first SCP analysis of pancreatic islets from multiple donors and T1DM islets, performed at this level of analytical depth. This provides methodological and biological insight as well as a reference dataset for future SCP studies and for any researcher interested in T1DM and in pancreatic islet physiology.

biochemistry↗

bioRxiv2025

Deep tissue optical 3D imaging reveals preferential preservation of extra-islet β-cells in late-onset Type 1 Diabetes

As residual {beta}-cell function may have positive effects on diabetes regulation in T1D, details on its spatial distribution and mass could provide important information for potential future therapeutic regimens. We implemented an optical 3D imaging pipeline to generate a first account of the 3D-spatial and volumetric distribution of the remaining {beta}-cells throughout the volume of an entire human late onset T1D pancreas at a microscopic resolution. As expected, {beta}-cell mass was dramatically lower than in the non-diabetic pancreas. However, the pancreatic head displayed a morphology and size resembling the non-diabetic pancreas and had a 3 times higher {beta}-cell density compared to the rest of the organ. Surprisingly, only a fraction of the residual {beta}-cells were located within islet structures. Instead, the absolute majority were present as extra-islet {beta}-cells, either as scattered individual cells or as clusters of {beta}-cells, spatially separated from all other endocrine cell-types. Jointly, these extra-islet {beta}-cells appeared roughly 60x less prone to succumb than islet associated {beta}-cells. In sharp contrast to {beta}-cell mass, -cell density appeared unaffected. This 3D whole organ depiction of an entire long standing, late onset, T1D pancreas shows that individual {beta}-cells may be preserved in a highly regionalized manner, potentially reflecting key aspects of disease dynamics.

pathology↗

bioRxiv2023

Illuminating the complete β-cell mass of the human pancreas - signifying a new view on the islets of Langerhans

Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, a new 3D imaging pipeline was applied to generate a first complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing a-cells, an observation with significant implications for both experimental and clinical research. One Sentence Summary: New islet heterogeneity identified in the human pancreas

cell biology↗

bioRxiv2021

A new animal model signifying a decisive bridge between innate immunity and the pathognomonic morphological characteristics of Type 1 Diabetes

Available animal models for Type 1 Diabetes (T1D) show limited similarities with the human disease and have no predictive value in screening for effective intervention therapies. Heat-inactivated bacteria instilled in the ductal compartment of the pancreas in healthy rats rapidly cause periductal inflammation and accumulation of mainly granulocytes and monocytes in the exocrine pancreas and in the peri-islet area mimicking the acute pancreatic inflammation in subjects with recent onset T1D. After three weeks, the triggered exocrine inflammation had vanished and pancreases showed normal morphology. However, a distinct accumulation of both CD4+ and CD8+ T cells within and adjacent to affected islets was found in one third of the rats, mimicking the pathognomonic insulitis in T1D. As in human T1D, the insulitis affected a fraction of all islets and was observed only in certain lobes of the pancreases. The presented animal model for T1D will allow detailed mechanistic studies to unravel a previously unknown interplay between bacteria-activated innate immunity and an acquired cellular immunity forming the immunopathological events described in humans at different stages of T1D. Summary StatementThe results presented signify a previously unknown decisive bridge between innate immunity and formation of the pathognomonic immunopathological events described in subjects with recent onset T1D.

immunology↗

bioRxiv2021

Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes and normal tissues

Defects in pancreatic islets and the progression of multi-tissue insulin resistance in combination with environmental factors are the main causes of type 2 diabetes (T2D). Mass spectrometry-based proteomics of five key-metabolic tissues on a cohort of 42 multi-organ donors provided deep coverage of the proteomes of pancreatic islets, visceral adipose tissue (VAT), liver, skeletal muscle and serum. Enrichment analysis of gene ontology (GO) terms built a tissue-specific map of the chronological order of altered biological processes across healthy controls (CTRL), pre-diabetes (PD) and T2D subjects. This unique dataset allowed us to explore alterations of entire biological pathways and individual proteins in multiple tissues. We confirmed the significant decrease of the citric acid cycle and the respiratory electron transport in VAT and muscle of T2D and we provided a thorough visual representation of the complete set of downregulated proteins. Importantly, we found widespread novel alterations in relevant biological pathways including the increase in hemostasis in pancreatic islets of PD, the increase in the complement cascade in liver and pancreatic islets of PD and the elevation in cholesterol biosynthesis in liver of T2D. Overall, our findings suggest inflammatory, immune and vascular impairments in pancreatic islets as potentially causal factors of insufficient insulin production and increased glucagon levels in the early stages of T2D. In contrast alterations in lipid metabolism and mitochondrial function in the liver and VAT/muscle, respectively, became evident later in manifest T2D. This first multi-tissue proteomic map indicates the temporal order of tissue-specific metabolic dysregulation in T2D development.

cell biology↗

bioRxiv2018

Characterization of the endocrine pancreas in Type 1 Diabetes: islet size is maintained but islet number is markedly reduced

Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of specific beta-cell loss. Since healthy pancreatic islets consist of ~65% beta cells, this would lead to reduced islet size if the beta cells are not replaced by other cells or tissue. The number of islets per pancreas volume (islet density) would not be affected.\n\nIn this study, we compared the islet density, size, and size distribution in subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. Results show that subjects with T1D, regardless of disease duration, had a dramatically reduced islet number per mm2, while the islet size was similar in all groups. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that frequently had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally expressed in beta cells.\n\nBased on our findings, we propose that failure during childhood to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

pathology↗

bioRxiv2018

Islet Gene View - a tool to facilitate islet research

Changes in the hormone-producing pancreatic islets are central culprits in type 2 diabetes (T2D) pathogenesis. Characterization of gene expression in islets how it is altered in T2D are therefore vital in understanding islet function and T2D pathogenesis. We leveraged RNA-sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. The IGW combines expression data for a given gene with phenotypical data such as T2D status, BMI, HbA1c, insulin secretion, purity of islets, etc.), regulation of gene expression by genetic variants e.g., expression quantitative trait loci (eQTLs) and relationship with expression of islet hormones. In IGW, 285 differentially expressed genes (DEGs) were identified in T2D donors islets compared to controls. Forty percent of the DEGs showed cell-type enrichment and a large proportion of them were significantly co-expressed with islet hormone-encoding genes like glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%) and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2 impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. Significance StatementWe present Islet Gene View (IGW), a web resource facilitating information on gene expression in human pancreatic islets from organ donors easily accessible to the scientific community. In IGW, we explored RNA expression from 188 donor-islets and examined their relationship with islet phenotypes including insulin secretion and expression of genes encoding islet hormones. GWAS have shown 403 genetic variants associated with risk of type 2 diabetes (T2D) risk, however, the target genes and function of these variants in islets are largely unknown. By linking T2D risk variants to expression in islets from T2D and non-diabetic donors as well as islet phenotypes, use of IGW provided new insight into mechanisms by which variants in these loci may increase risk of T2D.

molecular biology↗