Single-cell decoding of human islet cell type-specific alterations in type 2 diabetes reveals converging genetic- and state-driven β-cell gene expression defects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Pancreatic islets maintain glucose homeostasis through coordinated action of their constituent endocrine and affiliate cell types are central to type 2 diabetes (T2D) genetics pathophysiology. Our understanding robust human islet type-specific alterations in T2D remains limited. Here, we report comprehensive single transcriptome profiling 245,878 cells from a 48-donor cohort spanning non-diabetic (ND), pre-diabetic (PD), states, identifying 14 distinct detected every donor each glycemic state. Cohort analysis reveals ∼25-30% loss functional beta mass vs. ND or PD donors resulting (1) reduced total numbers/proportions (2) reciprocal 'high function' gain senescent β-cell subpopulations. We identify β-cells 511 differentially expressed genes (DEGs), including new (66.5%) validated (e.g., FXYD2, SLC2A2, SYT1 ), significant neuronal transmission vitamin A metabolism pathway alterations. Importantly, demonstrate newly identified DEG roles viability and/or insulin secretion link 47 DEGs diabetes-relevant phenotypes knockout mice, implicating them as potential causal dysfunction genes. Additionally, nominate candidate therapeutic targets 27 for which genetic risk variants (GWAS SNPs) pathophysiology (T2D ND) exert concordant expression effects. provide this freely accessible atlas data exploration, analysis, hypothesis testing. Together, study provides genomic resources insights into dysfunction.

Language: Английский

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Single-cell genomics and spatial transcriptomics in islet transplantation for diabetes treatment: advancing towards personalized therapies

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 20, 2025

Diabetes mellitus (DM) is a global health crisis affecting millions, with islet transplantation emerging as promising treatment strategy to restore insulin production. This review synthesizes the current research on single-cell and spatial transcriptomics in context of transplantation, highlighting their potential revolutionize DM management. Single-cell RNA sequencing, offers detailed look into diversity functionality within grafts, identifying specific cell types states that influence graft acceptance function. Spatial complements this by mapping gene expression tissue's context, crucial for understanding microenvironment surrounding transplanted islets interactions host tissues. The integration these technologies comprehensive view cellular microenvironments, elucidating mechanisms underlying function, survival, rejection. instrumental developing targeted therapies enhance performance patient outcomes. emphasizes significance avenues informing clinical practices improving outcomes patients through more effective strategies. Future directions include application personalized medicine, developmental biology, regenerative predict disease progression responses. Addressing ethical technical challenges will be successful implementation integrated approaches practice, ultimately enhancing our ability manage improve quality life.

Language: Английский

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DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets

Metabolism, Journal Year: 2025, Volume and Issue: 164, P. 156132 - 156132

Published: Jan. 11, 2025

Language: Английский

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The role of endoplasmic reticulum stress in type 2 diabetes mellitus mechanisms and impact on islet function

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e19192 - e19192

Published: March 28, 2025

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder characterized by insulin resistance and dysfunction of islet cells. Endoplasmic reticulum (ER) stress plays crucial role in the pathogenesis progression T2DM, especially function survival β-cells. β-cells are particularly sensitive to ER because they require substantial synthesis secretion energy. In early stages increased demand for exacerbates β-cell stress. Although unfolded protein response (UPR) can temporarily alleviate this stress, prolonged or excessive leads pancreatic cell apoptosis, resulting insufficient secretion. This review explores mechanisms its impact on We discuss how activates UPR signaling pathways regulate folding degradation, but when becomes excessive, these may contribute death. A deeper understanding impacts cells could lead development novel T2DM treatment strategies aimed at improving slowing disease progression.

Language: Английский

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Recent progress in modeling and treating diabetes using stem cell-derived islets

Stem Cells Translational Medicine, Journal Year: 2024, Volume and Issue: 13(10), P. 949 - 958

Published: Aug. 19, 2024

Abstract Stem cell-derived islets (SC-islets) offer the potential to be an unlimited source of cells for disease modeling and treatment diabetes. SC-islets can genetically modified, treated with chemical compounds, or differentiated from patient derived stem model These models provide insights into pathogenesis vulnerabilities that may targeted treatment. themselves are also being investigated as a cell therapy However, transplantation process is imperfect; side effects immunosuppressant use have reduced SC-islet therapeutic potential. Alternative methods this include encapsulation, immunomodulating molecules, genetic modification SC-islets. This review covers recent advances using understand different diabetes pathologies therapy.

Language: Английский

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β‐Cell gene expression stress signatures in types 1 and 2 diabetes

Journal of Diabetes, Journal Year: 2024, Volume and Issue: 16(11)

Published: Nov. 1, 2024

Diabetes mellitus (DM) is a chronic metabolic disorder that occurs when pancreatic β-cells can no longer produce enough insulin to maintain normal blood glucose levels. DM presently affects 10.5% of the world adult population. While T1D disease "mistaken identity," where immune system attacks and destroys in context islet inflammation (insulitis),1 T2D associated with sedentary lifestyles high-fat diets, typically involving ineffective use progressive loss β-cell function.1 Both diseases result from multifaceted interactions between genetic environmental factors, failure as core mechanism pathogenesis. In T1D, arises complex interaction cells β-cells, chemokine cytokine release signals stressed or dying attract activate islets lead apoptosis.2 Beyond destruction by system, it now accepted stress impaired function these significantly contribute onset progression disease.1-3 T2D, driven an interplay resistance dysfunction genetically susceptible individuals, perhaps also impairing secretion eventually survival, although less degree than T1D.1, 4, 5 The complexity diabetes pathogenesis makes very difficult identify specific causes disease, which hampers development adequate therapies protect thus prevent disease. This difficulty was well described Tolstoy, his masterpiece "War Peace," published 1869 (in this case addressing Napoleonic war against tsarist Russia): "…the impulse seek innate soul man. And human intellect, inkling on immense variety circumstances conditioning phenomena, any one may be separately conceived cause it, snatches first most easily understood approximation, says here cause." pathophysiology, had led simplistic view "one gene, protein, disease." However, sequencing genome subsequent advent omics technologies allow interrogating whole parallel often sequential way, our understanding changed: we focus gene transcription factor networks post-transcriptional post-translational mechanisms. single-cell RNA (scRNA-seq) has provided new tool for dissecting molecular intricacies underlying mechanisms closer its real "immense circumstances." A recent study Maestas et al. focused utilizing vitro models investigate effects ER inducers (thapsigargin, brefeldin A) inflammatory cytokines (IFNγ, IL1β, TNFα, their combination) using five donors scRNA-seq analysis.6 interesting information, but limited number conditions model have not fully captured vivo context. To further signatures potentially present analyzed data Human Pancreas Analysis Program (HPAP).7, 8 HPAP provides extensive public database non-diabetic individuals affected offering valuable resource disease-specific transcriptional profiles β-cells. We re-analyzed up 12.2023, includes 10X Genomics 27 non-diabetic, 7 10 previously pipeline.9 employed indexed signature scoring method,9-11 profile six sets signatures, namely, inflammation, senescence, autophagy, apoptosis, endoplasmic reticulum (ER) protein processing, unfolded response (UPR). collected previous study, comprises 80 genes highly stimulated (i.e., >3 fold) IFN-α, IFN-γ, IL-1β insulin-producing EndoC-βH1 cells.9 remaining are derived Reactome Kyoto Encyclopedia Genes Genomes (KEGG) databases included following genes: 157 cellular senescence; 146 autophagy; 140 apoptosis; 170 processing; 92 UPR. potential limitation analysis diverse recovered three groups (15 281 controls, 585 1455 T2D), due both different inherent course (associated isolating diabetes). spite methodological limitation, revealed all were upregulated showing higher scores forms (Figure 1). Notably, exhibited >200% increase score compared controls. There clear apoptosis (20%–43%), only mild (6%–27%) These results confirm extend observations al.6 experience multiple stress, while emphasizing undergo more severe line faster massive T2D.5 Proper processing under necessitates physiological transient activation UPR, prolonged excessive ("terminal" UPR) trigger cell death.5 understand relationship UPR senescence diabetes, conducted correlation above index scores. significant positive 2), strongest observed 2A), detection histology markers T1D.12 causality developed regression formulations: ~ + autophagy found signaling pathways together effectively predict death (R2 = 0.80) 0.75). implications ours findings twofold. First, targeting pathways—particularly senescence—may offer therapeutic strategy and, extent, T2D. observations, however, must considered caution instance alone sufficient many secretory phenotype downstream factors NF-κB STATs,13 part autoimmune-induced insulitis,2, making discriminate senescence- inflammation-induced T1D. support role components contributing demonstration targeted elimination senescent non-obese (NOD) diabetic mice,14 fact early residual patients T1D.15 indicated Excessive and/or contributes promoting resistance.16 IRE1, UPR's master regulators, induces degeneration at "terminal" level, inhibition IRE1 mouse protects provide opportunities diabetes.17 Moreover, another regulator, namely eIF2α kinase PERK, reverses translation blockade prevents NOD mice.18 Of interest, there crosstalk stresses, deletion ATF6 IRE1α mice before insulitis leads p21-driven paradoxically reduces terminal incidence diabetes.15 Future research should explore leading-edge discussed above, combined impact survival across types diabetes. comment highlights method based 44 donors. Key indicate (and extent T2D) characterized elevated disturbances pathways. Strong correlations senescence. add relevant information emphasize relevance studying tissues autoimmune degenerative search better address level complexity.10, 19 Decio L. Eizirik conceptualized Xiaoyan Yi performed drafted manuscript. contributed reviewing, editing, adding content. authors approved final version keeping latest guidelines International Committee Medical Journal Editors. serve guarantors work. grateful Database Consortium publicly available. Research supported grants Breakthrough (formerly JDRF (3-SRA-2022-1201-S-B [1] 3-SRA-2022-1201-S-B [2])); National Institutes Health - Islet Network Beta Cell Death & Survival Pancreatic β-Cell Gene Networks Therapy (HIRN-CBDS) (grant U01 DK127786); NIDDK grants, RO1DK126444 RO1DK133881-01. declare conflicts interest related commentary.

Language: Английский

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Beta cells are essential drivers of pancreatic ductal adenocarcinoma development

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease. For instance, endocrine islet beta (β) cell secretion of insulin or cholecystokinin (CCK) promotes progression pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. However, the cellular molecular mechanisms that govern signaling tumorigenesis remain incompletely understood. We find β ablation impedes PDAC development mice, arguing pancreas is critical for tumorigenesis. Conversely, obesity induces hormone dysregulation, alters CCK-dependent peri-islet transcriptional states, enhances proximal tumor formation. Single-cell RNA-sequencing,

Language: Английский

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Coxsackievirus B infection invokes unique cell-type specific responses in primary human pancreatic islets

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Coxsackievirus B (CVB) infection has long been considered an environmental factor precipitating Type 1 diabetes (T1D), autoimmune disease marked by loss of insulin-producing β cells within pancreatic islets. Previous studies have shown CVB negatively impacts islet function and viability but do not report on how virus individually affects the multiple cell types present in human primary Therefore, we hypothesized that various populations unique transcriptional responses to infection. Here, performed single-cell RNA sequencing cadaveric islets treated with either or poly(I:C), a viral mimic, for 24 48 hours. Our global analysis reveals differentially induces dynamic changes associated processes functions over time whereas poly(I:C) promotes immune response progressively increases treatment duration. At resolution, find infects all at similar rates yet cell-type specific β, α, ductal having strongest response. Sequencing functional data suggest mitochondrial respiration morphology distinct ways α cells, while also promoting generation reactive oxygen species. We observe increase expression long-noncoding

Language: Английский

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Anti-diabetic effects of marine natural products through redox modulation via Nrf2/HO-1 cytoprotective pathways

Frontiers in Marine Science, Journal Year: 2024, Volume and Issue: 11

Published: Nov. 13, 2024

Diabetes mellitus (DM), a major global health concern, is chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, current study attempts to highlight anti-diabetic effects molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, damage are linked most human pathologies specifically DM. The Nrf2/HO-1 pathway key defense mechanism developed cells combat ROS burst. Marine strong pharmacological potential triggering antioxidant declining inflammation How potentially alleviate DM type diabetes (T2D) its related issues especially focused on. literature was thoroughly analyzed open discussion about specific well-established elucidate possible applications. Furthermore, opportunities pros cons of using bioactive complementary treatment for also discussed. diverse characteristics products, with regard control, offer promising drug discovery interventions clinical trials.

Language: Английский

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DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 24, 2024

Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic β-cell stress and apoptosis. However, the mechanisms underpinning protective effects of remain unknown. Biochemical studies, qPCR, proteomics, immuno-confocal microscopy were conducted to determine underlying β-cells. DOC2b- enriched or-depleted primary islets (human mouse) lines challenged with or without proinflammatory cytokines, global heterozygous knockout mice subjected multiple-low-dose-streptozotocin (MLD-STZ), used for these studies. A significant elevation stress-induced CXCL10 mRNA was observed depleted mouse islets. enrichment markedly attenuated levels non-diabetic also reduced total-NF-κB p65 protein T1D mimicking cytokines. IKKβ, NF-κB p65, STAT-1 capable associating cytokine-challenged cytokine-stressed corresponded a reduction activated total IKKβ levels. Total IκBβ increased DOC2b-enriched acute cytokine challenge. Cytokine-induced Intriguingly, prevents ER-stress-IKKβ crosstalk rat INS1-832/13 line. The involve attenuation IKKβ-NF-κB signaling, expression.

Language: Английский

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