β‐Cell gene expression stress signatures in types 1 and 2 diabetes DOI Creative Commons
Xiaoyan Yi, Décio L. Eizirik

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

Linking molecular pathways and islet cell dysfunction in human type 1 diabetes DOI Creative Commons
Theodore dos Santos,

Xiao Qing Dai,

Robert C. Jones

et al.

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

Published: Feb. 21, 2025

Summary Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β-cells, along with dysregulated glucagon secretion from pancreatic α-cells. We conducted an integrated analysis that combines electrophysiological and transcriptomic profiling, machine learning, islet cells T1D donors to investigate mechanisms underlying their dysfunction. Surviving β-cells exhibit altered properties signatures indicative increased antigen presentation, metabolic reprogramming, impaired protein translation. In α-cells, we observed hyper-responsiveness exocytosis, which are associated upregulated immune signaling, disrupted transcription factor localization lysosome homeostasis, as well dysregulation mTORC1 complex signaling. Notably, key genetic risk signals for were enriched in transcripts related α-cell dysfunction, including MHC class I closely linked Our data provide novel insights into molecular underpinnings cell dysfunction T1D, highlighting pathways may be leveraged preserve residual β-cell function modulate activity. These findings underscore interplay between stress, cellular identity shaping phenotypes T1D. Highlights show electrical reprogramming stress. Transcripts alleles Upregulated nuclear factors associate α-cells hyper-activity, lysosomal imbalance promotes secretion.

Language: Английский

Citations

1
β‐Cell gene expression stress signatures in types 1 and 2 diabetes DOI Creative Commons
Xiaoyan Yi, Décio L. Eizirik

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

Citations

2