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

---

Gut Commensal Barnesiella Intestinihominis Ameliorates Hyperglycemia and Liver Metabolic Disorders

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract Recent studies have highlighted the role of gut microbiota in type 2 diabetes (T2D). Improving dysbiosis can be a potential strategy for prevention and management T2D. Here, this work finds that abundance Barnesiella intestinihominis is significantly decreased fecal T2D patients from 2‐independent centers. Oral treatment live B. (LBI) considerably ameliorates hyperglycemia liver metabolic disorders HFD/STZ‐induced models db/db mice. LBI‐derived acetate has similar protective effects against Mechanistically, enhances fibroblast growth factor 21 (FGF21) through inhibition histone deacetylase 9 (HDAC9) to increase H3K27 acetylation at FGF21 promoter. The screening puerarin Gegen Qinlian decoction microbiota‐dependent manner improved by promoting . This study suggests commensal puerarin, respectively as probiotic prebiotic

Language: Английский

---

Towards a new taxonomy of preterm birth

Journal of Perinatology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract Disease categories traditionally reflect a historical clustering of clinical phenotypes based on biologic and nonbiologic features. Multiomics approaches have striven to identify signatures develop individualized categorizations through tests and/or therapies for ‘personalized’ medicine. Precision health classifies syndromes into endotype clusters novel technological advancements, which can reveal insights the etiologies phenotypical syndromes. A new taxonomy preterm birth should be considered in this context, as not all infants similar gestational ages are same because most different vulnerabilities hence trajectories. Even choice interventions may affect observed conditions. Thus, prematurity would help advance field neonatology, but also obstetrics perinatology by adopting anticipatory more targeted care with intent preventing treating some common newborn pathologic

Language: Английский

---

Expanding applications of therapies based on GLP1

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Language: Английский

---

Vitamin C encapsulated biomimetic nanogels with macrophage membrane decoration for chronic wound healing

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: unknown, P. 159080 - 159080

Published: Dec. 1, 2024

Language: Английский

---