Type 2 diabetes (T2D) is a progressive disorder denoted by hyperglycemia and impaired insulin secretion. Although a decrease in β-cell function and mass is a well-known trigger for diabetes, the comprehensive mechanism is still unidentified. Here we carried out single-cell RNA sequencing (scRNA-seq) of pancreatic islets from prediabetic and diabetic db/db mice, an animal model of T2D. We discovered a diabetes-specific transcriptome landscape of endocrine and nonendocrine cell types with subpopulations of β and α cells. We recognized a new prediabetic gene, Anxa10, that was induced by, and regulated Ca2+ influx from metabolic stresses. Anxa10-overexpressed β cells displayed suppression of glucose-stimulated intracellular Ca2+ elevation and potassiuminduced insulin secretion. Pseudotime analysis of β cells predicted this Ca2+-surge responder-cluster proceeded to mitochondria dysfunction and also endoplasmic reticulum stress. Other trajectories comprised dedifferentiation and transdifferentiation, emphasizing acinar-like cells in diabetic islets. Altogether, our data provides a new insight into Ca2+ allostasis and β cell failure processes.

Single-cell transcriptome profiling of pancreatic islets from early diabetic mice identifies Anxa10 for Ca2+ allostasis toward β-cell failure.

ABSTRACT Amniotic fluid (AF) is a valuable source of extracellular vesicles (EVs) derived from the fetoplacental unit. Preclinical and clinical studies have highlighted promising applications of AF‐EVs and their role in cellular communication, yet our understanding of AF‐EV physiology remains limited. This study aimed to examine the physiological importance of AF‐EVs in fetal development from the second trimester to term gestation. We obtained AF samples from routine second‐trimester amniocentesis and prelabour Caesarean section at term. We isolated EVs using a combination of differential centrifugation, filtration and ultracentrifugation and characterised them using nanoparticle tracking analysis, cryo‐electron microscopy and Western blotting. The differential EV proteome was analysed using label‐free proteomics. We assessed the second trimester and term AF‐EV properties through an enrichment analysis. The EV size and protein enrichment difference revealed a gestational‐age‐dependent variation in the predominant EV subtype. Second‐trimester‐derived EVs were enriched in ectosomes, while term EVs contained a significant proportion of exosomes. We identified several morphologies of AF‐EVs, including unilamellar, multilamellar, multicompartmental and granular‐centred EVs, across gestational ages. Proteomics analysis of AF‐EVs identified 4137 proteins with high confidence, of which 1090 exhibited significant differential enrichment between the two groups. Second‐trimester‐enriched AF‐EV proteins represented molecule assembly processes, metabolism and organogenesis. At term, AF‐EV proteins corresponded to impending newborn functions such as immunity and digestion. In conclusion, we provide compelling evidence that EV biogenesis and secretion in the fetoplacental unit undergo significant alterations across gestational ages, revealing a complex and dynamic physiology and intercellular communication that adapts to the needs of the developing fetus. 

Amniotic Fluid Extracellular Vesicle Properties Evolve With Gestational Age and Reflect Fetal Development

pdf/identification-of-plasma-extracellular-vesicle-protein-30eo0nga0xpf.pdf

Identification of plasma extracellular vesicle protein biomarkers in diabetic retinopathy progression

The management of wounds remains a significant healthcare challenge, highlighting the need for effective wound healing strategies. To address this, it is crucial to explore the molecular mechanisms underlying tissue repair as well as explore potential therapeutic approaches. Trypsin, as a serine protease, has been clinically utilized for wound healing for decades; however, it still lacks systemic investigation on its role and related mechanism. This study aimed to investigate the effects of low-dose trypsin on wound healing both in vitro and in vivo. While trypsin is an endogenous stimulus for protease-activated receptor 2 (PAR2), we discovered that both low-dose trypsin and synthesized PAR2 agonists significantly enhanced the migration, adhesion, and proliferation of fibroblasts and macrophages, similar to the natural repair mechanism mediated by mast cell tryptase. Moreover, such cell functions induced by trypsin were largely inhibited by PAR2 blockade, indicating the participation of trypsin via PAR2 activation. Additionally, low-dose trypsin notably expedited healing and regeneration while enhancing collagen deposition in skin wounds in vivo. Importantly, upon stimulation of trypsin or PAR2 agonists, there were significant upregulations of genes including claudin-7 (Cldn7), occludin (Ocln), and interleukin-17A (IL-17A) associated with proliferation and migration, extracellular matrix (ECM), tight junction, and focal adhesion, which contributed to wound healing. In summary, our study suggested that a low-dose trypsin could be a promising strategy for wound healing, and its function was highly dependent on PAR2 activation.

Low-Dose Trypsin Accelerates Wound Healing via Protease-Activated Receptor 2

Pancreatic beta-cell dysfunction is a central feature of type 2 diabetes mellitus (T2DM), yet the influence of biological sex on beta-cell pathophysiology remains underexplored [1,2]. Epidemiological studies consistently demonstrate sex differences in T2DM risk profiles, complications, and therapeutic responses; however, the mechanistic basis underlying these disparities is not fully understood [3,4]. In particular, sex differences at the level of pancreatic beta-cell biology have not been investigated in depth

pdf/exploring-sex-specific-mechanisms-in-type-2-diabetes-nksjrnwn1kar.pdf

Exploring Sex-Specific Mechanisms in Type 2 Diabetes Mellitus by Single-Cell Analysis in Pancreatic Islets

Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways.

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Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways.