Search Results (119)

Type 1 diabetes is caused by autoimmune destruction of insulin-secreting β-cells within islets of Langerhans. Transplantation of donor islets can improve glycaemic control, but current clinical islet transplantation protocols are compromised by extensive loss of β-cell functional mass soon after implantation. Co-incubation in vitro or co-transplantation in vivo of mesenchymal stromal cells (MSCs) with isolated islets improves their functional survival, although the underlying mechanisms remain obscure. Here, we show that MSC-derived extracellular vesicles (MSC-EVs) are alone sufficient to recapitulate many of the beneficial effects of MSCs on islet functional survival, offering the possibility of simple cell-free treatments to improve the outcomes of islet transplantation. We used LC- analysis and small RNA sequencing to analyse the protein and microRNA (miRNA) molecular cargos of MSC-EVs. Proteomic analysis identified >100 proteins from the Uniprot Mouse Database, including β-cell G protein-coupled receptor (GPCR) agonists which we have previously shown to enhance β-cell functional survival. MSC-EVs contained ~300 distinct miRNAs and we identified five highly enriched miRNAs that were significantly upregulated in MSC-EV-treated islets, notably miR-21a-5p. MSC-EV treatment also altered the expression of a distinct set of islet mRNAs known to be involved in islet metabolism and function. These observations may enable the further simplification of the islet pretreatment strategy by focusing on defined GMP-grade biologically active molecules rather than whole heterogeneous EV populations. Full article

Toxic metals from industrialization and urbanization pose major human health risks, and mixture-based exposure requires broader toxicity assessment. This study investigated the effects of a mixture of arsenic, lead, mercury, cadmium, chromium (VI), and nickel on pancreatic function in rats (45 male/45 female; n = 5 per group), focusing on sex- and duration-specific differences after 28 and 90 days of exposure. The metals were administered as a single mixture dissolved in deionised water via oral gavage. Evaluated parameters included pancreatic metal levels, histopathology, serum glucose, amylase, malate dehydrogenase 1 (MDH-1) activity, redox status, and bioelements. Dose levels were based on human exposure data to reflect realistic scenarios. Metals accumulated in pancreatic tissue, causing dose- and time-dependent histopathological changes, including acinar cell vacuolization, vascular congestion, and Langerhans islet alterations. Males showed more pronounced vascular and islet changes, while females had greater acinar alterations. In males, higher doses decreased glucose and amylase and increased MDH-1 activity, while females showed more variable responses. Males demonstrated adaptive responses to oxidative stress over time, while females experienced more persistent stress. These findings reveal sex-, dose-, and duration-dependent effects of toxic metal(oid) mixtures on pancreatic function, indicating that individually safe doses may be harmful when combined. Full article

Hexavalent chromium, a widespread heavy metal, induces apoptosis via the mitochondrial pathway through Bax (pro-apoptotic) and Bcl2 (anti-apoptotic) proteins. Hypericum perforatum, rich in antioxidants, can neutralise free radicals. This study investigated the effects of CrVI on the pancreas and the protective role of Hypericum perforatum. Five groups of animals were used: control, Cr (CrVI for 3 months), CrH (CrVI + 2.5% Hypericum perforatum extract made from flowers, for 3 months), Cr2 (CrVI for 3 months + distilled water for 1 month), and CrH2 (CrVI for 3 months + Hypericum perforatum extract for 1 month). Samples were collected for histological analysis, gene expression (qRT-PCR), and blood glucose level analysis. CrVI exposure (Cr, Cr2) caused pancreatic damage: oedema, reduced islet size, endocrine cell vacuolisation, and endothelial swelling. Lesions were milder in CrH, while CrH2 resembled the control group. The Bax/Bcl2 ratio increased under CrVI (highest in Cr2), indicating apoptosis, but decreased toward control values in CrH and CrH2. Blood glucose levels confirmed these findings. CrVI proved toxic to the endocrine pancreas, inducing structural and molecular alterations that impaired carbohydrate metabolism. Administration of Hypericum perforatum extract reduced these effects, confirming its antioxidant action and potential as a protective agent against CrVI-induced oxidative stress. Full article

Intraoperative assessment of pancreatic quality, followed by sampling for the potential isolation of Langerhans islets for subsequent autotransplantation, is currently a key component of post-total pancreatectomy diabetes mellitus treatment. The aim of this study was to quantitatively evaluate pancreatic parenchymal stiffness using optical coherence elastography (OCE) imaging, and to investigate the utility of the OCE method as a potential indicator of islet yield after pancreatectomy. A total of 41 freshly excised human pancreatic specimens, containing pancreatic ductal adenocarcinoma (PDAC) and surrounding non-tumorous tissues post-pancreatectomy, were studied. In this research, the stiffness (Young’s modulus, kPa) and its color-coded 2D distribution were calculated for various pancreatic samples using compression OCE. Stiffness values were compared between intact pancreatic parenchyma (islet-poor and islet-rich) and pancreatic lesion groups (parenchymal fibrosis and/or PDAC invasion). The data were confirmed by histological analysis. In addition, the measured stiffness values for various morphological groups of the pancreatic samples were compared with the number of isolated islets obtained from pancreatic samples after collagenase treatment. The study demonstrated that OCE can effectively distinguish areas of pancreatic lesions and identify intact pancreatic parenchyma containing Langerhans islets. A highly significant increase in mean stiffness (p < 0.0001) was observed in postoperative pancreatic samples exhibiting signs of parenchymal fibrosis or PDAC invasion compared to unaffected, intact pancreatic parenchyma. For the first time, a relationship between stiffness values and the number of isolated pancreatic islets was demonstrated; in particular, the number of isolated islets significantly decreased (≤110 pcs/g) in samples exhibiting stiffness values above 150 kPa and below 75 kPa. The optimal stiffness range for the efficient isolation of islets (≥120 pcs/g) from pancreatic tissue was identified as 75–150 kPa. The study introduces a novel approach for rapid and objective intraoperative assessment of pancreatic tissue quality using real-time OCE data. This technique facilitates the identification of regions affected by pancreatic lesions and supports the selection of intact pancreatic parenchyma, potentially enhancing the accuracy of Langerhans islet yield predictions during surgical resection. Full article

Islet encapsulation has the potential to enable transplantation without requirement for life-long immunosuppression. The period between implantation and revascularisation is most harmful for encapsulated islets as they receive nutrients and oxygen exclusively via diffusion. This critical time gap must be bridged with a temporary oxygen supply to prevent inflammation and apoptosis. Hence, we compared the efficiency of individual components of an oxygen-delivering matrix (hyaluronic acid (HA); HA + perfluorodecalin nanoemulsion; HA + perfluorodecalin nanoemulsion + oxygen) to provide a substitute for the extracellular matrix and to facilitate human islet survival. The islets were loaded into silicone-based macroencapsulation devices with multi-scale porous membranes designed to optimise revascularisation. Four to five days of normoxic culture revealed that non-oxygen-charged nanoemulsion prevented islet disintegration but did not reduce necrosis or apoptosis. Oxygen supply decreased the generation of reactive oxygen species and chemokines, thereby increasing islet yield. Stimulated insulin secretion of encapsulated islets was marginal and severely delayed. Islets incubated in oxygen-precharged nanoemulsion were characterised by the highest stimulation index. These data suggest that islet survival in macroencapsulation devices can be optimised with a multi-functional matrix providing mechanical support and temporary oxygen supply to reduce the production of pro-inflammatory mediators. Suitable oxygen delivery systems with an extended life span must identified before in vivo experiments can be undertaken. Full article

Background: Pancreatic hamartoma (PH) is an exceptionally rare, benign, mass-forming lesion accounting for less than 1% of all pancreatic tumors. Its rarity and non-neoplastic nature contribute to significant diagnostic challenges, often leading to misclassification as malignant disease. This study presents a case of PH and a systematic review of all reported cases, with emphasis on histopathological and imaging characteristics. Methods: A comprehensive electronic search of PubMed, Scopus, and Web of Science was conducted up to 1 April 2025, to identify eligible case reports and series. Results: We describe a 37-year-old woman with a cystic lesion of the pancreatic tail, ultimately confirmed histologically as a cystic pancreatic hamartoma following distal pancreatectomy with splenectomy, with an uneventful postoperative course. Of 687 screened studies, 51 met the inclusion criteria, comprising 77 cases (68 adults, 9 pediatric). PHs occurred most frequently in males (52.9%), with a mean age of 59.5 ± 12.9 years, and were often asymptomatic (57.4%). The pancreatic head was the most common site (52.9%). On MRI, PHs typically exhibited low T1-weighted and high T2-weighted signal intensity, with no FDG uptake (82%) and moderate or no restriction on DWI, distinguishing them from neuroendocrine tumors (NETs). Histologically, most lesions were solid (64.7%) or solid–cystic (35.3%), with low spindle cell cellularity and absent Langerhans islets. Conclusions: Low T1WI signal and moderate DWI signal are the key features distinguishing PHs from NETs. Incorporating these findings with EUS-FNA and immunohistochemistry can support a provisional diagnosis and help avoid unnecessary radical surgery. Full article

The treatment of type 1 diabetes through pancreatic islet transplantation faces significant limitations, including donor organ shortages and poor islet survival due to post-transplantation loss of extracellular matrix support and inadequate vascularization. Developing biocompatible scaffolds that mimic the native islet microenvironment could substantially improve transplantation outcomes. This study aimed to create and evaluate decellularized (DCL) matrices from porcine organs as potential platforms for islet transplantation. Porcine lung and pancreatic tissues were decellularized using four different protocols combining detergents (Triton X-100, SDS and SDC) with optimized incubation times. The resulting matrices were characterized through DNA quantification and histological staining (H&E and Van Gieson). Islet viability was assessed in vitro using Live/Dead staining after 3 and 7 days of culture on the matrices. In vivo biocompatibility was evaluated by implanting matrices into rat omentum or peritoneum, with histological analysis at 1-, 4-, and 8 weeks post-transplantation. Protocols 3 (for lung tissue) and 4 (for pancreas tissue) demonstrated optimal decellularization efficiency with residual DNA levels below 8%, while preserving the collagen and elastin networks. In vitro, islets cultured on decellularized lung matrix had maintained 95% viability by day 7, significantly higher than the controls (60%) and pancreatic matrix (83%). The omentum showed superior performance as an implantation site, exhibiting minimal inflammation and fibrosis compared to the peritoneum sites throughout the 8-week study period. These findings establish DCL as a promising scaffold for islet transplantation due to its superior preservation of ECM components and excellent support of islet viability. This work provides a significant step toward developing effective tissue-engineered therapies for diabetes treatment. Full article

Background/Objectives: Vitexin and isovitexin are bioactive flavonoids with promising pharmacological effects; however, they have poor bioavailability. Microencapsulation with biodegradable polymers is a promising strategy for improving their stability, bioavailability, and biocompatibility. This study aimed to optimize the formulation parameters to obtain microspheres with desired properties in terms of size, loading ratio, and vitexin–isovitexin release. Methods: Microspheres were prepared using alginate as the core matrix and a chitosan outer layer. A Design of Experiment approach using response surface methodology was employed. The hypoglycemic effects of the obtained microspheres were evaluated. Results: The formulation using 1.17% low-viscosity alginate, 7.60% calcium chloride, 5.78% Tween 80, and 5.00% Span 80 resulted in microspheres with optimal mean size (10.78 µm), high loading ratio (22.45%) and encapsulation efficiency (68.92%). The in vitro release of vitexin–isovitexin from microspheres was completed within 24 h in controlled manner. The microspheres were found to be non-toxic in vivo and exhibited hypoglycemic effects after 21 days at doses equivalent to 30 and 60 mg/kg of vitexin–isovitexin. The potential mechanisms might involve increasing the size of Islets of Langerhans and improving pancreatic β-cell function and insulin resistance, as observed in alloxan-induced diabetic mice. Conclusions: This work successfully developed alginate–chitosan-based microspheres for the controlled release of vitexin–isovitexin while maintaining their bioactivities. Full article

Ionizing radiation at early stages leads to radiation-induced death of Langerhans islet cells and acinar cells, resulting in the development of acute/subacute pancreatitis. Conducting studies on radiation-induced changes in the pancreas following electron beam irradiation appears to be of great interest, and the evaluation of radioprotective agents for safeguarding normal tissues from radiation is equally important. The aim of this study was to preclinically investigate the antioxidant properties of N-Acetylcysteine in an animal model of radiation-induced pancreatitis over a three-month period. In this study, it was proven for the first time that even electrons can lead to characteristic signs of radiation-induced pancreatitis, the degree of which was assessed based on the levels of insulin, glucose, and amylase. Thus, conducting electron therapy also increases the risks of insulin resistance, as well as X-ray and gamma radiation. For the first time, a comprehensive analysis of biochemical, morphological, and immunohistochemical markers in the pancreas of a large cohort of electron-irradiated animals was conducted, including both acute and delayed effects of electron exposure. The crucial role of interleukins in shaping both the cellular and vascular components of the inflammatory response was identified. Additionally, the radioprotective properties of N-Acetylcysteine during electron irradiation of the pancreas were evaluated for the first time, and its effectiveness in reducing both acute and late complications of electron therapy was demonstrated. Thus, it can be concluded that N-Acetylcysteine is capable of effectively suppressing the inflammatory response in the pancreas. Full article

Insulin-degrading enzyme is a zinc metalloprotease that degrades low-molecular-weight substrates, including insulin. Ubiquitous expression, high evolutionary conservation, upregulation of Ide in stress situations, and literature findings suggest a broader function of Ide in cell physiology and protein homeostasis that remains to be elucidated. We used proteomics and transcriptomics approaches to search for leads related to a broader role of Ide in protein homeostasis. We combined an analysis of the proteome and single-cell transcriptome of Ide^+/+ and Ide^−/− pancreatic islet cells with an examination of the interactome of human cytosolic Ide using proximity biotinylation. We observe an upregulation of pathways related to RNA processing, translation and splicing in Ide^+/+ relative to Ide^−/− islet cells. Corroborating these results and providing a potential mechanistic explanation, proximity biotinylation reveals interaction of Ide with several subunits of CCR4-NOT, a key mRNA deadenylase regulating gene expression “from birth to death”. We propose a speculative model in which human and murine Ide cooperate with CCR4-NOT to control protein expression in proteotoxic and metabolic stress situations through cooperation between their deadenylase and protease functions. Full article

A hallmark of type 2 diabetes mellitus (T2DM) is the presence of abundant amyloid deposits composed of amyloid polypeptide (amylin) within the pancreatic islets of Langerhans. Given its high prevalence among diabetic individuals, human amylin fibrillization has long been considered a key pathogenic factor in T2DM. Co-secreted with insulin, amylin can misfold and aggregate, inducing β-cell toxicity, impairing insulin secretion, and accelerating disease progression. Emerging evidence also indicates that amylin accumulates in the brains of patients with Alzheimer’s disease, where it may interact with amyloid-β (Aβ) to promote neurodegeneration. Although the underlying mechanisms remain under investigation, amylin aggregates have been shown to disrupt mitochondrial function, trigger endoplasmic reticulum stress, and activate the NLRP3 inflammasome. Additionally, T2DM-associated cerebrovascular alterations may compound cognitive decline. This review, based on a comprehensive literature search across major biomedical databases up to January 2025, synthesizes current evidence on amylin as a molecular link between metabolic and neurodegenerative disorders. We highlight pancreatic β-cell amylin aggregation as a potential early marker of dementia risk in T2DM and examine its relationship with proteostasis-associated proteins. Finally, we discuss emerging diagnostic and therapeutic strategies targeting amylin pathology, offering new perspectives on preventing or delaying neurodegeneration in individuals with T2DM. Full article

The edible mushroom Coprinus comatus has a long history of use in metabolic diseases, which is increasingly documented by modern research. Due to its favorable nutritional composition, it was assumed that this mushroom could accelerate tissue recovery after acutely induced damage with subsequent disturbance of primarily carbohydrate metabolism. To test this hypothesis, the alloxan diabetes model was used, where experimental animals’ change in body weight and biochemical and histological indicators of recovery were monitored. Before performing the in vivo part, HPLC analysis of the C. comatus extract was carried out with subsequent in silico and in vitro tests. Comparing the animals treated with the mushroom in three different doses, no significant change in body weight was observed. Still, the change was also noticed in the lipid status and glycemia, with a dose-dependent beneficial effect. Morphometric analysis of pancreatic tissue stained by immuno-histochemical methods showed that long-term treatment with C. comatus leads to increased numerical density, nuclear volume, and absolute number of beta cells of the islets of Langerhans, which suffered severe damage after alloxan administration. Overall, C. comatus may contribute to faster tissue recovery after acute diabetic-relevant damage with chronic consequences. Full article

Background/Objectives: Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes mellitus in rats. Methods: Induction of diabetes mellitus was produced by injecting an intraperitoneal dose of nicotinamide (60 mg/kg) to 16-hour-fasted rats, then after 15 min, an intraperitoneal dose of streptozotocin (60 mg/kg) was injected. The rats with diabetes were orally treated with linagliptin (1 mg/kg), diosmin (10 mg/kg), and both of them every other day for 4 weeks. Results: The elevated hepatic glucose-6-phosphatase and glycogen phosphorylase activities, the lowered concentrations of serum insulin, C-peptide, and hepatic glycogen, and the diminished hepatic antioxidant defense system of nicotinamide/streptozotocin-induced diabetic rats were all potentially improved by the therapies. The treatments also improved the deteriorated adiponectin and resistin mRNA expression in visceral adipose tissue of nicotinamide/streptozotocin-induced diabetic rats. In addition, the treatments induced a recovery of damaged islets of Langerhans and a regeneration of islet cells in association with the enhancement of the formation of insulin granules in β-cells and the improvement of kidney function; the combined effect was the most potent. Conclusions: Diosmin alone or in combination with linagliptin has potent antidiabetic effects, which were managed through their insulinotropic and insulin-improving actions. The diosmin in combination with linagliptin has the most potent antihyperglycemic effects. Full article

Background: Our previous study demonstrated that miR-140-3p induced osteocalcin expression in osteoblastic MC3T3-E1 cells. In this study, we investigated the direct effects of miR-140-3p on bone turnover in senescence-accelerated mice. Methods: In order to evaluate the effects of miR-140-3p, we formulated lipid nanoparticles (LNPs) containing miR-140-3p (100 μg/mL), with or without flotillin-2 (Flo2), a microvesicle marker excreted by osteoblasts. LNP was administered into the right tibia of the P6 strain of senescence-accelerated mice (SAMP6). Four-week-old SAMP6 males were divided into three groups: control, LNP, and LNP + Flo2. LNPs were administered five times, once every three days. No gait abnormalities were observed in any group. Two days after the last administration of LNPs, blood and urine samples were collected to measure bone turnover markers and blood chemistry and to perform urinalysis. Bone histomorphometry was performed on the left femur, contralateral to the administration site. The pancreas was removed for insulin staining of the Langerhans islets. Results: The LNP + Flo2 group showed greater bone volume, trabecular thickness, and osteoid thickness in bone histomorphometry. Carboxylated osteocalcin, a bone formation marker, was also higher in the LNP + Flo2 group, indicating that LNP + Flo2 activated osteoblastic function. Insulin levels in the islets of Langerhans did not differ across the groups, consistent with under-carboxylated osteocalcin levels. Conclusions: LNP + Flo2 effectively improved bone metabolism. Full article

Bi-hormonal islet endocrine cells have been proposed to represent an intermediate state of cellular transdifferentiation, enabling an increase in beta-cell mass in response to severe metabolic stress. Beta-cell plasticity and regenerative capacity are thought to decrease with age. We investigated the ontogeny of bi-hormonal islet endocrine cell populations throughout the human lifespan. Immunofluorescence microscopy was performed for insulin, glucagon, and somatostatin presence on paraffin-embedded sections of pancreata from 20 donors without diabetes aged between 11 days and 79 years of age. The mean proportional presence of glucagon-, insulin-, and somatostatin-immunoreactive cells within islets was 27.5%, 62.1%, and 12.1%, respectively. There was no change in the relative presence of alpha- or beta-cells with advancing age, but delta-cell presence showed a decline with age (R² = 0.59, p < 0.001). The most abundant bi-hormonal cell phenotype observed co-stained for glucagon and insulin, representing 3.1 ± 0.3% of all islet cells. Glucagon/somatostatin and insulin/somatostatin bi-hormonal cells were also observed representing 2–3% abundance relative to islet cell number. Glucagon/insulin bi-hormonal cells increased with age (R² = 0.30, p < 0.05) whilst insulin/somatostatin (R² = 0.50, p < 0.01) and glucagon/somatostatin (R² = 0.35, p < 0.05) cells decreased with age of donor. Findings show that bi-hormonal cells are present within human pancreatic islets throughout life, perhaps reflecting an ongoing potential for endocrine cell plasticity. Full article