Search Results (1,003)

Cystic fibrosis is a multisystem disorder caused by mutations in the CFTR gene that lead to impaired ion and fluid transport across secretory epithelia. Although the therapeutic impact of CFTR modulators has been extensively studied in airway epithelia, their efficacy in extra-pulmonary tissues, such as the pancreas, has been less explored. This study evaluated the effects of the CFTR modulators, VX770 (ivacaftor), VX661 (tezacaftor), and VX445 (elexacaftor), administered either individually or in combination, on CFPAC-1 cells, a pancreatic ductal epithelial cell line derived from a cystic fibrosis patient harboring the F508del CFTR mutation. The cells were cultured and differentiated onto porous supports, and a panel of functional parameters was assessed. These included transepithelial electrical conductance, fluid reabsorption, apical surface fluid pH, protein concentration, and microviscosity, the latter analyzed with multiple particle tracking. To simulate a pro-inflammatory micro-environment, the cells were preconditioned with lipopolysaccharide (LPS). Treatment with VX661 and VX445 resulted in significant improvement in epithelial function, with the triple combination producing the most pronounced rescue. Pro-inflammatory stimulation by LPS increased the production of cytokine IL6, IL-8, and IL-1β, as well as the protein content of the apical surface fluid. Despite the LPS pro-inflammatory stimulus, CFTR modulators preserved or slightly enhanced their efficacy in restoring CFTR-mediated ion and fluid transport. However, they did not reduce cytokine expression under pro-inflammatory conditions. Collectively, these findings show that CFTR modulators can restore critical aspects of cystic fibrosis pancreatic epithelial physiology in vitro, even under pro-inflammatory stress, supporting their potential relevance beyond the airway disease. Full article

Background: Ramulus Mori (Sangzhi) Alkaloids (SZ-A) are natural hypoglycemic compounds known to enhance insulin secretion. Given the emerging role of the gut microbiota in regulating β-cell function, in this study, we aimed to investigate whether SZ-A exert their beneficial effects through modulating the gut microbiota and its metabolites. Methods: A diabetic mouse model was established using a high-fat diet and streptozotocin, followed by 20 weeks of SZ-A treatment. Gut microbiota and metabolites were profiled via 16S rRNA sequencing and liquid chromatography–mass spectrometry, respectively. Spearman’s correlation analysis was used to explore associations between gut microbiota and metabolites. Single-cell RNA sequencing (scRNA-seq) was used to assess gene expression and signaling pathway changes in β cells. Results: Our results demonstrate that SZ-A alleviated hyperglycemia and increased islet numbers in T2DM mice. SZ-A treatment also reshaped the gut microbiota, notably enriching quantities of Lactobacillus and norank_f__Eubacterium_coprostanoligenes_group, which may contribute to increasing levels of 2-methoxyestradiol (2-ME), a bioactive metabolite. Moreover, scRNA-seq revealed an increased proportion of COMT⁺ cells in the islets, suggesting that 2-ME may also be synthesized within the islets. In vitro, 2-ME suppressed HIF-1α signaling and promoted insulin secretion, indicating that 2-ME may act as a crucial mediator of the beneficial effects of SZ-A. Conclusions: SZ-A improve β-cell function by increasing 2-ME levels via gut microbiota modulation and islet production, ultimately suppressing HIF-1α signaling and restoring β-cell homeostasis. Full article

Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, β-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based therapies suggest that the gut contributes actively beyond nutrient absorption. Yet, a cohesive framework integrating these observations remains absent, leaving a critical gap in our understanding of T2DM’s upstream pathophysiology. This work builds upon the anti-incretin theory, which posits that nutrient-stimulated neurohormonal signals—termed “anti-incretins”—arise from the proximal intestine to counteract incretin effects and regulate glycemic homeostasis. The excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, disrupts this balance and may cause insulin resistance and β-cell depletion, leading to T2D. We hypothesize that the neuroendocrine signals produced by cholecystokinin (CCK)-I and secretin-S cells, both located in the proximal intestine, function as endogenous anti-incretins. In this context, we hypothesize a novel model centered on the chronic overstimulation of I and S cells by high-fat, high glycemic index modern diets. This drives what we term “amplified digestion”—a state marked by heightened vagal and hormonal stimulation of biliary and pancreatic secretions, increased enzymatic and bile acid activity, and alterations in bile acid composition. This condition leads to an extended breakdown of carbohydrates, lipids, and proteins into absorbable units, thereby promoting excessive nutrient absorption and ultimately contributing to insulin resistance and progressive β-cell failure. Multiple lines of clinical, surgical, and experimental evidence converge to support our model, rooted in the physiology of digestion and absorption. Western dietary patterns appear to induce an over-digestive adaptation—marked by excessive vagal and hormonal stimulation of biliary and pancreatic secretion—which amplifies digestive signaling. This heightened state correlates with increased nutrient absorption, insulin resistance, and β-cell dysfunction. Interventions that disrupt this maladaptive signaling—such as truncal vagotomy combined with duodenal bypass—may offer novel, physiology-based strategies for T2DM treatment. This hypothesis outlines a potential upstream contributor to insulin resistance and T2DM, grounded in digestive tract-derived neurohormonal dysregulation. This gut-centered model may provide insight into early, potentially reversible stages of the disease and identify a conceptual therapeutic target. Nonetheless, both the hypothesis and the accompanying surgical strategy—truncal vagotomy combined with proximal intestinal bypass—remain highly exploratory and require systematic validation through mechanistic and clinical studies. Further investigation is warranted to clarify the molecular regulation of I and S enteroendocrine cells, including the genetic and epigenetic factors that may drive hypersecretion. While speculative, interventions—surgical or pharmacologic—designed to modulate these digestive signals could represent a future avenue for research into T2DM prevention or remission, pending rigorous evidence. Full article

Prediabetes and early type 2 diabetes mellitus (T2D) are increasingly recognized as states of both metabolic and neurochemical dysregulation. This narrative review synthesizes emerging evidence of alterations in key neurotransmitter systems—dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate—in individuals with prediabetes and diabetes. Beyond peripheral insulin resistance and β-cell dysfunction, disturbances in the central nervous system, especially related to neurotransmitter signaling, may play a role in disease onset and progression. Neuroimaging studies reveal early imbalances in excitatory and inhibitory neurotransmitters, while biochemical and histological findings demonstrate altered receptor expression in both the brain and pancreatic islets. These changes affect metabolic control and are implicated in mood, cognition, and feeding behavior. We investigate the mechanistic links between neurotransmitter dysfunction and glucose metabolism, including the roles of brain insulin resistance, inflammation, mitochondrial stress, and gut–brain axis signaling. Finally, we discuss therapeutic strategies that target neurochemical pathways and highlight the need for longitudinal, sex-aware, and multi-omics studies to refine early interventions. Understanding the neurobiological roots of early T2D could revolutionize risk assessment and open doors for new neuro-metabolic treatments. Full article

Diabetes mellitus (DM) is a complex metabolic disease characterized by significantly elevated blood glucose levels as a result of dysfunctional or impaired pancreatic β-cells, leading to insulin deficiency. This condition can result in severe complications, including cardiovascular diseases, kidney failure, vision impairment, and nerve damage. Currently available anti-diabetic drugs do not fully prevent the progression of these complications. Moreover, they often have significant side effects. The gut microbiota plays a crucial role in influencing diet, energy metabolism, and blood glucose levels. Research shows a strong link between microbiota dysbiosis and DM, as well as the severity of its complications. Commensal bacteria can help manage blood glucose levels, reduce inflammation, regulate metabolism, and enhance the gut barrier. Conversely, opportunistic pathogens can worsen insulin resistance, promote metabolic disorders, disrupt gut integrity, and affect appetite and weight. This article describes the characteristics of gut microbiota in various types of DM and explores the role of the “gut microbiota–metabolite–signaling pathway” axis in DM and its complications. In addition, it highlights the therapeutic potential of traditional Chinese medicine and dietary interventions through modulation of the gut microbiota and metabolites. The aim is to provide comprehensive evidence supporting the integration of TCM dietary therapy, targeted dietary strategies, and specific probiotics as alternative and complementary therapies for DM and its complications. Full article

Systematic Background/Objectives: Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which pancreatic β-cells are selectively destroyed, predominantly by autoreactive T lymphocytes. Despite decades of research, the achievement of durable immune tolerance remains elusive. This review presents a historically grounded and forward-looking perspective on the evolution of immunotherapy in T1DM, from early immunosuppressive interventions to advanced precision-based cellular approaches. Specifically, we focus on systemic immunosuppressants (e.g., corticosteroids, cyclosporine), monoclonal antibodies (e.g., anti-CD3, anti-IL-1, anti-TNF), regulatory cell-based approaches (e.g., Tregs, CAR-Tregs, MDSCs), and β-cell replacement strategies using stem cell-derived islets. Methods: We analyzed major clinical and translational milestones in immunotherapy for T1DM, with particular attention to the transition from broad immunosuppression to targeted modulation of immune pathways. Emerging data on cell-based therapies, artificial intelligence (AI)-driven stratification, and personalized intervention timing have been incorporated to provide a comprehensive overview of current and future directions. Results: Initial therapies such as corticosteroids and cyclosporine offered proof-of-concept for immune modulation, yet suffered from relapse and toxicity. The introduction of monoclonal antibodies (e.g., teplizumab) marked a shift toward immune-specific intervention, particularly in stage 2 preclinical T1DM. More recent approaches include low-dose IL-2, checkpoint modulation, and antigen-specific tolerance strategies. Cellular therapies such as Treg adoptive transfer, chimeric antigen receptor Tregs (CAR-Tregs), and stem cell-derived islet replacements (e.g., VX-880) have shown promise in preserving β-cell function and modulating autoimmunity. Myeloid-derived suppressor cells (MDSCs), although still preclinical, represent a complementary avenue for immune tolerance induction. Concurrently, AI-based models are emerging as tools to stratify risk and personalize immunotherapeutic timing, enhancing trial design and outcome prediction. Conclusions: In conclusion, the historical progression from broad immunosuppression to precision-driven strategies underscores the importance of stage-specific, mechanism-based interventions in T1DM. The convergence of targeted biologics, regenerative cell therapies, and β-cell replacement approaches, supported by AI-enabled patient stratification, offers a realistic path toward durable immune tolerance and functional β-cell preservation. Continued integration of these modalities, coupled with rigorous long-term evaluation, will be essential to transform these scientific advances into sustained clinical benefit. Full article

Vitamin D has emerged as a modulatory factor in the pathogenesis and management of diabetes mellitus due to its influence on pancreatic β-cell function, immune regulation, and inflammatory pathways. This narrative review critically examines mechanistic and clinical evidence linking vitamin D status with type 1 diabetes (T1DM), type 2 diabetes (T2DM), and gestational diabetes (GDM). In T1DM, vitamin D’s immunomodulatory effects are thought to protect β-cells from autoimmune destruction; epidemiological studies associate vitamin D sufficiency with lower T1DM incidence and improved glycemic control, although causality remains under investigation. In T2DM, vitamin D deficiency is associated with worsened metabolic control and may contribute to disease development in at-risk individuals; however, it does not influence the initial onset of T2DM in patients who are already diagnosed. Intervention trials indicate that correcting the deficiency can modestly improve insulin sensitivity, β-cell function, and metabolic parameters. GDM has similarly been linked to hypovitaminosis D, with low maternal vitamin D levels associated with higher GDM risk and adverse perinatal outcomes; mechanistic insights suggest that adequate vitamin D supports glucose homeostasis in pregnancy, and emerging trials demonstrate improved insulin resistance with maternal vitamin D supplementation. Across these diabetes subtypes, maintaining sufficient vitamin D levels appears to confer metabolic benefits and may serve as an adjunct to current preventive and therapeutic strategies. However, definitive evidence from large-scale trials is required to establish optimal vitamin D supplementation protocols and confirm its efficacy in diabetes care. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

(1) Background: Epidemiological studies link ozone (O₃) exposure to diabetes risk, but mechanisms and early biomarkers remain unclear. (2) Methods: Female mice exposed to 0.5/1.0 ppm O₃ were assessed for glucose tolerance and HOMA (homeostasis model assessment) index. Genes related to impaired glucose tolerance and insulin resistance were screened through the Comparative Toxicogenomics Database (CTD), and verified using quantitative real-time PCR. In addition, liver histopathological observations and the determination of basic biochemical indicators were conducted, and targeted metabolomics analysis was performed on the liver to verify glycogen levels and gene expression. In vitro validation was conducted with HepG2 and Min6 cell lines. (3) Results: Fasting blood glucose and insulin resistance were elevated following O₃ exposure. Given that the liver plays a critical role in glucose metabolism, we further investigated hepatocyte apoptosis and alterations in glycogen metabolism, including reduced glycogen levels and genetic dysregulation. Metabolomics analysis revealed abnormalities in fructose metabolism and glycogen synthesis in the livers of the O₃-exposed group. In vitro studies demonstrated that oxidative stress enhances both liver cell apoptosis and insulin resistance in pancreatic islet β cells. (4) Conclusions: O₃ triggers prediabetes symptoms via hepatic metabolic dysfunction and hepatocyte apoptosis. The identified metabolites and genes offer potential as early biomarkers and therapeutic targets. Full article

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

Background: Uric acid has been proposed as a diabetogenic factor while its effect on pancreatic β cell function remains elusive. This study aimed to explore the impact of uric acid levels on β cell function and delineate its underlying molecular mechanisms. Methods: Both in vivo hyperuricemia diet-induced mouse models and in vitro pancreatic β cell models were utilized. Results: A progressive decrease in glucose-stimulated insulin secretion and increase in β cell apoptosis were observed in the hyperuricemia diet-induced mouse model, and these could be effectively restored by urate-lowering therapy. The dose- and time-dependent direct effects of uric acid on β cell apoptosis and insulin secretion were further confirmed in both INS-1E cells and primary isolated islets. Mechanistically, the primary role of expression of the endoplasmic reticulum stress marker C/EBP homologous protein (CHOP) was detected by RNA sequencing, and the inflammatory factor NLRP3 and pro-apoptotic genes were significantly upregulated by uric acid treatment. Conclusions: Together, our findings indicate a direct crosstalk between uric acid and β cells via CHOP/NLRP3 pathway, providing a new understanding of the diabetogenic effect of uric acid. Full article

Gestational diabetes mellitus (GDM) occurs in approximately 9–25% of pregnancies and, if left undiagnosed or inadequately controlled, can lead to adverse outcomes for both the mother and the fetus, short and long term. GDM is characterized by glucose intolerance with onset or first recognition during pregnancy and is a multifactorial condition with a pathophysiology that remains incompletely understood. It is strongly associated with a chronic low-grade inflammatory state that contributes to insulin resistance, a hallmark of GDM pathogenesis. Among the fundamental pro-inflammatory cytokines implicated in this process, TNF-α and IL-6 play central roles. TNF-α is a cytokine primarily secreted by activated macrophages, as well as by adipocytes in the context of obesity. Many studies have shown that its levels are elevated in pregnant women with GDM compared to normoglycemic pregnant individuals. IL-6 is another pro-inflammatory cytokine secreted by immune cells, adipose tissue, and the placenta. It is found in higher concentrations in the maternal circulation during pregnancies complicated by GDM. Both TNF-α and IL-6 act synergistically to perpetuate a pro-inflammatory intrauterine environment. Their combined effects exacerbate insulin resistance and may impair pancreatic β-cell compensation during pregnancy, facilitating the onset of GDM in genetically or metabolically susceptible individuals. Recent research has identified various maternal serum biomarkers, such as TNF-α and IL-6, that may hold promise for the early detection of GDM. The aim of our study is to evaluate whether TNF-α and IL-6 can be used as diagnostic tools for the early diagnosis of GDM, allowing for timely intervention and reducing the risk of associated maternal and fetal complications. Full article

Type 1 diabetes (T1D) is caused by autoimmune-mediated destruction of pancreatic β-cells, resulting in insulin deficiency. While islet transplantation presents a potential therapeutic approach, its clinical application is impeded by limited donor availability and the risk of immune rejection. This study proposes an innovative islet encapsulation strategy that utilizes decellularized porcine pancreatic extracellular matrix (pECM) as the sole biomaterial to engineer bioactive, immunoprotective microcapsules. Rat islets were encapsulated within pECM-based microcapsules using the electrospray technology and were compared to conventional alginate-based microcapsules in terms of viability, function, and response to hypoxic stress. The pECM microcapsules maintained a spherical morphology, demonstrating mechanical robustness, and preserving essential ECM components (collagen I/IV, laminin, fibronectin). Encapsulated islets exhibited sustained viability and superior insulin secretion over a two-week period compared to alginate controls. The expression of key β-cell transcription factors (PDX1, MAFA) and structural integrity were preserved. Under hypoxic conditions, pECM microcapsules significantly reduced islet apoptosis, improved structural retention, and promoted functional recovery, likely due to antioxidant and ECM-derived cues inherent to the pECM. In vivo transplantation in immunocompetent mice confirmed the biocompatibility of pECM microcapsules, with minimal immune responses, stable insulin/glucagon expression, and no adverse systemic effects. These findings position pECM-based microencapsulation as a promising strategy for creating immunoprotective, bioactive niches for xenogeneic islet transplantation, with the potential to overcome current limitations in cell-based diabetes therapy. Full article

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells. The regeneration of durable insulin-producing β-cells remains a critical challenge. This study investigated the regenerative potential of Fraction-B (FB), a catfish skin-derived preparation rich in growth factors, in a T1D rat model to regenerate active β-cells. Sprague Dawley rats with T1D caused by streptozotocin injection received daily intraperitoneal injections of FB for 8 weeks. FB treatment significantly reduced blood glucose to a level close to that of normal control animals, increased serum insulin and C-peptide, and restored pancreatic insulin content. Histopathological and immunohistochemical analyses confirmed the regeneration of insulin-producing β-cells in pancreatic islets. FB treatment also improved diabetes-related health issues through a reduction in inflammation and oxidative stress, and an improvement in lipid profiles without toxicity or side effects. The regenerated β-cells remained functional for 48 weeks without the use of immunosuppressants, until the animals were sacrificed. These findings suggest FB treatment to be a promising procedure for translational research into T1D 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