Search Results (997)

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

Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to identify and characterize a novel mesothelin-associated anti-senescence (MAAS) effect in PDAC. Methods: A proteogenomic analysis of PDAC tissue samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was performed to evaluate MSLN-associated senescence pathways using WebGestalt. Human and murine PDAC cell lines with modified MSLN expression were analyzed for senescence phenotypes via SA-β-gal staining, Western blotting of key regulators (P53, P21^waf1, and P16^ink4a), γH2AX immunoblotting, and IL-8 quantification using ELISA. Results: The CPTAC analysis revealed an inverse correlation between MSLN expression and DNA damage/repair pathways. MSLN-deficient cells exhibited classic senescence features—growth arrest, an enlarged morphology, and elevated SA-β-gal activity. The expression of P53, P21^waf1, and P16^ink4a was upregulated, alongside increased γH2AX levels, indicating the activation of the DNA damage response. IL-8 secretion was significantly higher in the MSLN knockdown cells and reduced in the MSLN-overexpressing cells, consistent with the modulation of the SASP. Notably, MSLN deficiency impaired cell viability without inducing overt cytotoxicity, supporting a shift toward senescence. Conclusions: Our findings uncover a previously unrecognized mechanism through which MSLN promotes tumor progression by suppressing senescence via P53-associated pathways. Targeting the MAAS pathway may offer a novel therapeutic strategy to restore tumor-suppressive senescence and enhance treatment efficacy in PDAC. Full article

Emerging evidence highlights the profound and lasting impact of severe illnesses such as COVID-19, particularly among individuals with underlying comorbidities. Patients with pre-existing conditions like diabetes mellitus (DM) are disproportionately affected, facing heightened risks of both disease exacerbation and the onset of new complications. Notably, the convergence of advanced age and DM has been consistently associated with poor COVID-19 outcomes. However, the long-term metabolic consequences of SARS-CoV-2 infection, especially its role in disrupting glucose homeostasis and potentially triggering or worsening DM, remain incompletely understood. This review synthesizes current clinical and experimental findings to clarify the bidirectional relationship between COVID-19 and diabetes. We critically examine literature reporting deterioration of glycemic control, onset of hyperglycemia in previously non-diabetic individuals, and worsening of metabolic parameters in diabetic patients after infection. Furthermore, we explore proposed mechanistic pathways, including pancreatic β-cell dysfunction, systemic inflammation, and immune-mediated damage, that may underpin the development or progression of DM in the post-COVID setting. Collectively, this work underscores the urgent need for continued research and clinical vigilance in managing metabolic health in COVID-19 survivors. Full article

Obesity and Type 2 Diabetes Mellitus (T2DM) are interrelated chronic conditions whose global prevalence continues to rise, posing significant clinical and socioeconomic challenges. Their pathophysiological intersection—commonly referred to as “diabesity”—is sustained by a complex interplay of mechanisms, including visceral adipose tissue inflammation, macrophage polarization, disrupted insulin signaling, and adipokine imbalance. These processes contribute to chronic low-grade systemic inflammation, impair pancreatic β-cell function, and exacerbate glucose intolerance. This review critically explores the mechanistic connections between obesity and T2DM, with a focus on recent advances in pharmacological therapies—such as GLP-1 receptor agonists, SGLT2 inhibitors, and dual GIP/GLP-1 receptor agonists—alongside evidence-based lifestyle modifications and bariatric procedures. By integrating current translational and clinical findings, we aim to provide a comprehensive perspective to support the development of more effective and individualized treatment strategies for diabesity. Full article

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including shifts in the balance between Firmicutes and Bacteroidetes, a reduction in butyrate-producing bacteria, and an increase in opportunistic pathogens. Gut microbiota-derived metabolites—such as short-chain fatty acids, bile acids, and amino acids—have been implicated in the pathogenesis of T2DM, highlighting the critical role of host-microbe interactions. In this overview, we discuss the gut microbiota dysbiosis associated with T2DM and explore the molecular links between microbiota-derived metabolites and the pathogenesis of diseases. Additionally, we explore potential therapeutic strategies, including probiotics and dietary interventions, to modulate the gut microbiota and its metabolites, providing insights for future clinical research and the development of novel treatments for T2DM. 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

Background/Objectives: Intrauterine growth restriction (IUGR) is associated with enhanced inflammatory activity, poor skeletal muscle glucose metabolism, and pancreatic β cell dysfunction that persist in offspring. We hypothesized that targeting heightened inflammation in IUGR-born neonatal lambs by supplementing anti-inflammatory ω-3 polyunsaturated fatty acids (ω-3 PUFAs) would improve metabolic outcomes. Methods: Maternal heat stress was used to produce IUGR lambs, which received daily oral boluses of ω-3 PUFA Ca²⁺ salts or placebo for 30 days. Results: Greater circulating TNFα and semitendinosus IL6R in IUGR lambs were fully resolved by ω-3 PUFA, and impaired glucose-stimulated insulin secretion, muscle glucose oxidation, and hypertension were partially rescued. Impaired glucose oxidation by IUGR muscle coincided with a greater glycogen content that was completely reversed by ω-3 PUFA and greater lactate production that was partially reversed. Ex vivo O₂ consumption was increased in IUGR muscle, indicating compensatory lipid oxidation. This too was alleviated by ω-3 PUFA. Conversely, ω-3 PUFA had little effect on IUGR-induced changes in lipid flux and hematology parameters, did not resolve greater muscle TNFR1, and further reduced muscle β2-adrenoceptor content. Conclusions: These findings show that targeting elevated inflammatory activity in IUGR-born lambs in the early neonatal period improved metabolic outcomes, particularly muscle glucose metabolism and β cell function. Full article