Search Results (138)

Background: Although diabetes mellitus is traditionally viewed as a systemic metabolic disorder, growing evidence indicates that it also affects the upper airways through vascular, inflammatory, and neuro-sensory mechanisms. The sinonasal mucosa, highly vascularized and immunologically active, may represent an early target of diabetic microangiopathy and immune–metabolic imbalance. Objectives: Our objectives are to synthesize current evidence on the rhinologic manifestations of DM, with a focus on chronic rhinosinusitis, olfactory dysfunction, and other nasal disorders, and to identify the main pathophysiologic and clinical patterns linking diabetes to sinonasal disease. Results: Evidence suggests that DM, particularly type 2 DM, increases susceptibility to CRSwNP and modulates the sinonasal microbiome toward Gram-negative predominance. Surgical outcomes after endoscopic sinus surgery are generally comparable between diabetics and non-diabetics when perioperative care is optimized. Olfactory dysfunction occurs more frequently and severely in diabetic patients, likely reflecting the combined effects of chronic inflammation, vascular compromise, and insulin resistance. Additional manifestations include recurrent epistaxis, delayed mucociliary clearance, and chronic cough. Allergic rhinitis appears to not be increased, and maybe even inversely related, especially among users of DPP-4 inhibitors. Conclusions: Diabetes intersects with rhinologic health through immune–metabolic, vascular, and epithelial pathways that may shape susceptibility, disease phenotype, and neurosensory decline. Future research should focus on disentangling type-specific mechanisms, metabolic biomarkers, and longitudinal outcomes, with the aim of developing precision-based approaches to rhinologic assessment and management in diabetic patients. Full article

Background/Objectives: Proinsulin, the precursor to insulin, has limited activity on the insulin receptor. Proinsulin levels increase with increasing insulin resistance in type 2 diabetes due to incomplete processing by the β-cell. To assess whether the development of peptides that could convert circulating proinsulin to insulin in the blood would provide therapeutic value, we used a quantitative systems pharmacology (QSP) model of glucose homeostasis. In silico hypothesis testing such as this is an example of how modeling can inform decisions in drug discovery. Methods: In silico hypothesis testing involved (1) the addition and qualification of proinsulin biology into a preexisting QSP model, (2) the creation and validation of virtual patients (VPs) for subpopulations of type 2 diabetics based on phenotypic traits, and (3) the simulation of clinical trials evaluating the therapeutic value of the conversion of circulating proinsulin to insulin in the VPs created. Results: Proinsulin conversion led to a ~0.2% reduction in HbA1c in VPs at varying stages of diabetes, a decrease that does not hold meaningful therapeutic value. The lack of significant impact on HbA1c was likely a result of the surprisingly small effect on plasma insulin levels from proinsulin, which has a significantly slower secretion and clearance rate. Although patients with higher proinsulin/insulin ratios showed the largest reductions, clinically significant ≥ 0.5% reduction in HbA1c required ratios of proinsulin/insulin above the reported physiological range. Conclusions: This effort demonstrates how in silico hypothesis testing using QSP modeling can provide insights on the probability of success of novel interventions with minimal time and resources. These efficiencies are a means of overcoming the pressures on the pharmaceutical industry to do more with less in providing therapies that improve the lives of patients. Full article

This study investigates the mechanisms underlying osteocyte injury in a high glucose (HG) environment and explores potential therapeutic targets and diagnostic markers for diabetic osteoporosis, a common complication of type 2 diabetes mellitus (T2DM). Hyperglycemia induces oxidative stress through the reactive oxygen species (ROS) production, which impair osteocytes and accelerate bone loss. To examine these effects, MLO-Y4 cells and primary mouse osteocytes were cultured under normal glucose and HG conditions, with additional treatments using N-acetylcysteine (NAC, ROS scavenger) and rapamycin (autophagy promoter and mTOR inhibitor). Cell viability, ROS levels, and the autophagy and apoptosis markers expression (Beclin1, LC3, p62, Bax, Bcl2, cytochrome C, and caspase3) were assessed using CCK8/ATP level assay, flow cytometry, Western blot, qRT-PCR, immunofluorescence, and TUNEL staining. The results showed that HG inhibits cell proliferation, induces insulin resistance, generates ROS, alters antioxidant enzymes, and promotes oxidative stress, leading to mTOR activation, subsequent autophagy inhibition, and osteocyte apoptosis. NAC mitigated these effects, while rapamycin prevented HG-induced apoptosis by inhibiting mTOR activation and promoting autophagy. This suggests that ROS-induced mTOR activation impairs autophagy and hinders the clearance of damaged osteocytes, triggering apoptosis. This research provides foundational evidence and novel insights into diabetic osteoporosis pathogenesis and potential therapies. Full article

CD93 is a highly glycosylated transmembrane glycoprotein with key functional domains, including a C-type lectin-like domain (CTLD) and epidermal growth factor (EGF)-like domains. Primarily expressed in endothelial cells (ECs), CD93 regulates critical physiological processes such as angiogenesis, cell adhesion, migration, and apoptotic cell clearance through interactions with ligands like multimerin-2 (MMRN2) and insulin-like growth factor-binding protein 7 (IGFBP7). Aberrant CD93 expression has been observed in various pathological conditions, including inflammation, cardiovascular diseases, autoimmune disorders, and cancer. Notably, CD93 is overexpressed in tumor-associated blood vessels, which is associated with poor prognosis and advanced disease stages. Targeting the CD93 signaling pathway has the potential to improve tumor vascular function and enhance the efficacy of immunotherapy, making it a promising therapeutic target. This review summarizes the current understanding of CD93’s structure, function, and disease mechanisms, providing a framework for further research and clinical translation in related fields. Full article

Background/Objectives: Chronic hepatitis C virus (HCV) infection is associated with a wide spectrum of extrahepatic manifestations, involving the immune, dermatologic, endocrine, vascular, and neuropsychiatric systems. Among these, mixed cryoglobulinemic vasculitis (CryoVas) remains one of the most clinically relevant complications. This work aims to provide a structured overview of HCV-related extrahepatic conditions and to analyze the clinical and virological outcomes of direct-acting antivirals (DAAs) in CryoVas patients. Methods: We first categorized and reviewed extrahepatic manifestations of HCV across five major domains: immune, inflammatory/metabolic/vascular, dermatological, thyroid, and neuropsychiatric. Subsequently, we conducted a comparative analysis of five clinical studies evaluating the impact of DAA therapy in patients with CryoVas. Data on demographics, clinical symptoms, treatment regimens, sustained virological response, and clinical response were extracted and summarized. Results: HCV was found to be associated with numerous extrahepatic conditions, including mixed cryoglobulinemia, non-Hodgkin lymphoma, autoimmune thyroiditis, insulin resistance, and neurocognitive symptoms. In the CryoVas subgroup analysis, virological response rates were uniformly high (88.9–100%), but clinical remission varied significantly. Complete response ranged from 39% to 90%, highlighting a discrepancy between viral eradication and extrahepatic symptom resolution. These findings underscore the need for individualized follow-up and further investigation into persistent immunological dysfunction post-sustained virological response (SVR). However, clinical outcomes were more variable: complete response (CR) varied between 39% and 90%, partial response (PR) ranged from 4% to 42%, and no response (NR) was reported in 0% to 40% of cases. Although significant improvement in key manifestations such as purpura, arthralgia, and neuropathy was frequently observed, a subset of patients continued to exhibit residual or refractory symptoms despite achieving SVR. Conclusions: HCV infection exerts multisystemic effects that extend beyond liver pathology. While DAAs offer near-universal virological clearance, the heterogeneous clinical response in CryoVas underscores the need for closer monitoring of extrahepatic outcomes. Future research should assess whether combining DAAs with immunomodulatory strategies can improve symptom control and long-term outcomes in patients with severe or refractory CryoVas. Full article

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study aims to investigate the impact of oxygen normalization on metabolic dysfunction in OSA patients using continuous positive airway pressure (CPAP) therapy, and in mice exposed to IH followed by a reoxygenation period. In the clinical study, 76 participants (44 OSA patients and 32 controls) were analyzed. OSA patients had higher insulin resistance, triglycerides, very low density lipoprotein (VLDL) content, and liver enzyme levels, along with a higher prevalence of liver steatosis. After 18 months of CPAP therapy, OSA patients showed significant improvements in insulin resistance, lipid profiles (total cholesterol and VLDL), liver function markers (AST and albumin), and steatosis risk scores (Fatty Liver Index and OWLiver test). In the experimental study, IH induced hepatic lipid accumulation, oxidative stress, and inflammation, and reoxygenation reversed these deleterious effects in mice. At the molecular level, IH downregulated fatty acid oxidation (FAO)-related genes, thus impairing the FAO process. Reoxygenation maintained elevated levels of lipogenic genes but restored FAO gene expression and activity, suggesting enhanced lipid clearance despite ongoing lipogenesis. Indeed, serum β hydroxybutyrate, a key marker of hepatic FAO in patients, was impaired in OSA patients but normalized after CPAP therapy, supporting improved FAO function. CPAP therapy improves lipid profiles, liver function, and MASLD progression in OSA patients. Experimental findings highlight the therapeutic potential of oxygen normalization in reversing IH-induced liver damage by FAO pathway restoration, indicating a metabolic reprogramming in the liver. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis are cardiometabolic twin disorders with shared underlying pathophysiological mechanisms such as insulin resistance and chronic inflammation. This review explores the salient role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in linking hepatic dysfunction to cardiovascular disease. Findings in mice with genetic modulation of Ceacam1 gene established a critical role for CEACAM1 protein in regulating insulin and lipid metabolism and endothelial integrity and modulating immune response. Loss of CEACAM1 in hepatocytes impairs insulin clearance, causing chronic hyperinsulinemia, a process that ultimately leads to insulin resistance and hepatic and extra-hepatic fat accumulation, which in turn causes inflammatory infiltration. This prompts a paradigm shift that positions impaired hepatic CEACAM1 function as a mechanistic underpinning of the link between insulin resistance, MASH, and atherosclerosis. Full article

Acne vulgaris is a multifactorial inflammatory skin disorder that significantly impairs quality of life and may signal underlying systemic dysfunction, particularly in adult women with treatment-resistant or atypical presentations. This case series presents three clinically and etiologically distinct examples of persistent acne in female patients, each associated with different contributing factors: long-term topical corticosteroid misuse, polycystic ovary syndrome (PCOS), and metabolic syndrome with autoimmune thyroiditis. All cases underwent comprehensive dermatologic evaluation, endocrine/metabolic assessments, and personalized therapeutic interventions, ranging from corticosteroid withdrawal and barrier repair to hormonal modulation and insulin-sensitizing therapy. Clinical progression was monitored for up to six months, revealing favorable responses in all cases, with substantial lesion clearance and improved skin quality. These real-world cases highlight the importance of an integrative, interdisciplinary diagnostic approach in refractory acne and support the need for individualized, long-term management strategies tailored to underlying systemic contributors. Full article

Lipid hormone imbalances involving glucocorticoids, thyroid hormones (THs), and sex hormones have widespread metabolic consequences, contributing to the global increase in obesity and insulin resistance. This review examines the complex role of disrupted lipid hormone pathways in the development of metabolic disorders, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Endocrine disorders such as hypercortisolism, hypothyroidism, and polycystic ovary syndrome (PCOS) are closely linked to MASLD through shared metabolic pathways. Mechanisms include glucocorticoid-induced gluconeogenesis and lipolysis, impaired lipid clearance in hypothyroidism, and the hyperandrogenism-induced downregulation of hepatic low-density lipoprotein (LDL) receptors. PCOS-related factors—such as central obesity, adipocyte hypertrophy, low adiponectin levels, and genetic predisposition—further promote hepatic steatosis. Thyroid dysfunction may also impair the hepatic deiodination of T4, contributing to lipid accumulation and inflammation. Given the overlapping pathophysiology among endocrine, hepatic, and reproductive disorders, multidisciplinary collaboration is essential to optimize diagnosis, treatment, and long-term cardiometabolic outcomes. Full article

Obesity-driven inflammation disrupts gut barrier integrity and promotes inflammatory bowel disease (IBD). Emerging evidence highlights gut hormones—including glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), cholecystokinin (CCK), and apolipoprotein A4 (APOA4)—as key regulators of metabolism and mucosal immunity. This review outlines known mechanisms and explores therapeutic prospects in IBD. GLP-1 improves glycemic control, induces weight loss, and preserves intestinal barrier function, while GLP-2 enhances epithelial repair and reduces pro-inflammatory cytokine expression in animal models of colitis. GIP facilitates lipid clearance, enhances insulin sensitivity, and limits systemic inflammation. PYY and CCK slow gastric emptying, suppress appetite, and attenuate colonic inflammation via neural pathways. APOA4 regulates lipid transport, increases energy expenditure, and exerts antioxidant and anti-inflammatory effects that alleviate experimental colitis. Synergistic interactions—such as GLP-1/PYY co-administration, PYY-stimulated APOA4 production, and APOA4-enhanced CCK activity—suggest that multi-hormone combinations may offer amplified therapeutic benefits. While preclinical data are promising, clinical evidence supporting gut hormone therapies in IBD remains limited. Dual GIP/GLP-1 receptor agonists improve metabolic and inflammatory parameters, but in clinical use, they are associated with gastrointestinal side effects that warrant further investigation. Future research should evaluate combination therapies in preclinical IBD models, elucidate shared neural and receptor-mediated pathways, and define optimal strategies for applying gut hormone synergy in human IBD. These efforts may uncover safer, metabolically tailored treatments for IBD, particularly in patients with coexisting obesity or metabolic dysfunction. Full article

Insulin-degrading enzyme (IDE) plays a critical role in regulating insulin levels in various tissues, including the brain, liver, and kidneys. In type 2 diabetes mellitus (T2DM), key features include insulin resistance, elevated insulin levels in the blood, and hyperglycemia. In this context, the function of IDE becomes particularly important; however, in T2DM, IDE’s function can be impaired. Notably, individuals with T2DM have a higher risk of developing Alzheimer’s disease (AD), suggesting that impaired IDE function may contribute to both diabetes and neurodegeneration. IDE has been studied for its ability to degrade Amyloid-β peptides, the primary constituents of amyloid plaques in AD. However, its role in Aβ clearance in vivo remains debated due to limited enzymatic efficacy under physiological conditions and differences in subcellular localization between IDE and its putative substrate. Other proteases, such as neprilysin, appear to play a more prominent role in preventing plaque formation. Additionally, the long-standing hypothesis that insulin competes with Aβ for IDE activity has been questioned, as brain insulin levels are too low to inhibit Aβ degradation significantly. Genetic variants in the IDE gene have been associated with increased AD risk, although the mechanisms by which they alter enzyme function are not yet fully understood. A deeper understanding of IDE’s role in the context of both metabolic and neurodegenerative diseases may provide valuable insights for the development of new therapeutic strategies. Full article

Background: Though evidence is limited, animal products like pork sausages and cheese may affect satiety differently due to their distinct protein, fat, and calcium content. This study therefore compared their acute effects on breakfast using appetite-related markers. Methods: A total of 11 women and 13 men, with a mean age of 23.0 ± 2.6 years and mean BMI of 24.5 ± 2.6 kg/m², participated in this crossover design study. Concentrations of active ghrelin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), insulin, glucose, leptin, and blood lipids were measured. Subjective feelings of appetite using visual analogue scales were analyzed (0–4 h) as a response to two test breakfasts meals with a similar energy and macronutrient content. Appetite feelings and energy intake from an ad libitum buffet lunch were subsequently measured. Data were analyzed using two different ANOVA methods. Results: The pork sausage breakfast was characterized by an earlier triglyceride (TG) peak than the cheese. A slower TG clearance was seen with the cheese breakfast. Ghrelin suppression was longer in the pork sausage breakfast. Active GLP-1 concentration was higher following the cheese breakfast and active GIP declined slower. The two ANOVA methods disagreed regarding the insulin effect. Subjective feelings of hunger before buffet and ad libitum energy intake were higher in males (791 ± 64 kcal) compared with females (344 ± 32 kcal), but did not differ between breakfast types. Conclusions: Acute consumption of pork and cheese of the same energy, fat, and protein content provided detectable differences in appetite-related hormones and lipid responses. Appetite and lipid metabolism were affected by the major differentiators of the test meals, namely calcium, fatty acids and amino acids compositions. Full article

Insulin dysregulation (ID) is associated with an increased risk of laminitis which often necessitates the need for clinical intervention. To test the contention that the prophylactic supplementation of nutraceuticals could mitigate ID in susceptible horses, 16 mature horses with a history of ID were supplemented with either the placebo (n = 8) or nutraceutical (n = 8) once daily. Horses were housed in dry lots with ad libitum access to grass hay and fed a concentrate twice daily to provide 0.5 g starch/kg BW/meal. A combined glucose–insulin tolerance test was performed on all horses before and after 4 weeks of treatment. Nutraceutical-supplemented horses had 61% greater (p = 0.05) glucose clearance rates compared to the placebo group. This resulted in a shorter time in the positive phase of glucose clearance (p = 0.03) for the nutraceutical group compared to the placebo group. Horses receiving the nutraceutical had lower (p = 0.003) insulin concentrations at 75 min and lower (p = 0.04) glucose concentrations at 45 min compared to the placebo. Prophylactic supplementation with nutraceuticals resulted in greater glucose clearance rates during a starch challenge, indicating that nutraceuticals can mitigate ID in susceptible horses consuming an excess of non-structural carbohydrate. Full article

The insulin receptor (IR) plays a crucial role in the growth and metabolism of animals. However, there are still many questions regarding the IR in crustaceans, particularly their role in shrimp growth and glucose metabolism. In this study, we identified a novel insulin-like receptor gene in Litopenaeus vannamei and cloned its full length of 6439 bp. This gene exhibited a highly conserved sequence and structural characteristics. Phylogenetic analysis confirmed it as an unreported RTK2-type IR, namely, LvRTK2. Expression pattern analysis showed that LvRTK2 is primarily expressed in female reproductive and digestive organs. Through a series of in vivo and in vitro experiments, including glucose treatment, exogenous insulin treatment, and starvation treatment, LvRTK2 was confirmed to be involved in the endogenous glucose metabolic pathway of shrimp under different glucose variations. Moreover, long-term and short-term interference experiments with LvRTK2 revealed that the interference significantly reduced the shrimp growth rate and serum glucose clearance rate. Further studies indicated that LvRTK2 may regulate shrimp growth by modulating the downstream PI3K/AKT signaling pathway and a series of glucose metabolism events, such as glycolysis, gluconeogenesis, glycogen synthesis, and glycogenolysis. This report on the characteristics and functions of LvRTK2 confirms the important role of RTK2-type IRs in regulating shrimp growth and glucose metabolism. Full article

Heart failure (HF) is a growing concern due to the aging population and increasing prevalence of comorbidities. Despite advances in treatment, HF remains a significant burden, necessitating novel therapeutic approaches. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have emerged as a promising treatment option, demonstrating benefits across the entire spectrum of HF, regardless of left ventricular ejection fraction (LVEF). This review explores the multifaceted mechanisms through which SGLT2is exert cardioprotective effects, including modulation of energy metabolism, reduction of oxidative stress, attenuation of inflammation, and promotion of autophagy. SGLT2is shift myocardial energy substrate utilization from carbohydrates to more efficient fatty acids and ketone bodies, enhancing mitochondrial function and reducing insulin resistance. These inhibitors also mitigate oxidative stress by improving mitochondrial biogenesis, reducing reactive oxygen species (ROS) production, and regulating calcium-signaling pathways. Inflammation, a key driver of HF progression, is alleviated through the suppression of proinflammatory cytokines and modulation of immune cell activity. Additionally, SGLT2is promote autophagy, facilitating the clearance of damaged cellular components and preserving myocardial structure and function. Beyond their glucose-lowering effects, SGLT2is provide significant benefits in patients with chronic kidney disease (CKD) and HF, reducing the progression of CKD and improving overall survival. The pleiotropic actions of SGLT2is highlight their potential as a cornerstone in HF management. Further research is needed to fully elucidate their mechanisms and optimize their use in clinical practice. Full article