Search Results (4,111)

Background: Excessive accumulation of glomerular extracellular matrix (ECM) is a key factor in the development and progression of diabetic nephropathy (DN). As kidney dysfunction has been reported in normoalbuminuric patients, identifying novel diagnostic and prognostic markers is essential for the prevention and treatment of DN. Methods: Urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) and ECM-related glycoproteins, i.e., fibronectin (FN) and laminin (LN), was measured in obese patients with newly diagnosed type 2 diabetes mellitus (T2DM) before and after 6 months of metformin therapy. Results: Baseline NGAL (1.27 (0.80–2.36) ng/mg Cr), FN (11.19 (5.31–21.56) ng/mg Cr) and LN (123.17 (54.56–419.28) pg/mg Cr) levels did not significantly differ between T2DM patients and controls (1.95 (1.09–2.97) ng/mg Cr, 11.94 (7.78–18.01) ng/mg Cr and 157.85 (83.75–326.40) pg/mg Cr, respectively). In multivariate regression analysis, the body mass index was identified as the only significant predictor influencing urinary NGAL and FN levels at baseline, with β = 0.249, p = 0.005 and β = 1.068, p = 0.010, respectively. Metformin treatment significantly increased urinary levels of both ECM proteins, i.e., FN (18.48 (11.64–32.46) ng/mg Cr) and LN (179.51 (106.22–414.68) pg/mg Cr), without any effect on NGAL levels (1.44 (0.81–2.72) ng/mg Cr). FN and LN were positively associated with NGAL both before (r = 0.709 and r = 0.646, both p < 0.001, respectively) and after (r = 0.594 and r = 0.479, both p < 0.001, respectively) therapy. No correlations were found between NGAL, FN, LN, and albuminuria. However, NGAL was positively correlated with the albumin/creatinine ratio (ACR) both before (r = 0.323, p < 0.05) and after (r = 0.287, p < 0.05) therapy, and negatively with estimated glomerular filtration rate (eGFR) in pre-treatment diabetics (r = −0.290, p < 0.05). FN and LN were also correlated with ACR (r = 0.384, p < 0.01 and r = 0.470, p < 0.001), although the association for LN was limited to untreated patients (r = 0.422, p < 0.01). Conclusions: Our results suggest that metformin has a beneficial effect on ECM turnover with a significant increase in urinary excretion of non-collagenous markers of glomerular injury, i.e., FN and LN. Additionally, ECM-related markers may serve as useful tools for monitoring early renal injury in obese diabetic patients. Full article

Metformin is the first-line medication for treating type 2 diabetes mellitus, with more than 200 million patients taking it daily. Its effects are extensive and play a positive role in multiple areas. Can its effects and potential mechanisms be explored through the urine proteome? In this study, 166 differential proteins were identified following the administration of 150 mg/(kg·d) of metformin to rats for five consecutive days. These included complement component C6, pyruvate kinase, coagulation factor X, growth differentiation factor 15, carboxypeptidase A4, chymotrypsin-like elastase family member 1, and L-lactate dehydrogenase C chain. Several of these proteins have been reported to be directly affected by metformin or associated with its effects. Multiple biological pathways enriched by these differential proteins, or proteins containing differentially modified peptides, have been reported to be associated with metformin, such as the glutathione metabolic process, negative regulation of gluconeogenesis, and the renin–angiotensin system. Additionally, some significantly changed proteins and enriched biological pathways, not yet reported to be associated with metformin’s effects, may provide clues for exploring its potential mechanisms. In conclusion, the application of the urine proteome offers a comprehensive and systematic approach to exploring the effects of drugs, providing a new perspective on the study of metformin’s mechanisms. Full article

Background: This study analyzes the effects of bariatric surgery on female sexual function, assessed using the Female Sexual Function Index (FSFI), and explores the impact of adherence to the Mediterranean diet during the postoperative period. Patients and methods: A retrospective observational study was conducted using a prospectively collected database, including heterosexual women with morbid obesity undergoing bariatric procedures. The FSFI questionnaire was applied before the intervention and 24 months after surgery. Adherence to the Mediterranean diet was evaluated using the PREDIMED questionnaire. Results: Among the 240 participants, 70.8% presented preoperative sexual dysfunction, which decreased to 20.5% two years post-surgery. Significant improvements were observed in all FSFI domains except for pain. Good adherence to the Mediterranean diet was associated with higher scores in the lubrication, orgasm, and satisfaction domains. Conclusions: Bariatric surgery significantly improves female sexual function, with the Mediterranean diet enhancing these benefits during the postoperative period. Future studies must investigate additional variables such as psychological factors, physical activity, and other lifestyle changes that may also influence sexual function. Full article

Background/Objectives: This study aims to investigate the relationship between serum fatty acid-binding protein 4 (FABP4) levels and the severity of periodontitis in systemically healthy individuals. Additionally, the study examines whether non-surgical periodontal treatment can reduce FABP4 levels, establishing its potential as a biomarker linking periodontitis to systemic diseases. Methods: A total of 89 participants with stage I, II, or III periodontitis were recruited, excluding individuals with systemic diseases. Clinical parameters such as clinical attachment level (CAL), probing depth (PD), and gingival index (GI) were recorded. Serum FABP4 levels and Porphyromonas gingivalis (P. gingivalis) antibody titers were measured before and after periodontal treatment using ELISA kits. Statistical analysis included t-tests, correlation analysis, and multiple linear regression to assess changes in FABP4 levels and their association with clinical parameters. Results: FABP4 and P. gingivalis antibody titers significantly increased with the severity of periodontitis (p < 0.001). After non-surgical periodontal treatment, FABP4 levels significantly decreased across all stages of periodontitis. Moderate positive correlations were observed between FABP4 and CAL, PD, GI, and P. gingivalis antibody titers (p < 0.05). Multiple linear regression showed that FABP4 levels increased significantly with the progression of periodontitis, independent of age and sex. Conclusions: The study indicates that FABP4 is a potential biomarker for linking periodontitis to systemic conditions such as cardiovascular diseases and diabetes. Non-surgical periodontal treatment reduced FABP4 levels, potentially contributing to the improvement of systemic conditions associated with elevated FABP4. Further research should explore the role of FABP4 in patients with periodontitis and systemic diseases to strengthen its clinical relevance. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), a progressive liver disease frequently associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity, has the potential to progress symptomatically to liver cirrhosis and, in some cases, hepatocellular carcinoma. Hence, an urgent need arises to identify and approve new therapeutic options to improve patient outcomes. Research efforts have focused on either developing dedicated molecules or repurposing drugs already approved for other conditions, such as metabolic diseases. Among the latter, antidiabetic and anti-obesity agents have received the most extensive attention, with pivotal trial results anticipated shortly. However, the primary focus underlying successful regulatory approvals is demonstrating a substantial efficacy in improving liver fibrosis and preventing or ameliorating cirrhosis, the key advanced outcomes within MASLD progression. Besides liver steatosis, the ideal therapeutic candidate should reduce inflammation and fibrosis effectively. Although some agents have shown promise in lowering MASLD-related parameters, evidence of their impact on fibrosis and cirrhosis remains limited. This review aims to evaluate whether antidiabetic and anti-obesity drugs can be safely and effectively used in MASLD-related advanced fibrosis or cirrhosis in patients with T2DM. Our paper discusses the molecules closest to regulatory approval and the expectation that they can address the unmet needs of this increasingly prevalent disease. Full article

Background: Although peptides are widely used in the clinical treatment of various diseases due to their strong biological activity, they usually require frequent injections owing to their poor in vivo half-life. Therefore, there is a strong clinical need for sustained peptide formulations. Methods: In this study, liraglutide (Lir) and biocompatible multivesicular liposomes (MVLs) were utilized as the model drug and sustained-release carriers, respectively. The drug release rate of Lir-MVLs was controlled by changing the ratio of SPC and DEPC with different phase transition temperatures (PTT, PTT_SPC = −20 °C, PTT_DEPC = 13 °C). Results: As the SPC ratio increased, Lir-MVLs had more flexible lipid membranes, poorer structural stabilization, and fewer internal vesicles with larger particle sizes, contributing to faster release of Lir. After subcutaneous injection of Lir-MVLs, the blood glucose concentration (BGC) of db/db mice decreased to different levels. When the SPC-DEPC ratio was greater than 85:15, the drug release rate was too fast; the BGC remained below 16 mM for only 2–4 days, while when the drug release rate was too slow, was the case when the SPC-DEPC ratio was less than 50:50, the BGC also remained below 16 mM for only 2–3 days. However, when the SPC-DEPC ratio was 75:25, the BGC could be maintained below 16 mM for 8 days, indicating that the release properties of this ratio best met the pharmacological requirements of Lir. Conclusions: This study investigated the effects of phospholipids with different PTT on the release characteristics of Lir-MVLs, and provided ideas for the design of sustained-release peptide preparations. Full article

Heme oxygenase (HO) metabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin-IXα (BV), the latter being reduced into bilirubin-IXα (BR) by the biliverdin reductase-A (BVR). Heme oxygenase exists as two isoforms, HO-1, inducible and involved in the cell stress response, and HO-2, constitutive and committed to the physiologic turnover of heme and in the intracellular oxygen sensing. Many studies have identified genetic variants of the HO/BVR system and suggested their connection in free radical-induced diseases. The most common genetic variants include (GT)n dinucleotide length polymorphisms and single nucleotide polymorphisms. Gain-of-function mutations in the HO-1 and HO-2 genes foster the ventilator response to hypoxia and reduce the risk of coronary heart disease and age-related macular degeneration but increase the risk of neonatal jaundice, sickle cell disease, and Parkinson’s disease. Conversely, loss-of-function mutations in the HO-1 gene increase the risk of type 2 diabetes mellitus, chronic obstructive pulmonary disease, and some types of cancers. Regarding BVR, the reported loss-of-function mutations increase the risk of green jaundice. Unfortunately, the physiological role of the HO/BVR system does not allow for the hypothesis gene silencing/induction strategies, but knowledge of these mutations can certainly facilitate a medical approach that enables early diagnoses and tailored treatments. Full article

The investigation of biomarkers for metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatohepatitis (MASH) reveals their potential for advancing disease treatment and addressing their notable overlap. The connection between MASH, obesity, and T2DM highlights the need for an integrative management approach addressing mechanisms like insulin resistance and chronic inflammation. Obesity contributes significantly to the development of MASH through lipid dysregulation, insulin resistance, and chronic inflammation. Selective biomarker targeting offers a valuable strategy for detecting these comorbidities. Biomarkers such as CRP, IL-6, and TNF-α serve as indicators of inflammation, while HOMA-IR, fasting insulin, and HbA1c are essential for evaluating insulin resistance. Additionally, triglycerides, LDL, and HDL are crucial for comprehending lipid dysregulation. Despite the growing importance of digital biomarkers, challenges in research methodologies and sample variability persist, necessitating further studies to validate diagnostic tools and improve health interventions. Future opportunities include developing non-invasive biomarker panels, using multiomics, and using machine learning to enhance prognoses for diagnostic accuracy and therapeutic outcomes. Full article

Objective: To investigate the feasibility of a machine learning (ML) model based on radiomic features to identify active giant cell arteritis (GCA) in the aorta and differentiate it from atherosclerosis in follow-up [¹⁸F]FDG-PET/CT images for therapy monitoring. Methods: To train the ML model, 64 [¹⁸F]FDG-PET scans of 34 patients with proven GCA and 34 control subjects with type 2 diabetes mellitus were retrospectively included. The aorta was delineated into the ascending, arch, descending, and abdominal aorta. From each segment, 95 features were extracted. All segments were randomly split into a training/validation (n = 192; 80%) and test set (n = 46; 20%). In total, 441 ML models were trained, using combinations of seven feature selection methods, seven classifiers, and nine different numbers of features. The performance was assessed by area under the curve (AUC). The best performing ML model was compared to the clinical report of nuclear medicine physicians in 19 follow-up scans (7 active GCA, 12 inactive GCA). For explainability, an occlusion map was created to illustrate the important regions of the aorta for the decision of the ML model. Results: The ten-feature model with ANOVA as the feature selector and random forest classifier demonstrated the highest performance (AUC = 0.92 ± 0.01). Compared with the clinical report, this model showed a higher PPV (0.83 vs. 0.80), NPV (0.85 vs. 0.79), and accuracy (0.84 vs. 0.79) in the detection of active GCA in follow-up scans. Conclusions: The current radiomics ML model was able to identify active GCA and differentiate GCA from atherosclerosis in follow-up [¹⁸F]FDG-PET/CT scans. This demonstrates the potential of the ML model as a monitoring tool in challenging [¹⁸F]FDG-PET scans of GCA patients. Full article

Background: Insulin resistance (IR) is a condition that precedes the onset of type 2 diabetes mellitus (T2DM), which is regarded as an established risk factor for atherosclerosis (AS). Considering that the same metabolic changes as those caused by IR are evidenced to promote the development of AS, we investigated whether IR estimated by the homeostasis model assessment of IR (HOMA-IR) could predict the occurrence of preclinical AS. Methods: The study participants were divided into two groups based on the presence of IR diagnosed during the baseline hospitalization and defined as a HOMA-IR value equal to or higher than 2.5. After a follow-up period of at least four years, a total of 79 (n = 79) were prospectively assessed in terms of the presence of preclinical AS, determined by either an abnormally low ankle–brachial index (ABI) (ABI < 0.9) or an increased carotid intima media thickness (CIMT) (CIMT > 1 mm). Results: Using the multivariate logistic regression analysis, it was demonstrated that the HOMA-IR was associated with an abnormally low ABI (odds ratio: 1.609, 95% confidence interval (CI): [1.041–2.487], p = 0.032). The Cox regression model revealed that the HOMA-IR was a predictor of both an abnormal ABI (hazard ratio: 1.435, CI: [1.076–1.913], p = 0.014) and increased CIMT (hazard ratio: 1.419, CI: [1.033–1.948], p = 0.031), independently of age, sex, dyslipidemia, smoking, triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and total cholesterol levels. Conclusions: IR, as estimated by the HOMA-IR, may be considered as a predictor of preclinical AS, independently of cardiovascular risk factors. Full article

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and beta cell dysfunction, resulting in hyperglycemia. Olive oil, a cornerstone of the Mediterranean diet, has attracted considerable attention due to its potential health benefits, including reducing the risk of developing T2DM. This literature review aims to critically examine and synthesize existing research regarding the impact of olive oil on the expression of genes relevant to T2DM. This paper also seeks to provide an immunological and genetic perspective on the signaling pathways of the main components of extra virgin olive oil. Key bioactive components of olive oil, such as oleic acid and phenolic compounds, were identified as modulators of insulin signaling. These compounds enhanced the insulin signaling pathway, improved lipid metabolism, and reduced oxidative stress by decreasing reactive oxygen species (ROS) production. Additionally, they were shown to alleviate inflammation by inhibiting the NF-κB pathway and downregulating pro-inflammatory cytokines and enzymes. Furthermore, these bioactive compounds were observed to mitigate endoplasmic reticulum (ER) stress by downregulating stress markers, thereby protecting beta cells from apoptosis and preserving their function. In summary, olive oil, particularly its bioactive constituents, has been demonstrated to enhance insulin sensitivity, protect beta cell function, and reduce inflammation and oxidative stress by modulating key genes involved in these processes. These findings underscore olive oil’s therapeutic potential in managing T2DM. However, further research, including well-designed human clinical trials, is required to fully elucidate the role of olive oil in personalized nutrition strategies for the prevention and treatment of T2DM. Full article

Background and Objectives: Recent studies have shed light on the association between genetic factors and diabetic retinopathy (DR) onset and progression. The purpose of our study was to investigate the association between rs4885322 single-nucleotide polymorphism (SNP) of the UCHL3 gene and rs11558538 SNP of the HNMT gene with the risk of DR in Greek patients with type 2 diabetes mellitus (T2DM). Materials and Methods: In our case–control study, we included 85 T2DM patients with DR and 71 T2DM patients without DR (NDR), matched by ethnicity and gender. Demographic and clinical data of all patients were collected, and then patients went through a complete ophthalmological examination and were genotyped for rs4885322 SNP of UCHL3 gene and for the rs11558538 SNP of HNMT gene. Statistical analysis was implemented by STATA v.16.1. Results: No significant differences in demographic and clinical data were observed between the DR and the NDR group (p-value ≥ 0.05), except for the lower mean of age, longer duration of DM, more frequent use of insulin therapy, and higher levels of hemoglobin A1c (HbA1c) in the DR group. The allelic effect of rs488532 increases the risk of DR by 2.04 times, and in the dominant genetic model, the risk of DR is elevated by 123%, while both associations are statistically significant (p-value < 0.05). Moreover, the allelic effect of rs11558538 is associated with a 3.27 times increased DR risk and, in the dominant genetic model, reveals an augmented risk of DR by 231%, while both associations are also statistically significant (p-value < 0.05). Conclusions: The rs4885322 SNP of the UCHL3 gene and the rs11558538 SNP of the HNMT gene are associated with DR risk in Greek patients with T2DM. However, further studies with larger samples and different ethnicities should be implemented to clarify the exact association of these SNPs and DR onset. Full article

Background/Objectives: Dementia associated with diabetes mellitus (DM) has been well documented in the literature, but studies utilizing early screening tools to target populations with mild cognitive dysfunction remain limited. This study aimed to investigate early cognitive decline by studying the relationships between “Ascertain Dementia 8” (AD8) questionnaire scores and glycemic control, lipid profiles, estimated glomerular filtration rate (eGFR), and the complications of diabetes. Methods: This case–control, cross-sectional, observational study was conducted at a medical center and an affiliated regional hospital in southern Taiwan from 30 June 2021 to 30 June 2023. Patients diagnosed with type 2 diabetes mellitus aged ≥40 years were recruited. Their past medical history, biochemical data, and AD8 score were collected at the same time. Results: The patients with glycated hemoglobin (HbA1c) levels of ≥7% had a higher risk of cognitive impairment than those with HbA1c levels of <7% (p < 0.001). The participants whose eGFR was <60 mL/min/1.73 m² had a higher mean AD8 score compared to those with an eGFR of ≥60 mL/min/1.73 m² (p = 0.008). The patients with a medical history of peripheral artery disease and diabetic neuropathy were also associated with a higher mean AD8 score (p < 0.001 and p = 0.017, respectively). Conclusions: By employing the AD8 questionnaire as a sensitive screening tool, our study suggests that early cognitive decline is significantly associated with poorer glycemic control, a lower glomerular filtration rate, peripheral artery disease, and diabetic neuropathy. Early detection of these risk factors may facilitate timely interventions and tailored treatment strategies to treat or prevent cognitive dysfunction. Full article

Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat model was induced to measure postprandial glycemic responses following glucose and starch ingestion. In vitro assays of enzymatic inhibition and the kinetic mode were performed to evaluate the inhibitory effect of BZYQF on α-amylase and α-glucosidase activities. The main constituent contents of BZYQF in a simulated digestion assay were measured to screen the active constituents in BZYQF against α-amylase and α-glucosidase activities via Pearson correlation and multiple linear regression analyses. Finally, the total flavonoids were purified from BZYQF to perform in vitro activity validation, and the flavonoid constituent activity was verified through molecular docking. Results: In vivo assays showed that BZYQF significantly reduced the blood glucose values of CON rats but not T2DM rats after glucose ingestion, while BZYQF significantly reduced the blood glucose levels by 15 min after starch ingestion in CON and T2DM rats, with more significant decreases in blood glucose levels in T2DM rats. In vitro enzymatic assays showed that BZYQF could inhibit the activities of α-amylase and α-glucosidase in competitive and non-competitive modes and in an uncompetitive mode, respectively. Furthermore, BZYQF showed a stronger inhibitory effect on α-glucosidase activity than on α-amylase activity. Simulated digestion showed that simulated gastric fluid and intestinal fluid changed the main constituent contents of BZYQF and their inhibition rates against α-amylase and α-glucosidase activities, and similar results were rarely found in simulated salivary fluid. Pearson correlation and multiple linear regression analyses revealed that the total flavonoids were the active constituents in BZYQF inhibiting α-amylase and α-glycosidase activities. This result was verified by examining the total flavonoids purified from BZYQF. A total of 1909 compounds were identified in BZYQF using UPLC-MS/MS, among which flavones were the most abundant and consisted of 467 flavonoids. Molecular docking showed that flavonoids in BZYQF were bound to the active site of α-amylase, while they were bound to the inactive site of α-glucosidase. This result supported the results of the enzyme kinetic assay. Conclusions: BZYQF significantly alleviated postprandial hyperglycemia in T2DM rats by inhibiting α-amylase and α-glycosidase activities, in which flavonoids in BZYQF were the active constituents. Full article

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver—a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework—the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome—to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic. Full article