Search Results (14,610)

Type 2 diabetes mellitus (T2DM) and obesity represent a growing global public health challenge, strongly associated with excess body weight, unhealthy dietary habits, and a sedentary lifestyle. The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein intake, and high fat consumption, induces a metabolic state known as ketosis, in which the body switches from glucose to fat as its primary energy source. KD has gained increasing interest as a strategy to improve glycemic control, reduce body weight, and improve lipid profiles in individuals with obesity and T2DM. The purpose of this narrative review is to summarize the current scientific evidence on the effects of KD on key metabolic parameters, including blood glucose levels, glycated hemoglobin (HbA1c), body weight, and body composition. The analysis is based on peer-reviewed articles retrieved from PubMed, Embase, and Scopus with particular emphasis on clinical studies that provide robust evidence on the efficacy and safety of KD in the treatment of metabolic disorders. Full article

Background/Objectives: The Prognostic Nutritional Index (PNI), which integrates serum albumin and lymphocyte count, reflects both nutritional and inflammatory status. However, its role in early renal function decline among patients with type 2 diabetes (T2D), particularly in relation to glycemic control, remains unclear. This study aimed to: (1) characterize the dose–response relationship between PNI and early renal function decline in type 2 diabetes using restricted cubic splines; (2) identify whether glycemic control (HbA1c) modifies the PNI–renal decline association; and (3) evaluate the clinical utility of combining PNI and HbA1c for risk stratification. Methods: We analyzed data from 1711 community-based participants with T2D who had preserved renal function at baseline. The PNI was calculated as serum albumin (g/L) + 5 × lymphocyte count (×10⁹/L). The primary outcome was a composite of rapid estimated glomerular filtration rate (eGFR) decline (>3 mL/min/1.73 m² per year) or incident chronic kidney disease (CKD) stage 3. Restricted cubic spline models, multivariable regression, and Johnson–Neyman analyses were used to examine non-linearity and effect modification by glycated hemoglobin (HbA1c). Results: A consistent inverse linear association was observed between PNI and the rate of eGFR decline (P for non-linearity > 0.05). Johnson–Neyman analysis further demonstrated that the protective association of PNI was statistically significant within an HbA1c range of 7.24% to 8.71%. Stratification by clinical cut-offs revealed a significant effect modification by glycemic status. The inverse linear association between PNI and renal risk was most pronounced under hyperglycemic stress, as evidenced by the markedly elevated incidence (50.0%) among individuals with both poor glycemic control (HbA1c ≥ 8%) and low PNI (<50). Conversely, under good glycemic control (HbA1c < 8%), this inverse association was substantially attenuated, with a lower incidence observed in the low-PNI subgroup (6.7%) than in the high-PNI subgroup (15.9%). These findings indicate that the protective role of PNI is conditional upon the glycemic milieu. Conclusions: The PNI demonstrates a stable linear association with early renal function decline in T2D, with its protective effect most pronounced at suboptimal HbA1c levels. Combining PNI and HbA1c effectively identifies a high-risk subgroup characterized by synergistic risk, underscoring the need for integrated nutritional and glycemic management. Full article

Background and Objectives: Patients with type 2 diabetes mellitus (T2DM) and ischemic stroke present with endothelial, vascular and left ventricular (LV) myocardial dysfunction. We investigated the effects of treatment with either glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose contrasporter-2 inhibitors (SGLT-2i) on endothelial glycocalyx, arterial stiffness, and LV myocardial strain in patients with metformin-treated T2DM and a prior ischemic stroke. Materials and Methods: A total of 54 consecutive patients with T2DM and ischemic stroke who attended a cardiometabolic outpatient clinic in Athens, Greece, and received either GLP-1RA (dulaglutide; n = 27) or SGLT-2i (empagliflozin; n = 27) were enrolled in the study. We measured the perfused boundary region (PBR) of the sublingual microvessels, a marker of glycocalyx thickness, as well as carotid-femoral pulse wave velocity (PWV) and LV global longitudinal strain (GLS), at baseline and at 4 and 12 months of treatment. Results: Twelve months after treatment, all patients had reduced glycosylated hemoglobin and body mass index (BMI) (p < 0.001). Patients treated with dulaglutide showed a greater reduction in BMI (−11.8% vs. −4.8%, p < 0.001) compared to those treated with empagliflozin. Compared to baseline, all patients had reduced PBR, PWV and GLS (p < 0.001) after 12 months of treatment. However, empagliflozin presented a greater decrease in PWV (−14% vs. −10.9%, p = 0.041), while dulaglutide resulted in a greater increase in GLS (14.7% vs. 8.3%, p = 0.024) compared to empagliflozin. In all patients, the reduction in PBR at 12 months was correlated with a decrease in PWV and with an increase in GLS (p < 0.05). Conclusions: Both dulaglutide and empagliflozin improve cardiovascular function in T2DM patients with ischemic stroke. Dulaglutide appears to be more effective in the improvement of LV myocardial strain, whereas empagliflozin is more effective in reducing arterial stiffness. Full article

Background/Objectives: Carbapenem-resistant Klebsiella spp. (CRK) causes healthcare-associated infections with high mortality. This study evaluated the clinical outcomes of ceftazidime–avibactam (CZA) therapy in CRK infections. Methods: Patients hospitalized in a tertiary care hospital in Türkiye between June 2021 and December 2022 with CRK-positive cultures, CZA susceptibility, and ≥72 h of CZA treatment were retrospectively analyzed. Results: Ninety-nine patients (61.6% male; mean age 63.7 ± 17.5 years) were included, 89.9% of whom were treated in the intensive care unit (ICU). Hypertension (29.3%), diabetes (28.3%), and malignancy (26.3%) were the most frequent comorbidities. The main infection types were bloodstream infection (56.6%) and ventilator-associated pneumonia (29.3%). CZA was used as monotherapy in 49.5%, and in combination in 50.5% of cases. The mean treatment duration was 13.2 ± 6.3 days. Clinical improvement occurred at 3.4 ± 1.2 days and microbiological eradication at 4.7 ± 2.1 days. Treatment success was achieved in 76.8% of patients, while 30- and 90-day mortality rates were 48.5% and 72.7%, respectively. Only treatment duration significantly affected clinical outcome (p < 0.001). Conclusions: CZA demonstrates favorable outcomes in CRK infections, with no significant difference between monotherapy and combination therapy. These findings support the use of CZA as an effective treatment option for severe CRK infections in real-world clinical settings and may help guide antimicrobial stewardship strategies in high-risk hospitalized patients. Full article

Disulfiram (DSF) is a well-established inhibitor of aldehyde dehydrogenases (ALDHs) and an FDA-approved drug for chronic alcoholism. DSF has gained attention as a versatile scaffold for drug repurposing. Its metabolite, diethyldithiocarbamate (DDTC), mediates multiple biological effects via metal chelation and covalent modification of key cysteine residues. Beyond its established anticancer properties, DSF modulates cancer stem cells, reactive oxygen species, proteasome function, and drug-resistance pathways. It also shows promise in metabolic disorders, including type 2 diabetes and obesity, by targeting enzymes such as fructose-1,6-bisphosphatase and α-glucosidase, and influences energy expenditure and autophagy. DSF exhibits antimicrobial and antiparasitic activity, enhances antibiotic efficacy against multidrug-resistant bacteria, and demonstrates antischistosomal and anti-Trichomonas effects, while also providing radioprotective benefits. The clinical translation of DSF is limited by poor solubility, rapid metabolism, and off-target effects; consequently, the development of DSF analogs has become a major focus. Structural optimization has yielded derivatives with improved selectivity, stability, solubility, and target specificity, enabling precise modulation of key enzymes while reducing adverse effects. A key structure-based strategy involves introducing bulkier substituents to exploit differences in ALDH active-site architecture and achieve target selectivity. This concept is exemplified by compounds (1) and (2), in which bulky substituents confer selective inhibition of ALDH1A1 while sparing ALDH2. This review provides a comprehensive overview of DSF analogs, their molecular mechanisms, and therapeutic potential, highlighting their promise as multifunctional agents for cancer, metabolic disorders, infectious diseases, and radioprotection. Full article

Type 2 diabetes mellitus (T2DM) is characterized not only by chronic hyperglycemia but also by profound adipose tissue dysfunction, including impaired lipid handling, low-grade inflammation, mitochondrial dysfunction, and extracellular matrix (ECM) remodeling. These adipose tissue alterations play a central role in the development of systemic insulin resistance, ectopic lipid accumulation, and cardiometabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, have emerged as highly effective therapies for T2DM and obesity. While their glucose-lowering and appetite-suppressive effects are well established, accumulating evidence indicates that semaglutide exerts pleiotropic metabolic actions that extend beyond glycemic control, with adipose tissue representing a key target organ. This review synthesizes current preclinical and clinical evidence on the molecular and cellular mechanisms through which semaglutide modulates adipose tissue biology in T2DM. We discuss depot-specific effects on visceral and subcutaneous adipose tissue, regulation of adipocyte lipid metabolism and lipolysis, enhancement of mitochondrial biogenesis and oxidative capacity, induction of beige adipocyte programming, modulation of adipokine and cytokine secretion, immunometabolic remodeling, and attenuation of adipose tissue fibrosis and ECM stiffness. Collectively, available data indicate that semaglutide promotes a functional shift in adipose tissue from a pro-inflammatory, lipid-storing phenotype toward a more oxidative, insulin-sensitive, and metabolically flexible state. These adipose-centered adaptations likely contribute to improvements in systemic insulin sensitivity, reduction in ectopic fat deposition, and attenuation of cardiometabolic risk observed in patients with T2DM. Despite compelling mechanistic insights, much of the current evidence derives from animal models or in vitro systems. Human adipose tissue-focused studies integrating molecular profiling, advanced imaging, and longitudinal clinical data are therefore needed to fully elucidate the extra-glycemic actions of semaglutide and to translate these findings into adipose-targeted therapeutic strategies. Full article

Background: Diabetic retinopathy is a leading cause of vision impairment and a significant complication of diabetes mellitus, especially in low- and middle-income countries. This study aimed to identify the barriers affecting diabetic retinopathy screening among people with diabetes mellitus. Methods: This cross-sectional study was conducted between April and October 2024 at the National Center for Diabetes, Endocrinology and Genetics. Data collection was performed using a structured, validated electronic questionnaire adapted from previous studies. Sample size calculation was carried out before data collection. Data were collected using a structured electronic questionnaire. A total of 998 responses were included in the study. The collected data incorporated sociodemographic characteristics, diabetes history, screening practices, and reported barriers. Descriptive and categorical data analyses were performed. Results: Of 998 participants, 82% were over 50 years old, 79% had type 2 diabetes mellitus, and 30% had never had an eye examination. Diabetic retinopathy was diagnosed in 12%. The main barriers to regular attendance among those previously screened (699) were as follows: lack of awareness of its importance (11%), believing that being asymptomatic made screening unnecessary (19%), and transportation difficulties (14%). Among those never screened (299), 56% lacked awareness, 62% believed being asymptomatic negates the need for screening, and 13% faced transportation difficulties. Age > 50 years, higher educational level, availability of health insurance, longer duration of diagnosis of diabetes mellitus, and HbA_1c > 7% were significantly associated with prior screening (p < 0.05). Conclusions: Public health strategies should enhance the education provided to people and physician–person communication and remove logistical obstacles to improve screening compliance. Full article

Background: Type 2 diabetes mellitus (T2DM) and periodontitis are highly prevalent immune-inflammatory diseases that interact bidirectionally. However, how early-onset T2DM, periodontitis, and adverse lifestyle behaviors collectively remodel the gingival plaque microbiome at the ecological network level remains poorly understood in Indian populations. Methods: A cross-sectional 16S rRNA gene (V3–V4) sequencing study was conducted on supragingival and subgingival plaque from 60 adults (30–40 years) recruited in Mumbai. Participants were categorized as healthy (H, n = 10), periodontitis (P, n = 10), T2DM (n = 20), and T2DM with periodontitis (T2DM_P, n = 20). Comprehensive demographic, anthropometric, metabolic, periodontal, dietary, lifestyle, and oral hygiene data were collected. Sequence data were processed using QIIME2–DADA2, followed by diversity, differential abundance, and genus-level co-occurrence network analyses (Spearman |r| ≥ 0.6, FDR < 0.05; core prevalence ≥ 70%). Results: α-diversity showed no marked depletion across groups, whereas Bray–Curtis β-diversity revealed significant global separation, with maximal dissimilarity between H and T2DM_P. Healthy individuals with favorable lifestyle behaviors harbored scaffold-forming taxa such as Corynebacterium matruchotii, Lautropia mirabilis, and Capnocytophaga spp. In contrast, P and T2DM_P groups showed enrichment of proteolytic, inflammation-adapted genera including Porphyromonas, Tannerella, Treponema, Fretibacterium, Peptostreptococcus, and Selenomonas. Network analysis revealed a shift from commensal-rich modular networks to densely connected, keystone-centered disease modules. Conclusion: Early-onset T2DM and periodontitis, particularly under adverse lifestyle behaviors, reorganize plaque microbial composition and interaction architecture rather than depleting diversity, highlighting plaque-based keystone taxa and networks as targets for microbiome-informed risk stratification and integrated medical–dental–lifestyle interventions. Full article

Background/Objectives: The Mediterranean (Med)-style and Dietary Approaches to Stop Hypertension (DASH) eating patterns are evidence-based nutrition interventions given their protective effects from cardiometabolic diseases. Little is known about adherence to each eating pattern among the Hispanic/Latine population. The objective of this cross-sectional analysis is to assess the alignment of reported dietary intakes of Hispanic/Latine adults to Med-style and DASH eating patterns and associations with clinical outcomes for diabetes mellitus and cardiovascular diseases. Methods: A sample of 5406 Hispanic/Latine adults from the National Health and Nutrition Examination Survey (2007–2018) was utilized. Alignment to the Med-style and DASH eating patterns was calculated by scoring indices tailored for overconsumption in the United States. Multiple linear regression determined associations between each respective eating pattern and clinical outcomes. Results: Hispanic/Latine adults in the United States have a mean DASH score of 11.2 and a Med-style score of 8.4 (out of 100), indicating poor alignment. Adjusted regression analysis showed increased alignment of both eating patterns was associated with a decrease in average blood pressure (DASH ꞵ = −0.095, p = <0.0001; Med-style: ꞵ = −0.128, p = 0.0002). Greater adherence to a Med-style eating pattern score was also associated with improved average hemoglobin A1c (ꞵ −0.007, p = 0.017). Neither diet pattern score was associated with total cholesterol. Conclusions: Evidence of low alignment to the Med-style and DASH eating patterns among Hispanic/Latine populations exacerbates the need for future work to understand cultural tailoring of evidence-based eating patterns to increase adherence and support improved cardiometabolic outcomes. Full article

Biological aging disrupts liver–gut intercommunication, resulting in the development of insulin resistance and type 2 diabetes, coupled with the imbalance of gut microbiome composition known as gut dysbiosis. Fermented red ginseng (FRG) is a renowned functional food substance showing its notable anti-inflammatory and anti-diabetic effects owing to its unique bioactive compounds known as ginsenosides. However, whether FRG could impact biological aging and age-related metabolic dysfunction is still unclear. The current study aimed to determine the health benefits of FRG in improving age-associated impaired insulin homeostasis and gut dysbiosis in 19-month-old male mice. Mice were fed with a normal chow diet (NCD) or NCD with FRG (300 mg/kg) for 14 weeks. FRG supplementation significantly improved insulin homeostasis by activating the hepatic protein kinase B (AKT) and proline-rich AKT substrate of 40 kDa (PRAS40). We also observed suppressed mRNA expression of proinflammatory cytokines and diminished inflammatory infiltrates in the liver of FRG-fed mice compared with NCD-only controls. Furthermore, alongside a decreased ratio of Firmicutes to Bacteroidetes, FRG administration enriched beneficial genera, including Muribaculaceae, Borkfalkiaceae, Parasutterella, and Clostridia vadin BB60 group, whereas FRG reduced the abundance of Erysipelotrichaceae and Dubosiella at the genus level. In summary, we suggest that FRG can be a potential anti-aging dietary supplement to manage age-driven dysregulation of insulin homeostasis and gut microbiota composition. Full article

Background/Objectives: Nailfold videocapillaroscopy (NVC) is a non-invasive method for visualizing systemic micro-circulation, primarily used in rheumatology. Many ocular diseases (e.g., glaucoma, diabetic retinopathy (DR), and central serous chorioretinopathy (CSC)) involve microvascular disturbances. Since microangiopathies are often systemic, NVC findings may reflect ocular pathology. This narrative review aimed to summarize current evidence linking NVC alterations with retinal, choroidal, and optic nerve diseases. Methods: A literature search of PubMed, Scopus, and Web of Science (2000–2025) was conducted using the keywords “nailfold videocapillaroscopy,” “ocular diseases,” “retinopathy,” and “glaucoma”. Results: Most available studies were cross-sectional and exploratory. In glaucoma, NVC abnormalities suggesting systemic hypoperfusion (reduced capillary density, avascular areas, tortuosity, and microhemorrhages) were frequently reported. CSC was associated with capillary dilation patterns (megacapillaries and aneurysmal dilations), supporting a congestive rather than ischemic microvascular profile. In DR, NVC abnormalities (reduced density and neoangiogenesis) correlated with DR severity. Associations were also found for AMD and idiopathic macular telangiectasia type 2 (MacTel2, also known as IMT). However, only a limited number of prospective studies assessed diagnostic performance, and data on sensitivity, specificity, or ROC-based validation remain scarce. Conclusions: Current evidence suggests that NVC reflects systemic microvascular alterations associated with several ocular diseases. While NVC shows potential as an adjunctive tool for risk assessment and phenotyping, its diagnostic validity has not yet been established. Limitations include the predominantly observational nature of the studies, heterogeneity of methodologies, and the lack of standardized diagnostic thresholds. Prospective trials integrating NVC with ocular imaging modalities, such as OCT angiography, are needed to determine its clinical utility. Full article

Background: In internal medicine, the management of type 2 diabetes mellitus (T2DM) is challenged by multimorbidity and polypharmacy. The fixed-dose combination of sitagliptin and extended-release metformin (SITA/MET ER) is a valuable option for frail and comorbid patients. Methods: This multicenter, retrospective, observational study involved five Italian Internal Medicine units. Consecutive patients with T2DM who initiated SITA/MET ER were included. Demographic, clinical, and laboratory data were collected at baseline (T0) and at follow-up (T1, 3–4 months). The primary endpoint was change in HbA1c; secondary endpoints included fasting plasma glucose (FPG), treatment adherence, adverse events, and modifications in concomitant antidiabetic therapies. Results: A total of 292 patients (mean age 70.8 ± 10.6 years; 43% female) were analyzed. At baseline, mean HbA1c was 7.4 ± 1.0% and FPG 150.2 ± 42.5 mg/dL, with significant reductions observed at follow-up (HbA1c 7.0 ± 0.8%, FPG 136.8 ± 29.6 mg/dL; both p < 0.05). SITA/MET ER was predominantly prescribed to patients with a complex clinical profile, as reflected by the high prevalence of microvascular (37%) and macrovascular (42%) complications. The use of sulfonylureas decreased from 11% to 3% (p < 0.001), while SGLT2 inhibitor and insulin use remained stable. Treatment adherence to SITA/MET ER was excellent, with full compliance reported and no adverse events recorded. Conclusions: In this real-world internal medicine study, SITA/MET ER improved glycemic control and was well tolerated among patients with complex clinical profiles. These findings support the role of SITA/MET ER as a flexible and practical therapeutic choice in this setting. Full article

Background/Objectives: Diabetic kidney disease (DKD) is the most prevalent form of chronic kidney disease and kidney failure globally. In the last decade, RAAS inhibitors, SGLT2 inhibitors, GLP-1-receptor agonists, and non-steroidal mineralocorticoid receptor antagonists have made significant advancements. However, despite the use of these drugs, patients with DKD often show a residual renal risk. In this narrative review, we synthesize current evidence on residual renal risk in DKD, focusing on underlying mechanisms, high-risk clinical phenotypes, and therapeutic gaps. Methods: A narrative review of current literature available in clinical trials, post hoc analysis studies, observational studies, and research into mechanisms of action or processes related to DKD was performed. Results: The central element of residual renal risk in DKD is persistent inflammation, fibrosis, tubulointerstitial injury/injury to both renal and vascular systems, and metabolic memory. These represent the four types of renal-related problems that have been identified. Non-albuminuric DKD, rapid progressors, late presenters with multiple comorbidities, tend to exhibit an extreme burden associated with some of these entities. Conclusions: The remaining risk factors that cannot be adequately addressed by current medical treatments represent major opportunities for improved clinical management, i.e., those at high-risk of kidney failure. Future research initiatives are required to further refine and improve therapeutic approaches for early intervention in patients with DKD. In addition, development of specific treatments targeting inflammation, fibrosis and metabolism in the kidney will lead to better therapeutic results and decreased risk of progressive loss of kidney function. Full article

Endometrial cancer (EC) is the most common gynecological cancer in developed countries, with approximately 417,000 new cases reported worldwide in 2020. Its incidence has been rising for the past 30 years, primarily due to population aging, obesity, and type 2 diabetes; obesity accounts for almost half of cases due to excessive estrogen production. The classic division into types I and II was replaced in 2013 by the molecular TCGA classification, which distinguishes four subtypes: POLE-ultramutated (best prognosis), MSI-hypermutated, copy-number low, and copy-number high (worst prognosis). This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. ctDNA monitoring supports therapeutic decisions. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies. Full article

Prediabetes is accompanied by early β-cell stress and oxidative imbalance before overt hyperglycemia. Circulating extracellular vesicle (EV) microRNAs (miRNAs) may capture early metabolic disturbances, but their mechanistic relevance remains unclear. Plasma EV miRNA profiles were analyzed across normoglycemia, prediabetes, and newly diagnosed type 2 diabetes, with validation in an independent cohort (n = 150). Functional studies were performed in pancreatic β-cells exposed to glucolipotoxic stress to examine miRNA regulation, IFN-α signaling, mitochondrial redox status, and insulin secretion. Six EV miRNAs, including miR-186-5p, were consistently reduced in prediabetes and correlated with glycemic and insulin resistance indices. In β-cells, glucolipotoxic stress selectively suppressed miR-186-5p, leading to derepression of IFNA2, activation of IFN-α–JAK/STAT signaling, increased mitochondrial ROS, impaired ATP/ADP dynamics, and reduced glucose-stimulated insulin secretion. Restoration of miR-186-5p or pharmacologic JAK inhibition mitigated these defects, and luciferase assays confirmed IFNA2 as a direct target of miR-186-5p. EV-associated miR-186-5p represents an early marker of metabolic stress in prediabetes and provides mechanistic insight into IFN-α–driven oxidative and secretory dysfunction in β-cells. Full article