Search Results (11,333)

Clinical trials suggest that daily vinegar ingestion improves fasting blood glucose concentrations, postprandial glucose excursions, and hemoglobin A1c levels in patients with prediabetes and type 2 diabetes. With the recent commercialization of continuous glucose monitoring (CGM) technologies, diabetes patients as well as other health-conscious individuals can evaluate the impact of food choices in real-time and make data-driven decisions to improve dietary behaviors. This 9-day, randomized crossover study documented CGM-derived glycemic patterns during vinegar ingestion in adults with prediabetes. Participants consumed two tablespoons of vinegar twice daily with meals for four days or a control tablet each morning for four days in random order. For each phase, fasting blood glucose on day four, average blood glucose across three days, and peak glucose excursion across three days were calculated. Fasting glucose concentrations of participants (n = 10 women; 36.6 ± 15.6 y; 33.9 ± 6.5 kg/m²) averaged 105.8 ± 20.6 mg/dL at baseline. Vinegar ingestion was associated with significant reductions in the mean glucose concentration (−4.4 mg/dL) and the frequency of blood glucose excursions > 140 mg/dL (−10%) in comparison to the control treatment, but fasting glucose concentrations were unaffected. These data suggest that vinegar-induced improvements in blood glucose can be observed in real-time using a CGM device in adults with prediabetes. Full article

Of the many clinical phenotypes of obesity, the most prevalent are metabolically “healthy” (MHO) and metabolically “unhealthy” (MUO) obesities, the latter being associated with a range of comorbidities, including type 2 diabetes mellitus (T2DM). The underlying causes of different obesity phenotypes and the mechanisms of conversion of one phenotype into another have yet to be fully elucidated. However, increasing evidence suggests the key role of low-grade metabolic inflammation (metaflammation) in the pathogenesis of obesity and metabolic dysfunction. The review presents a comprehensive description of changes in immune cell populations and pro-inflammatory mediators, as well as a detailed comparative mapping of the adipose tissue immune landscape during MHO/MUO transition. Based upon a conceptual model for the intensification of metaflammation during MHO progression and conversion to MUO, a pattern of dynamical changes that accompany MHO/MUO transition is described. Though many parameters demonstrate significant differences in multiple cross-sectional and some longitudinal studies, only a few of them (CRP, IL-6, IL-17A, absolute counts of leukocytes and neutrophils) meet the criteria of a validated biomarker in clinical setting. A lack of standardization in MHO definition and heterogeneity in the severity of MUO make the search for predictive biomarkers a challenge. The review also discusses the mechanisms underlying metabolic memory and the incomplete reversibility of metabolic disturbances after bariatric surgery. Full article

Mulberrofuran A (MFA), a natural product originally isolated from the root bark of Morus alba L. (Sang-Bai-Pi), is a structurally distinctive mulberry-derived 2-arylbenzofuran bearing a prenyl-related side chain. Although MFA has attracted attention because of its phytochemical uniqueness and reported biological relevance, the available evidence specific to MFA remains limited and fragmented. In addition, pharmacological interpretations are often complicated by the frequent use of indirect evidence derived from structurally related mulberrofuran analogues, other arylbenzofurans, or complex Morus extracts. This review critically summarizes current knowledge on the chemistry, occurrence, and biological relevance of MFA, while explicitly distinguishing direct MFA-specific evidence from indirect and contextual evidence. Available studies suggest that MFA may be associated with antimicrobial activity and modulation of arachidonic acid-related inflammatory pathways, whereas its putative roles in metabolic regulation, cardiovascular protection, antiviral activity, antioxidant effects, and anticancer relevance are currently supported mainly by structurally related compounds or broader mulberry literature rather than robust MFA-specific validation. We further discuss the limitations of the current evidence base, including methodological heterogeneity, incomplete statistical reporting, the lack of pharmacokinetic and toxicity data, and the absence of clinical validation. Rather than establishing MFA as a confirmed therapeutic agent, the available literature supports its consideration as an emerging natural product candidate that warrants rigorous chemical, pharmacological, and translational investigation. Full article

Diabetes mellitus (DM), particularly Type 2 DM (T2DM), is increasingly recognized as both a risk factor and an early manifestation of pancreatic ductal adenocarcinoma (PDAC), yet the molecular mechanisms bridging these conditions remain poorly understood. There is growing evidence that chronic metabolic stress in diabetes induces persistent cellular reprogramming and metabolic memory through stable post-translational and epigenetic alterations, independent of conventional insulin resistance, obesity, and inflammatory pathways. We aim to elucidate how hyperglycaemia and metabolic overload contribute to the accumulation of major intermediates, such as acetyl-CoA, Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), and reactive oxygen species, which induce broad changes in post-translational modifications in diabetes-induced PDAC. A comprehensive literature search was conducted using electronic databases, including PubMed, Scopus, and Web of Science databases, to retrieve studies published between 2005 and 2025. This review synthesizes current understanding of post-translational modifications (PTM) dynamics in diabetes-associated PDAC, with emphasis on their role in modulating oncogenic pathways such as KRAS-MAPK and PI3K-AKT. We introduce the concept of PTM remodeling, wherein transient metabolic perturbations become persistently stabilized, contributing to metabolic memory and tumor initiation. In addition, we examine how PTM-driven alterations influence the pancreatic tumor microenvironment, including stromal activation, immune evasion, and metabolic crosstalk, reinforcing a bidirectional link between tumor progression and systemic metabolic dysfunction. Furthermore, emerging therapeutic strategies targeting PTM-regulating enzymes, metabolic substrates, and signaling nodes are discussed as potential approaches to disrupt this axis. Collectively, precision targeting of PTM-mediated metabolic reprogramming represents a promising framework for early intervention and therapeutic development in PDAC associated with diabetes. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the leading cause of chronic liver disease globally, mirroring the increasing prevalence of obesity, insulin resistance, and type 2 diabetes. Early detection of hepatic steatosis is vital for cardiometabolic risk assessment; however, conventional imaging is costly and impractical for population screening. This study aimed to develop interpretable machine-learning models to predict ultrasound-detected hepatic steatosis within the MASLD spectrum using routinely available clinical and biochemical data. Methods: We analyzed data from 644 adults, 50% of whom had ultrasound-detected hepatic steatosis. Preprocessing, imputation, and feature selection were implemented within a single scikit-learn pipeline to avoid information leakage. An Elastic Net-regularized logistic regression identified the top 20 predictors, which were subsequently used across nine supervised machine learning (ML) classifiers. Model performance was evaluated via repeated stratified 5-fold cross-validation (25 resamples) using accuracy, F1 score, sensitivity, specificity, Youden’s J, balanced accuracy, and Area Under the Receiver Operating Characteristic Curve (AUROC). Interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: Participants with ultrasound-detected hepatic steatosis exhibited greater adiposity, insulin resistance, and dyslipidemia compared with controls [p < 0.05 for body mass index (BMI), waist circumference, glucose, glycated hemoglobin (HbA1c), triglycerides]. Elastic Net selection highlighted Weight, Ponderal Index, Fibrosis-4 Index (FIB-4), blood urea nitrogen (BUN)/Creatinine ratio, Aspartate Aminotransferase to Platelet Ratio Index (APRI), and Visceral Adiposity Index as the strongest predictors. Logistic Regression and Gradient Boosting achieved the best performance (accuracy = 0.65 ± 0.03; AUROC = 0.71 ± 0.04; balanced accuracy = 0.66 ± 0.06), outperforming rule-based indices such as Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) reported in the literature. SHAP analysis confirmed clinically coherent feature effects, with higher anthropometric and hepatic injury indices increasing the predicted probability of ultrasound-detected hepatic steatosis. Conclusions: Routinely available clinical and biochemical parameters can predict hepatic steatosis with moderate accuracy using transparent, interpretable ML models. Logistic Regression and Gradient Boosting provided best discrimination and robust internal performance, offering a pragmatic, low-cost approach for early identification of ultrasound-detected hepatic steatosis within the MASLD spectrum in primary and metabolic care settings. Full article

Aims: The aim of this study was to investigate the associations between symptomatic hearing loss (HL), neuropathy, and nephropathy in subjects with Type 2 diabetes mellitus (T2DM). Furthermore, the study evaluated whether HL was associated with chronic low-grade inflammation, assessed based on plasma levels of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), and explored potential sex-specific differences. Materials and Methods: We included 4245 subjects with T2DM from The Danish Centre for Strategic Research in Type 2 Diabetes cohort. Symptomatic HL was defined using ICD-10 codes. In 2016, a questionnaire was sent out to evaluate neuropathy using the Michigan Neuropathy Screening Instrument (MNSI ≥ 4). Nephropathy was defined as urinary albumin-to-creatinine ratio (UACR) >30 mg/g. Plasma levels of TNF-α, IL-6, and hsCRP were measured at enrolment from 2010 to 2016. Multivariable logistic regression was used, adjusting for covariates. Results: Neuropathy was significantly associated with HL (OR = 1.83, 95%CI [1.42, 2.35], p < 0.001), and the association was stronger in women (OR = 2.74 [1.81, 4.14], p < 0.001) compared to men (OR = 1.44 [1.04, 1.99], p < 0.05) (P-interaction = 0.020). No significant association was found between nephropathy and HL. Among inflammatory markers, only the highest tertile of TNF-α levels was significantly associated with HL compared to the lowest tertile (OR = 1.40 [1.07, 1.82], p < 0.05) without any sex interaction. Conclusions: In subjects with T2DM, neuropathy was associated with symptomatic HL, and the association seemed to be stronger in females. Among chronic low-grade inflammation markers, only TNF-α was significantly associated with symptomatic HL. Additionally, no significant association was found between nephropathy and HL. Full article

Background/Objectives: This study evaluated whether a low-carbohydrate diabetes-specific enteral formula improves glycemic control and insulin requirement compared with a standard enteral formula in critically ill patients with type 2 diabetes mellitus (T2DM) under pandemic-related product accessibility constraints. Methods: This retrospective observational study included adult ICU patients with T2DM receiving enteral nutrition between August 2021 and August 2023. Patients were grouped according to enteral formula type as standard enteral formula or diabetes-specific enteral formula. All patients received continuous nasogastric enteral feeding according to routine ICU practice. Glycemic control was managed using intravenous insulin infusion protocols. One hundred eligible patients were analyzed. Results: Fifty patients were included in each group. Baseline characteristics were broadly comparable, although differences in BMI and feeding rate were observed. Mean glucose level, daily insulin requirement, hypoglycemia, hyperglycemia, and glycemic variability were similar between groups (all p > 0.05). However, the number and percentage of days within the target glycemic range were higher in the diabetes-specific formula group (both p = 0.021). Clinical outcomes were comparable between groups. In multivariable analysis, mean glucose level independently predicted insulin requirement and glycemic variability, whereas formula type did not. Product-related costs were lower in the diabetes-specific formula group (all p < 0.001). Conclusions: Diabetes-specific enteral formula did not improve mean glucose level or insulin requirement in critically ill patients with T2DM, although it was associated with better maintenance of the target glycemic range and lower product-related costs. Enteral formula choice should therefore be individualized rather than routinely determined by diabetes status alone. Full article

Objective: This study assessed the blood-pressure effects of various exercise regimens in middle-aged and older adults with type 2 diabetes, considering baseline levels, to clarify dose–response relationships for personalized exercise guidance. Methods: We conducted a dose–response network meta-analysis. Systematic searches were performed in Web of Science, EMBASE, PubMed and Cochrane Library. Baseline blood pressure was modelled as an explanatory variable via meta-regression. Thirty-six eligible RCTs of physical-activity interventions in older adults with type 2 diabetes reporting blood-pressure outcomes were included. Results: In stage 1–2 hypertension, mind–body activities were associated with the greatest systolic blood-pressure reduction and appear to be the most effective intervention based on available evidence. For diastolic blood pressure, combined aerobic-resistance training was effective in stage 1 hypertension. Dose–response analysis indicated that clinically meaningful reductions occur at modest volumes (668 and 657 MET-min/week for systolic and diastolic pressures, respectively), aligning with the lower end of international activity guidelines. Conclusions: Individualized exercise prescription based on baseline blood pressure may offer a useful non-pharmacological strategy for hypertension management in older adults with type 2 diabetes. By quantifying the required activity dose, this work provides an evidence base for integrating structured exercise into precision care for this high-risk population. Full article

Background: Low-density lipoprotein cholesterol (LDL-C) is a central modifiable driver of atherosclerotic cardiovascular disease, yet cardiovascular risk in type 2 diabetes mellitus (T2DM) may be better captured by longitudinal LDL-C exposure than by a single LDL-C measurement. We examined the association of current LDL-C, cumulative LDL-C burden, and prior time below LDL-C targets with incident acute coronary syndrome (ACS) in patients with T2DM. Methods: We conducted a retrospective longitudinal cohort study using routinely collected electronic health-record data. Patients with T2DM and at least one valid LDL-C measurement between 1 January 2018 and 31 December 2023 were followed from the first eligible LDL-C measurement until incident ACS or administrative censoring on 31 March 2024. LDL-C was modeled using time-updated start–stop Cox regression. The primary exposure was current LDL-C category: <1.4, 1.4 to <1.8, 1.8 to <2.6, 2.6 to <3.4, 3.4 to <4.9, and ≥4.9 mmol/L. Secondary exposure metrics were cumulative LDL-C burden above prespecified thresholds and prior percentage of follow-up time below LDL-C targets. Models were adjusted for age, sex, hypertension, chronic kidney disease, HbA1c, T2DM duration, and calendar year of baseline LDL-C measurement; HbA1c and T2DM duration were multiply imputed. Results: The analytic cohort included 106,185 patients, 426,965 LDL-C intervals, and 5416 incident ACS events over 419,251.0 person-years. Compared with current LDL-C <1.4 mmol/L, adjusted ACS risk was higher for current LDL-C 3.4 to <4.9 mmol/L (HR 1.35, 95% CI 1.21–1.50) and ≥4.9 mmol/L (HR 1.94, 95% CI 1.63–2.32), whereas lower LDL-C categories were not clearly different from the reference category after adjustment. Each 1 mmol/L-year higher cumulative LDL-C burden was associated with higher ACS risk across evaluated thresholds, with HRs ranging from 1.04 to 1.13. Greater prior time below LDL-C targets was associated with lower ACS risk, with HRs of 0.97–0.98 per 10% higher time below target. Findings were consistent in sensitivity analyses restricted to patients with at least three LDL-C measurements, landmark analyses, and complete-case analysis. Conclusions: In patients with T2DM, incident ACS risk was associated with very high current LDL-C and with longitudinal LDL-C exposure captured by cumulative burden and time below target. These findings support sustained, target-oriented LDL-C control and suggest that longitudinal LDL-C metrics may complement single LDL-C values in cardiovascular risk assessment. Full article

Background: Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor with potent antioxidant and anti-inflammatory properties, has been shown to protect against cardiac injury. However, its therapeutic potential in diabetic cardiomyopathy (DCM) induced by Type 2 diabetes mellitus (T2DM) and the underlying mechanisms remain poorly understood. Methods: A T2DM mouse model was established via a high-fat diet and low-dose STZ. We investigated the cardioprotective effects of 12-week oral PQQ administration, assessing fasting blood glucose, oral glucose tolerance, cardiac function, myocardial histopathology, blood biochemistry, mitophagy, and NLRP3 inflammasome activation. In vitro experiments using AC16 cardiomyocytes exposed to palmitic acid and high glucose were also conducted. Results: Results showed PQQ significantly improved cardiac function, attenuated remodeling, and reduced proinflammatory cytokines in mice with T2DM, regulated key mitophagy-related proteins (Parkin, Beclin-1, LC3B-II, p62), and downregulated NLRP3 inflammasome pathway components (Caspase-1, NLRP3, IL-1β, IL-18). In vitro experiments demonstrated that PQQ reduced reactive oxygen species (ROS) production, improved mitochondrial membrane potential, promoted mitophagy, and inhibited NLRP3 inflammasome-mediated pyroptosis. Conclusions: PQQ alleviates DCM in mice with T2DM by improving mitochondrial quality control, promoting mitophagy, and subsequently inhibiting NLRP3 inflammasome-mediated pyroptosis, highlighting its potential as a promising therapeutic agent for T2DM-associated cardiomyopathy. Full article

Background/Objectives: Visit-to-visit glycated hemoglobin A1c (HbA1c) variability is associated with cardiovascular diseases (CVDs) and all-cause mortality, independent of mean HbA1c levels. Metabolic dysfunction–associated steatotic liver disease (MASLD) is associated with CVDs and mortality. We aimed to clarify the association between annual HbA1c variability and MASLD development in individuals with type 2 diabetes (T2D). Methods: A retrospective cohort study was conducted in 402 Japanese patients (219 men, 183 women) with T2D. The participants’ HbA1c levels were measured every 2 months, and their HbA1c coefficient of variation (HbA1c-CV) was calculated from the HbA1c in the past year. We statistically evaluated the association between HbA1c-CV and noninvasive clinical indices of MASLD, including the hepatic steatosis index (HSI), fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease fibrosis score (NFS). Results: Multiple regression analysis of clinical variables and each MASLD index showed that all liver fibrosis indices, including the FIB-4 index (p < 0.001), APRI (p = 0.005), and NFS (p < 0.001), were positively correlated with HbA1c-CV, whereas the HSI was not (p = 0.148). These associations remained even after adjusting for the medications used in the participants. Conclusions: The development of liver fibrosis, estimated using noninvasive blood biochemical indices, is independently and positively associated with annual HbA1c-CV in individuals with T2D. This result suggests that a comprehensive approach, including early MASLD risk stratification, may be beneficial for optimal diabetes management. Full article

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The most common types—type 1 and type 2 diabetes—have different etiologies and pathophysiological mechanisms. Type 1 diabetes (T1DM) results from autoimmune destruction of the insulin-producing pancreatic β-cells, leading to the development of absolute insulin deficiency, whereas in type 2 diabetes (T2DM), impaired carbohydrate metabolism is primarily caused by insulin resistance and relative insulin deficiency. Current diagnostic criteria do not allow for the detection of the disease at the preclinical stage. MicroRNA (miRNA) influences post-translational regulation of gene expression by inhibiting mRNA translation and also promotes mRNA degradation. The aim of this review is to summarize current evidence on the role of microRNAs in the pathogenesis of T1DM and T2DM and to evaluate their potential as early diagnostic biomarkers and therapeutic targets. It is demonstrated that T1DM and T2DM exhibit altered expression of specific microRNAs involved in β-cell apoptosis, autoimmune inflammation, and insulin signaling. In T1DM, key miRNAs include miR-21, miR-25, miR-146a, and miR-375, which reflect β-cell destruction and the autoimmune process. In T2DM, critical roles are played by miR-9, miR-29, miR-34a, miR-103/107, miR-126, miR-143, and miR-375, which regulate insulin secretion, lipid metabolism, and tissue insulin sensitivity. Particular attention is given to microRNAs whose expression changes several years before clinical disease onset (miR-15a, miR-126, miR-375), offering opportunities for early diagnosis. Data are presented on circulating miRNAs in stable biological fluids (blood, urine). It should be emphasized, however, that the proposed microRNA panel currently represents only a potential diagnostic tool. This panel requires further validation and confirmation by clinicians in large-scale prospective studies and does not yet claim to be ready for routine clinical use. Nevertheless, the development of such a universal microRNA panel, followed by thorough clinical evaluation, has promising biomedical potential, which will not only allow for the diagnosis of diabetes at an early stage but also identify new therapeutic targets for personalized medicine. Full article

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article

Diabetes mellitus is a chronic and increasingly prevalent metabolic disorder characterized by persistent hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. Despite the availability of pharmacological agents that effectively manage blood glucose levels, many are associated with adverse effects, limited efficacy over time, and high costs. Consequently, there is growing interest in alternative therapies, especially those derived from traditional medicinal plants, that have long been employed in various cultures for managing diabetes. Recent advances in phytochemistry have identified bioactive plant secondary metabolites with promising antidiabetic properties. This review aims to provide a comprehensive overview of plant-derived compounds that exhibit inhibitory activity against key diabetes-related enzymes, including α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4). These enzymes play critical roles in glucose metabolism and insulin signaling pathways. The review highlights the structural diversity of these natural inhibitors, their mechanisms of action, and their effectiveness in preclinical models. Understanding the molecular interactions and pharmacological profiles of these metabolites may facilitate the development of safer and more effective antidiabetic agents. Full article