Search Results (542)

Background/Objectives: This 12-week randomized controlled trial investigated whether progressive resistance training combined with vitamin D supplementation produces enhanced combined improvements in cardiometabolic profiles and functional capacities compared with monotherapies in elderly Korean women with type 2 diabetes mellitus (T2DM) and vitamin D deficiency. Methods: In a 2 × 2 factorial design, 52 women (aged 65–80 years) with T2DM and serum 25(OH)D < 20 ng/mL were assigned to four groups: Exercise + Vitamin D (Ex + VitD, n = 15), Exercise + Placebo (Ex + Placebo, n = 13), Vitamin D only (VitD, n = 11), or Control (n = 13). Exercise groups completed supervised progressive resistance training three times weekly, and vitamin D groups received 2000 IU/day cholecalciferol. Results: The Ex + VitD group achieved significant improvements in HbA1c (−0.13%, p = 0.019), fasting glucose (−0.79 mmol/L, p < 0.001), insulin (−1.96 μU/mL, p = 0.050), and HOMA-IR (−0.77, p = 0.020). Serum 25(OH)D increased substantially (+15.57 ng/mL, p < 0.001). Calcitonin rose exclusively in the Ex + VitD group (+2.57 pg/mL, p < 0.001, d = 3.34), while monotherapies showed no change. Total cholesterol (−23.93 mg/dL), triglycerides (−25.07 mg/dL), and LDL-cholesterol (−10.20 mg/dL) decreased significantly. Both exercise groups showed marked strength gains (chair stand +8.33 to +10.00 repetitions, p < 0.001) and balance improvements (functional reach +2.47 to +4.46 cm, p ≤ 0.033). Conclusions: Twelve weeks of progressive resistance training combined with vitamin D supplementation produced enhanced combined improvements in glycemic control, insulin sensitivity, calcitonin secretion, muscular strength, and lipid metabolism in elderly women with T2DM and vitamin D deficiency, targeting complementary pathways that neither intervention engaged alone. Full article

Background: Impaired glucose tolerance (IGT) is the principal prediabetic stage preceding type 2 diabetes mellitus (T2D), yet islet-specific biomarkers capable of tracking progressive molecular changes from normal glucose tolerance (NGT) through IGT to T2D remain unestablished. We sought to identify a multi-gene biomarker panel with monotonically increasing expression and causal support across the full glycemic continuum. Methods: Two human islet transcriptomic datasets (GSE76895, GSE164416; n = 181: NGT 50, IGT 56, T2D 75) were integrated following ComBat batch correction. Candidate biomarkers were identified at the intersection of limma differential expression and weighted gene co-expression network analysis (WGCNA), then refined through a five-algorithm machine learning consensus (LASSO, random forest, XGBoost, SVM-RFE, elastic net). Progressive expression was assessed by the Jonckheere–Terpstra (J–T) trend test. Two-sample Mendelian randomization (MR) with eQTLGen cis-eQTL instruments, Steiger directionality testing, and Bayesian colocalization provided causal inference. A diagnostic model was internally validated via 1000-iteration bootstrap resampling. Cell-type specificity was verified using single-cell RNA sequencing (GSE200044; 127,919 cells). Results: A 12-gene biomarker panel (ALDOB, DKK3, PCOLCE2, KCNE4, INHBA, IRF8, ITGB2, LAPTM5, MYOF, RAMP3, RUNX2, S100A4) was identified, with all members passing Bonferroni-corrected J–T trend testing across the NGT–IGT–T2D axis (p ≤ 2.4 × 10⁻³). Notably, a direct IGT-versus-NGT transcriptome-wide comparison (11,948 genes) yielded no significant DEGs after FDR correction, indicating that prediabetic islet signals are subtle and detectable only through progressive trend analysis on preselected candidates. Nevertheless, the mean IGT-stage effect size of the 12 hub genes reached 41.9% of the T2D value, with KCNE4 achieving 94.0% (nominal p = 1.75 × 10⁻⁴), identifying it as the earliest-altered biomarker. Two-sample MR using whole-blood eQTLs suggested protective effects of genetically proxied MYOF (OR 0.999, FDR = 1.68 × 10⁻⁴) and RUNX2 (OR 0.998, FDR = 1.68 × 10⁻⁴) on T2D risk, with Steiger testing supporting an expression-to-disease direction (p < 10⁻³⁶). However, Bayesian colocalization indicated independent causal variants at both loci (PP.H3 > 0.76, PP.H4 < 0.001), substantially weakening the causal interpretation and suggesting that the MR associations may reflect linkage disequilibrium rather than shared causal biology. The panel achieved a bootstrap-corrected AUC of 0.833 (apparent 0.879) with PR-AUC of 0.951. Single-cell validation confirmed upregulation of 7 hub genes in β cells and revealed cell-type-specific patterns invisible in bulk data, including bidirectional INHBA regulation between β and α cells and progressive α-cell proportion expansion (28.97% → 46.41%). Pathway enrichment converged on three mechanistic axes: extracellular matrix remodeling, immune activation, and autoimmune-like responses, with direct enrichment of the type 1 diabetes pathway (hsa04940). Conclusions: This study establishes a 12-gene progressive islet biomarker panel spanning the NGT–IGT–T2D continuum, supported by machine learning robustness, genetic causal evidence, diagnostic modeling, and single-cell biological validation. KCNE4 emerges as a candidate early-warning biomarker for prediabetes, while MYOF and RUNX2 represent causally supported compensatory targets, collectively providing a multilayered foundation for T2D risk stratification and precision intervention. From a clinical perspective, the identification of progressive islet biomarkers at the prediabetic stage provides molecular support for early lifestyle intervention, reinforcing that timely detection and behavioral modification remain the most effective strategies to prevent T2D progression. Full article

Background: Type 2 diabetes mellitus (T2D) is one of the fastest-growing chronic diseases worldwide, affecting an estimated 589 million adults in 2024, with projections rising to 853 million by 2050. Dietary modification is a cornerstone of both T2D prevention and management. Among the various dietary approaches, plant-based dietary patterns have gained increasing attention; however, uncertainty remains regarding the optimal dietary composition and the contribution of specific food groups. Methods: This narrative review summarizes the current evidence on plant-based dietary patterns and their association with T2D prevention and metabolic control, with a particular focus on legumes, dietary fiber, and red and processed meat. Evidence from prospective cohort studies, randomized controlled trials, and meta-analyses was evaluated. Results: Higher adherence to healthy plant-based dietary patterns was consistently associated with up to a 30% lower risk of developing T2D, improved insulin sensitivity, and approximately a 0.30–0.47 percentage-point reduction in glycated hemoglobin (HbA_1c). Greater consumption of legumes and dietary fiber was linked to improved glycemic control, enhanced but heterogeneous modulation of gut microbiota composition, reduced low-grade inflammation, and beneficial effects on body weight and lipid metabolism. In contrast, higher intake of processed meat and unprocessed red meat was consistently associated with an increased risk of T2D. Importantly, unhealthy plant-based diets characterized by refined grains, sugar-sweetened beverages, and highly processed foods provided little metabolic benefit and may even increase diabetes risk by up to 13%. The interpretation of the available evidence is limited by the predominance of observational studies, heterogeneous definitions of plant-based dietary patterns, self-reported dietary assessments, and the limited availability of long-term randomized controlled trials. Conclusions: Current evidence supports healthy plant-based dietary patterns as an effective strategy for the prevention and management of T2D. Dietary patterns emphasizing whole plant foods, including legumes, whole grains, fruits, vegetables, nuts, and seeds, while limiting processed and excessive red meat intake, are associated with improved metabolic health. Future high-quality randomized controlled trials with standardized dietary definitions are needed to further define the optimal composition of plant-based diets for diabetes prevention and treatment. Full article

Osteocalcin (OC), a bone protein, is evaluated by its proteoforms, which are implicated in various illnesses. Rapid, clinically used immunoassays are well-established. Epitope dependence, fragment cross-reactivity, uneven identification across carboxylation states, and lack of standardization restrict their efficacy. This study aims to characterize various OC proteoforms in patients with type 2 diabetes mellitus (T2DM) and vitamin D insufficiency and to develop a mass spectrometric immunoassay (MSIA) for their detection. The first MRM-MSIA test to specifically detect OC proteoforms in plasma with vitamin D deficiency-induced alterations in T2DM patients was developed and validated. A precise and selective MRM-MSIA was developed to assess OC fragments in plasma from T2DM patients with normal (DN) or deficient (DD) vitamin D levels. The approach examined OC-1 (aa64–71), OC-2 (aa64–70), and OC-3 (aa72–93) proteoforms. It met international linearity, precision, and accuracy criteria with variability <15% and intra/inter-day accuracy of 88.8% to 110.1%. The DD group had significantly higher OC-1 levels than the DN group. The receiver operating characteristic (ROC) curve for OC-1 produced an AUC of 0.8263 (95% confidence interval [CI], p = 0.0004). The developed MRM-MSIA measures plasma OC proteoforms with good specificity and sensitivity, making it a promising clinical diagnostic tool. Full article

Background: Non-proliferative diabetic retinopathy (NPDR) is a common microvascular complication of type 2 diabetes mellitus (T2DM) associated with chronic inflammation, metabolic dysregulation, and multiple interacting systemic factors. This study evaluated the associations of inflammatory biomarkers, serum 25-hydroxyvitamin D [25(OH)D], electrolyte homeostasis, and lipid-derived indices with NPDR. Methods: In this cross-sectional study with prospective recruitment, 98 patients with T2DM were classified into NPDR (n = 55) and non-DR (n = 43) groups. Clinical characteristics, hematological inflammatory indices, serum interleukin-6 (IL-6), C-reactive protein (CRP), 25(OH)D, electrolyte concentrations, lipid profile, and derived biomarkers—including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), LDL-C/HDL-C ratio, and calculated serum osmolarity—were compared. Receiver operating characteristic (ROC) analysis and multivariable logistic regression were performed to assess discriminatory performance and independent associations with NPDR. Results: Patients with NPDR had significantly lower serum 25(OH)D concentrations than the non-DR group (16.6 ± 7.5 vs. 21.0 ± 5.2 ng/mL, p < 0.001). Serum IL-6 levels (4.2 ± 3.1 vs. 2.8 ± 1.4 pg/mL, p = 0.047), NLR (p = 0.043), LDL-C/HDL-C ratio (p = 0.031), and calculated serum osmolarity (p = 0.033) were significantly higher, whereas lymphocyte count and the lymphocyte-to-monocyte ratio were significantly lower. Among individual biomarkers, serum 25(OH)D showed the best discriminatory performance (AUC = 0.712). A multivariable model including insulin therapy, IL-6, serum 25(OH)D, and the LDL-C/HDL-C ratio demonstrated good discrimination (AUC = 0.813), with 81.8% sensitivity and 81.4% specificity. Bootstrap validation supported the stability of the model. Conclusions: NPDR was associated with lower serum 25(OH)D concentrations, systemic inflammation, and a less favorable LDL-C/HDL-C ratio. A multivariable model integrating inflammatory, metabolic, and nutritional biomarkers showed better discriminatory performance than individual biomarkers. The association between insulin therapy and NPDR likely reflects greater diabetes severity rather than a direct effect of insulin. These findings are exploratory, and prospective studies in larger independent cohorts are needed to determine whether these biomarkers improve risk stratification beyond established clinical factors. Full article

Background: Sodium–glucose co-transporter-2 (SGLT-2) inhibitors are widely prescribed for type 2 diabetes mellitus (T2DM) because of their cardiovascular and renoprotective benefits. However, their use is associated with euglycemic diabetic ketoacidosis (EDKA), a rare but potentially life-threatening complication characterized by severe ketoacidosis despite relatively normal blood glucose levels. Failure to discontinue SGLT-2 inhibitors before surgery, as recommended in current guidelines, together with perioperative fasting and surgical stress, increases the risk of EDKA. Diagnostic complexity is compounded when concurrent postoperative surgical complications provide an alternative explanation for persistent metabolic acidosis. Methods: A 71-year-old man with T2DM receiving uninterrupted empagliflozin underwent direct lateral interbody fusion under general anesthesia. On postoperative day 2, he developed severe high anion-gap metabolic acidosis (pH 7.204, HCO₃⁻ 10.1 mEq/L) with near-normal blood glucose levels (178 mg/dL). Pneumoperitoneum identified on imaging was attributed to Hemovac drain-related peritoneal injury, and emergent laparoscopic exploration was performed under a working diagnosis of surgical sepsis. Although surgical source control was successfully achieved, severe metabolic acidosis persisted postoperatively (pH 7.275). Euglycemic diabetic ketoacidosis is an uncommon diabetic complication associated with several perioperative risk factors, including prolonged fasting and surgical stress. Subsequent serum ketone analysis demonstrated markedly elevated beta-hydroxybutyrate levels (4.8 mmol/L), confirming co-existing EDKA. Results: Following empagliflozin discontinuation, targeted treatment with concurrent insulin–dextrose infusion resulted in complete resolution of acid-base imbalance within five days. Conclusions: A concurrent surgical complication appeared to mask EDKA and contributed to a delay in its recognition. In patients receiving SGLT-2 inhibitors, metabolic acidosis that persists after an apparent surgical cause has been addressed should prompt measurement of serum ketones, irrespective of the blood glucose concentration. Structured perioperative protocols for SGLT-2 inhibitor management and postoperative ketone surveillance may help to prevent similar events. Full article

Background/Objectives: Albuminuria is an important marker of kidney and cardiovascular risk in adults with type 2 diabetes mellitus (T2DM). Regional data from Mexico remain limited among patients with preserved estimated glomerular filtration rate (eGFR) and no previous diagnosis of diabetic kidney disease. This study aimed to describe albuminuria categories observed at a single screening assessment and to explore clinical factors associated with higher urinary albumin-to-creatinine ratio (uACR) categories in adults with T2DM receiving care at a regional hospital in western Mexico. Methods: This exploratory single-center cross-sectional study included 119 adults with T2DM (mean age, 53.3 ± 11.7 years), preserved eGFR (≥60 mL/min/1.73 m²), and no previous diagnosis of diabetic kidney disease. Albuminuria was classified from a single first-morning uACR measurement as A1 (<30 mg/g), A2 (30–300 mg/g), or A3 (>300 mg/g). Exploratory multivariable ordinal logistic regression evaluated factors associated with higher uACR categories. A secondary exploratory binary model evaluated screen-detected uACR ≥ 30 mg/g (A2/A3 versus A1). Results: A1 was observed in 67 patients (56.3%), A2 in 40 (33.6%), and A3 in 12 (10.1%); 52 patients (43.7%) had uACR ≥ 30 mg/g at screening. The median uACR was 25.6 mg/g, the median HbA1c was 11.2%, and the median fasting glucose was 280 mg/dL. In the exploratory ordinal model, longer T2DM duration (OR 1.51 per 5 years; 95% CI 1.09–2.10; p = 0.012), higher HbA1c (OR 1.18 per 1% increase; 95% CI 1.01–1.38; p = 0.036), and lower eGFR (OR 0.69 per 10 mL/min/1.73 m² increase; 95% CI 0.55–0.88; p = 0.003) were associated with higher uACR categories after adjustment for the measured covariates. In the secondary binary model, longer T2DM duration and lower eGFR were associated with screen-detected uACR ≥ 30 mg/g. Conclusions: A single screening assessment identified uACR ≥ 30 mg/g in 43.7% of this selected regional cohort. These findings represent screen-detected albuminuria and do not establish persistent albuminuria, diabetic kidney disease, temporality, or causality. Confirmation with repeated uACR measurements and validation in larger longitudinal multicenter studies with detailed medication data are required. Full article

Diabetic kidney disease (DKD) remains a major cause of advanced chronic kidney disease (CKD) and cardiovascular (CV) mortality, despite optimization of renin–angiotensin–aldosterone system (RAAS) blockade and the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are cardiometabolic agents with significant efficacy on glycemic control, body weight, blood pressure (BP), lipid profile, and systemic inflammation. In experimental studies, GLP-1 RAs showed direct renal effects by modulating natriuresis, intrarenal hemodynamics, oxidative stress, endothelial dysfunction, and tubular apoptosis. Randomized clinical trials and real-life analyses have demonstrated reductions in albuminuria and slowing of glomerular filtration rate (GFR) decline. The first study with a primary renal endpoint for semaglutide confirms its nephroprotective potential. This narrative review synthesizes the renal mechanisms involved. The clinical evidence for GLP-1 RA in DKD positions this class alongside SGLT2i and non-steroidal mineralocorticoid receptor antagonists (ns-MRAs) for the management of patients with type 2 diabetes mellitus (T2D), CKD, and very high cardiorenal risk. Full article

Type 2 diabetes mellitus (T2D) is increasingly recognized as a major risk factor for Alzheimer’s disease (AD), supporting the concept that chronic metabolic dysfunction contributes to neurodegeneration. Recent advances have identified caveolin-1 (CAV-1), the principal structural protein of caveolae, as an important regulator of insulin signaling, lipid metabolism, mitochondrial homeostasis, neurovascular integrity, and amyloid precursor protein processing. Since our previous review published in 2020, substantial evidence has demonstrated that altered CAV-1 expression and function are associated with AD-related pathology under diabetic conditions through multiple mechanisms, including endothelial dysfunction, impaired brain insulin signaling, disruption of mitochondria–endoplasmic reticulum contact sites (MERCSs), neuroinflammation, mitochondrial dysfunction, and defective autophagy. Experimental studies further show that restoring neuronal or endothelial CAV-1 expression improves insulin signaling, preserves synaptic function, attenuates amyloid pathology, and ameliorates cognitive decline in preclinical models. This review summarizes recent advances in understanding of the CAV-1-dependent mechanisms linking T2D and AD and discusses the emerging potential of CAV-1 as a biomarker and therapeutic target for diabetes-associated neurodegeneration. Collectively, current evidence identifies CAV-1 as a central molecular hub integrating metabolic, vascular, and neurodegenerative pathways and supports its further investigation as a promising therapeutic target. Full article

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug action beyond the classic glycemic target. This study examined the effect of co-administration of an Artemisia herba-alba Asso (Asteraceae) aqueous extract on the glucose-lowering effect of dapagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor. Methods: qualitative phytochemical screening and total phenolic and total flavonoid content were used to characterize the aqueous preparation. Male Wistar albino rats were divided into eight groups (10 rats each): four healthy and four diabetic rats induced with streptozotocin (STZ). Vehicle control, oral administration of an aqueous A. herba-alba preparation (0.39 g/kg twice daily), dapagliflozin (0.143 mg/kg/day), or a combination of both was given for 30 days. At baseline and days 7, 14, 21, and 30, glycated hemoglobin (HbA1c) was measured by nephelometry. Parallel fasting blood glucose (FBG) was monitored. Results: the diabetic animals treated with the combination regimen showed the greatest and most sustained decrease in HbA1c (from 4.42 ± 0.40% at baseline to 3.44 ± 0.17% at day 30; p < 0.001) and the greatest decrease in FBG (from 186.0 to 122.2 mg/dL). A. herba-alba monotherapy had little effect on HbA1c and had minimal effect on FBG (214.9 to 217.6 mg/dL); dapagliflozin monotherapy had a modest effect on HbA1c. The untreated diabetic controls (n = 10) showed a progressive increase in HbA1c from 4.45 ± 0.60% at 72 h post-induction to 11.90 ± 0.99% by day 30 (p < 0.001), consistent with delayed hemoglobin glycation relative to the rise in blood glucose. The repeated-measures ANOVA showed a highly significant interaction between time and treatment (p < 0.001). Conclusions: this study showed that the phytochemically defined aqueous A. herba-alba preparation is a beneficial adjunct to SGLT2 inhibitor therapy, an effect not observed with either treatment alone. Full article

Background/Objectives: The relationship between hyperuricemia and diabetic retinopathy (DR) remains controversial despite both conditions being associated with vascular endothelial dysfunction. This study aimed to investigate the longitudinal association between hyperuricemia and the onset and progression of DR in patients with type 2 diabetes mellitus (T2D). Methods: We conducted a retrospective cohort study using patient data from initial visits between 2005 and 2022. Patients were categorized at baseline as having no DR (NDR), simple DR (SDR). The primary endpoint was the onset of DR from NDR, and the secondary endpoint was the progression of DR from SDR. Kaplan–Meier and Cox proportional hazards analyses were employed for statistical evaluation. Results: The study included 1972 patients (1702 with NDR and 270 SDR). In the overall NDR cohort, hyperuricemia was not significantly associated with the onset or progression of DR. However, upon stratification by baseline HbA1c, hyperuricemia was significantly associated with a higher incidence of DR within the high-HbA1c subgroup (≥9%) of the NDR cohort (HR 2.40, 95% CI [1.27–4.55]). Similarly, within the SDR cohort, a Kaplan–Meier analysis demonstrated a significantly higher rate of DR progression in the hyperuricemia group, exclusively among patients with HbA1c ≥ 9% (p = 0.01). Conclusions: Hyperuricemia is independently associated with the onset and progression of DR in T2D patients with poor glycemic control While often co-occurring with other DR risk factors, hyperuricemia may serve as a potential marker for the development of retinopathy in this high-risk population. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg/kg, i.p.) and confirmed by fasting blood glucose ≥ 200 mg/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal–Wallis, Dunn’s with Bonferroni correction, Mann–Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal–Wallis H = 94.3, p < 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% ± 0.15), statistically indistinguishable from healthy groups (p ≥ 0.33), and was the only diabetic regimen with a declining trajectory (−0.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% ± 0.20), approaching that of untreated diabetic controls (9.31% ± 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy–diabetic divergence 2.33–3.13 points). Random Forest prediction was accurate (R² = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective β-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug–disease interactions during combination therapy. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) and menopause are associated with low levels of vitamin D (25[OH]D). Primary trials reported the effects of cholecalciferol supplementation on glycemia and T2DM incidence with conflicting results. This uncontrolled longitudinal prospective study aimed to evaluate changes in metabolic and cardiovascular parameters in postmenopausal women with T2DM during sequential cholecalciferol supplementation. Methods: Thirty-four postmenopausal women (mean of 63.8 ± 7.5 years) with T2DM received 1000 IU/day of cholecalciferol for 12 months, followed by 2000 IU/day for another 12 months. Fasting blood tests, anthropometric assessments, and physical examinations were performed at baseline, 12 months, and 24 months after the intervention. The levels of 25(OH)D, fasting glycemia, glycated hemoglobin, fasting insulin, homeostasis model assessment (HOMA) of insulin resistance, HOMA of β-cell function (HOMA-β), total cholesterol, high-density lipoprotein cholesterol (HDL-c), triglycerides, and C-reactive protein were evaluated. Systolic blood pressure (SBP), diastolic blood pressure, waist circumference (WC), waist-to-hip ratio, and body mass index were also assessed. Results: Serum 25(OH)D and HDL-c levels increased over time during the follow-up period. Lower WC and SBP values were observed across follow-up assessments. Although fasting blood glucose values showed a median of 120 mg/dL at baseline and 110 mg/dL after cholecalciferol supplementation, and HOMA-β values were approximately 35% higher at the end of follow-up, these differences were not statistically significant (p = 0.059 and p = 0.158, respectively). Conclusions: The long-term 25(OH)D dosing regimen had modest beneficial effects on glucose homeostasis, lipid profiles, and blood pressure in postmenopausal women with T2DM. This study contributes to the search for an optimal daily 25(OH)D dose in postmenopausal women with diabetes. Full article

Background: Syzygium cumini and other Myrtaceae plants are widely used as traditional remedies for dysglycemia, yet clinical evidence remains fragmented and heterogeneous. This study aimed to evaluate the efficacy and safety of S. cumini and related Myrtaceae interventions in individuals with dysglycemia. Methods: A systematic review and meta-analysis of randomized controlled trials was conducted in accordance with PRISMA 2020 and registered in PROSPERO (CRD420261332539). PubMed, Scopus, Embase, MEDLINE, and Web of Science were searched from inception to 3 September 2025. Eligible trials enrolled participants with type 2 diabetes mellitus (T2DM) or prediabetes and evaluated Myrtaceae interventions versus controls. Random-effects meta-analyses were performed to estimate mean differences (MDs) with 95% confidence intervals (CIs). Results: Thirteen trials comprising 802 participants were included. Myrtaceae interventions were associated with a statistically significant but modest reduction in fasting plasma glucose (MD −14.40 mg/dL, 95% CI −23.12 to −5.67; I² = 98.57%). However, effects on postprandial glucose (MD −12.99 mg/dL, 95% CI −27.74 to 1.76; I² = 97.93%) and HbA1c (MD −0.46%, 95% CI −0.98 to 0.06; I² = 99.20%) were not statistically significant. Overall effects on lipid outcomes and laboratory safety markers were also not significant. Subgroup analyses suggested possible variation by participant type, plant part, formulation composition, comparator type, and treatment duration, but these findings were exploratory and accompanied by substantial heterogeneity. Conclusions: Myrtaceae interventions may provide a modest short-term reduction in fasting glycemia among adults with T2DM or prediabetes. However, the clinical significance and generalizability of this finding remain uncertain due to high heterogeneity, short follow-up, absence of low-risk trials, and low to very low certainty of evidence. Current evidence does not support consistent benefits for PPG, HbA1c, lipid outcomes, or long-term safety. These interventions should be considered promising but unproven adjuncts rather than alternatives to standard dysglycemia management. Full article