Search Results (175)

Background/Objectives: Observational studies have found inverse associations between 25-hydroxyvitamin D concentration and risk of hypertension, hypercholesterolemia and type 2 diabetes (T2D). More robust evidence from large-scale randomized controlled trials, however, is limited or inconclusive. Methods: The D-Health Trial (N = 21,315) is a randomized, double-blind, placebo-controlled trial of supplementation with monthly doses of 60,000 international units of oral vitamin D₃, conducted in Australians aged 60–84 years. Commencing treatment with anti-hypertensive, lipid-modifying, or anti-diabetic drugs was used as a surrogate for incident hypertension, hypercholesterolemia, and T2D, respectively. Outcomes were ascertained via linkage with the Australian Pharmaceutical Benefits Scheme database. Follow-up began 6 months after randomization; we excluded participants without linked data, and those who were prevalent cases or who died prior to start of follow-up. Flexible parametric survival models were used to estimate the effect of vitamin D supplementation on each outcome. Results: We included 10,964 participants (vitamin D, n = 5456 [49.8%]; placebo, n = 5508 [50.2%]) in the analysis of hypertension, 12,126 participants (vitamin D, n = 6038 [49.8%]; placebo, n = 6088 [50.2%]) in the analysis of hypercholesterolemia, and 17,846 (vitamin D, n = 8931 [50.0%]; placebo, n = 8915 [50.0%]) in the analysis of T2D. Over a median follow-up of 4.6 years, 2672 (24.4%), 2554 (21.1%), and 779 (4.4%) participants developed hypertension, hypercholesterolemia, and T2D, respectively. Vitamin D supplementation had no material effect on the incidence of any of hypertension (HR 1.00; 95% CI 0.93 to 1.08), hypercholesterolemia (HR 1.05; 95% CI 0.97 to 1.13), or T2D (HR 0.97; 95% CI 0.84 to 1.12). Conclusions: Monthly supplements of vitamin D did not alter the incidence of any of the three conditions in older, largely vitamin D-replete Australians. Full article

Background: Phytotherapeutic agents, including Momordica charantia, have been proposed as complementary strategies to enhance metabolic control in type 2 diabetes mellitus patients on oral antidiabetic drugs. Methods: This was a real-world, longitudinal, comparative cohort study with treatment escalation, conducted in patients with type 2 diabetes mellitus receiving metformin therapy. All patients were initially prescribed add-on dapagliflozin at 10 mg/day and re-evaluated after 6 months. Based on glycemic response at 6 months, patients were stratified into two groups: 70 patients with persistent inadequate glycemic control received adjunctive supplementation with a standardized Momordica charantia extract for 3 months (intervention group), while 85 patients who achieved glycemic targets continued dual antidiabetic therapy alone (control group). Anthropometric, hemodynamic, and metabolic parameters were assessed at baseline, 6 months, and 9 months from baseline. Results: Between-group analyses revealed divergent glycemic trajectories during the 6–9 month interval. In the intervention group, HbA1c decreased from 7.82 ± 0.58% at baseline to 6.93 ± 0.30% at 6 months and to 6.34 ± 0.42% at 9 months, while in the control group, glycemic parameters showed only modest additional changes after 6 months. The reduction in HbA1c and fasting plasma glucose between 6 and 9 months was significantly greater in patients receiving Momordica charantia compared with controls (p < 0.001). Fasting plasma glucose declined from 138.4 ± 17.5 mg/dL at baseline to 122.3 ± 13.1 mg/dL at 6 months and to 113.3 ± 12.2 mg/dL at 9 months in the intervention group. Dapagliflozin therapy was associated with significant improvements in body weight, BMI, and blood pressure at 6 months in both groups, whereas adjunctive Momordica charantia supplementation did not produce significant additional effects on anthropometric or hemodynamic parameters. Conclusions: Adjunctive Momordica charantia supplementation was associated with additional improvements in glycemic control compared with continuation of dual antidiabetic therapy alone, with the most pronounced effects observed for HbA1c and fasting plasma glucose. These findings support a potential adjunctive role for phytotherapeutic supplementation in patients with suboptimal glycemic control receiving contemporary standard therapy. Full article

Background: Systemic inflammation plays a central role in the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Hematologic inflammatory indices-such as the Systemic Immune-Inflammation Index (SII), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Monocyte-to-Lymphocyte Ratio (MLR)-have emerged as accessible markers of chronic inflammation, yet longitudinal comparisons across oral antidiabetic therapies remain limited. This study uniquely integrates longitudinal correlation and network analyses in a large real-world T2DM cohort, allowing assessment of the temporal stability and class-specific inflammatory patterns across four oral antidiabetic therapies. Methods: This retrospective, longitudinal study analyzed 13,425 patients with T2DM treated with Biguanidines, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Sodium–Glucose Cotransporter-2 (SGLT-2) inhibitors or Thiazolidinediones (TZDs) between 2020 and 2024. Data were retrieved from the Probel^® Hospital Information System and included baseline, early (30–180 days), and late (180–360 days) follow-up laboratory results. Systemic inflammatory indices were computed from hematologic parameters, and correlations among inflammatory and biochemical markers were assessed using Spearman’s coefficients. Results: At baseline, all hematologic indices were strongly intercorrelated (SII–NLR r = 0.83, p < 0.001; SII–PLR r = 0.73, p < 0.001), with moderate associations to C-reactive protein (CRP; r ≈ 0.3–0.4) and weak or no correlations with Ferritin (r ≈ −0.1). These relationships remained stable throughout follow-up, confirming reproducibility of systemic inflammatory coupling. Longitudinally, SII and NLR showed modest early increases followed by significant declines at one year (p < 0.05), while PLR and MLR remained stable. Class-specific differences were observed: SGLT-2 inhibitors and TZDs demonstrated stronger and more integrated anti-inflammatory networks, whereas Biguanidines and DPP-4 inhibitors exhibited moderate coherence. Principal Component Analysis (PCA) explained 62.4% of total variance and revealed distinct clustering for TZD and SGLT-2 groups, reflecting class-specific inflammatory modulation. Conclusions: Systemic inflammatory indices (SII, NLR, PLR) provide reproducible and accessible measures of low-grade inflammation in T2DM. Despite overall inflammation reduction with treatment, drug-specific patterns emerged-SGLT-2 inhibitors and TZDs showed greater anti-inflammatory coherence, while Biguanidines and DPP-4 inhibitors maintained moderate effects. Full article

Type 2 diabetes mellitus (T2DM) involves chronic hyperglycemia, insulin resistance, low-grade inflammation, and oxidative stress that drive cardiometabolic and renal damage despite current therapies. Sodium–glucose cotransporter (SGLT) inhibitors have reshaped the treatment landscape, but residual risk and safety concerns highlight the need for new agents that combine glucose-lowering efficacy with redox–inflammatory modulation. LASSBio-1986 is a synthetic N-acylhydrazone (NAH) derivative designed as a gliflozin-like scaffold with the potential to interact with SGLT1/2 while also influencing oxidative and inflammatory pathways. Here, we integrated in silico and in vivo approaches to characterize LASSBio-1986 as a multifunctional antidiabetic lead in murine models of glucose dysregulation. PASS and target class prediction suggested a broad activity spectrum and highlighted transporter- and stress-related pathways. Molecular docking indicated high-affinity binding to both SGLT1 and SGLT2, with a modest energetic preference for SGLT2, and ADME/Tox predictions supported favorable oral drug-likeness. In vivo, intraperitoneal LASSBio-1986 improved oral glucose tolerance and reduced glycemic excursions in an acute glucose challenge model in C57BL/6 mice, while enhancing hepatic and skeletal muscle glycogen stores. In a dexamethasone-induced insulin-resistance model, LASSBio-1986 improved insulin sensitivity, favorably modulated serum lipids, attenuated thiobarbituric acid-reactive substances (TBARS), restored reduced glutathione (GSH) levels, and rebalanced pro- and anti-inflammatory cytokines in metabolic tissues, with efficacy broadly comparable to dapagliflozin. These convergent findings support LASSBio-1986 as a preclinical, multimodal lead that targets SGLT-dependent glucose handling while mitigating oxidative and inflammatory stress in models relevant to T2DM. Chronic disease models, formal toxicology, and pharmacokinetic studies, particularly with oral dosing, will be essential to define its translational potential. Full article

Background/Objectives: Population aging increases the healthcare burden of chronic diseases. We aimed to characterize the sociodemographic and clinical characteristics of Aged Madrid, a cohort comprising 98.6% of the population aged 75 years and older in Madrid, Spain. Methods: Observational study with a five-year retrospective baseline period (2015–2019) to assess baseline vascular and metabolic risk. Data were taken from primary care electronic medical records, hospital discharge summaries, and pharmacy records. Results: 587,603 individuals (mean age: 84 years ± 5.8 years, 61.3% women) were analysed. Obesity affected 31.3% (more frequent in women), while type 2 diabetes occurred in 23.8% (predominantly in men). Hypertension (52.8%), dyslipidaemia (61.6%), and chronic kidney disease (21.7%) were more frequent in women. Atrial fibrillation was the leading cardiovascular condition in women (15.1%), while acute myocardial infarction predominated in men (8.2%). The most prescribed drug classes were antihypertensives (53.8%), statins (44.2%), and oral antidiabetics (26.4%). Among antihypertensives, diuretics (53.9%), ACE inhibitors (27.4%), and ARBs (25.3%) were most used, often in combinations such as diuretics + ACE inhibitors (30.1%). Diabetes treatments favoured metformin and DPP-4 inhibitors; 5.2% received insulin. Conclusions: Sex-based differences emerged in biochemical, anthropometric, and lifestyle variables. Men showed a higher prevalence of cardiovascular diseases and several cardiometabolic risk factors, while women used fewer lipid-lowering and antidiabetic agents. Diuretics were the predominant antihypertensives, and antidiabetic therapy largely followed guideline recommendations. Although 60% of statin users had no prior cardiovascular disease, and their use was concentrated mainly among individuals with major cardiometabolic risk conditions and declined with advancing age, suggesting an age- and risk-sensitive prescribing pattern rather than indiscriminate use. Full article

Metformin, the most widely prescribed oral antihyperglycemic agent, is established as the first-line therapy for type 2 diabetes mellitus (T2DM) owing to its efficacy, affordability, and safety. Increasing evidence indicates that its benefits extend beyond glycemic control, encompassing cardiovascular protection and diabetes prevention in individuals at elevated cardiometabolic risk. Mechanistic studies demonstrate that metformin exerts pleiotropic effects through activation of AMP-activated protein kinase, modulation of the gut microbiota, inhibition of pro-inflammatory and oxidative stress pathways, and improvements in endothelial function, lipid metabolism, and insulin sensitivity. These actions address core drivers of atherosclerosis and metabolic dysfunction, many of which occur independently of glucose lowering. In patients with T2DM, the cardiovascular benefits of metformin are well recognized, including reductions in all-cause mortality and cardiovascular events. In individuals without diabetes but at high cardiovascular risk—such as those with prediabetes, obesity, or metabolic syndrome—evidence is more limited, as most data are derived from subgroup analyses or trials with surrogate endpoints. Nonetheless, consistent signals suggest that metformin may delay the progression from prediabetes to overt diabetes and potentially confer vascular protection, particularly in carefully selected high-risk populations. Clinical trials and meta-analyses have demonstrated that metformin reduces incident diabetes by approximately one quarter in high-risk adults, with stronger effects observed in younger, overweight individuals, women with prior gestational diabetes, and those treated for longer durations. However, uncertainties remain regarding its long-term cost-effectiveness, optimal dosing strategies, and cardiovascular benefits in non-diabetic populations. The ongoing VA-IMPACT trial (NCT02915198) is expected to clarify whether metformin reduces major cardiovascular events in prediabetic patients with atherosclerotic disease. Taken together, metformin represents more than an antidiabetic drug. Its pleiotropic mechanisms, favorable safety profile, and low cost support its potential integration into broader cardiometabolic prevention strategies, including primary prevention. Expanding its role beyond diabetes management may offer a cost-effective, widely accessible intervention with significant public health impact. Full article

Currently, there are various approaches to the treatment of diabetes. Regarding type 2 diabetes (T2D), treatment focuses on blood glucose control. When changes in lifestyle do not achieve this glycemic control, the option is to start therapy with antidiabetic drugs such as metformin. However, long-term metformin use causes disturbances that may affect treatment approaches. This review examines recent advances in nanotechnology that have developed new forms of drug administration that can improve the efficacy of the treatment, where nanomaterials, nanostructures, and nanoparticle design are involved, so that they provide controlled and gradual release. The use of biopolymers (as drug delivery systems) has ensured biocompatibility, biodegradability, and low toxicity. There are several methods for obtaining a drug delivery system, including electrospinning, electrospraying, nanoprecipitation, etc. These systems improve drug delivery and can be used orally, transdermally, or intravenously, among means of administration. This review describes the new forms of the administration of metformin in the treatment of T2D, based on the encapsulation of metformin in polymeric matrices such as proteins, polysaccharides, and lipids, among others. Full article

Background and Objectives: Contrast-induced nephropathy (CIN) remains a significant complication following invasive coronary procedures. The HALP score—a composite index derived from hemoglobin, albumin, lymphocyte, and platelet counts—reflects nutritional and inflammatory status and may serve as a predictive biomarker for CIN. The aim of our study is to evaluate the relationship between the HALP score and the development of CIN in non-ST segment elevation myocardial infarction (NSTEMI) patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI). Materials and Methods: This retrospective study included 577 NSTEMI patients who underwent CAG or PCI between December 2022 and June 2025. Patients were divided into two groups based on CIN development. The HALP score was calculated and compared between groups. Results: Of the 577 NSTEMI patients included, 74 (12.8%) developed CIN. Patients who developed CIN were significantly older and had a higher prevalence of diabetes mellitus (DM), worse baseline renal function, and lower levels of hemoglobin, albumin, HDL cholesterol, and lymphocytes (p < 0.001). They also showed higher neutrophil counts, troponin-T levels, and received greater volumes of contrast media (CM). Oral antidiabetic drug (OAD) use was positively associated with CIN, while angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use showed a negative association in univariate analysis. The HALP score was significantly lower in the CIN (+) group than CIN (−) group (15.88 ± 28.48 vs. 53.86 ± 28.48, p < 0.001). Multivariate analysis identified older age, DM, reduced left ventricular ejection fraction, elevated creatinine, increased neutrophils, lower hemoglobin, albumin, and lymphocytes, and higher CM volume as independent predictors of CIN. The HALP score remained a strong inverse predictor of CIN (OR: 0.895; 95% CI: 0.865–0.924; p < 0.001) and the Mehran score was positively associated with CIN risk (OR: 1.578; 95% CI: 1.154–2.087; p < 0.001). Covariate-adjusted receiver operating characteristic (AROC) analysis demonstrated that the HALP score showed good predictive accuracy (AUC: 0.780), with 74.3% sensitivity and 83.3% specificity at a cutoff of 24.1. Conclusions: The HALP score is a simple, accessible, and cost-effective biomarker with strong predictive value for CIN in NSTEMI patients undergoing invasive coronary procedures. Full article

Background/Objectives: Long-term outcomes of patients with left main coronary artery (LMCA) disease and diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) are incompletely investigated. The aim of this study was to assess the 10-year clinical outcomes after PCI according to diabetic status and antidiabetic therapy in patients with LMCA. Methods: This study represents a pooled analysis of two randomized trials (n = 1257 patients) on LMCA PCI focused on the prespecified subgroups of diabetic patients. Patients were categorized in groups according to the diabetic status and antidiabetic therapy (oral drugs or insulin therapy). The primary endpoint was 10-year all-cause mortality. Results: Overall, 361 patients had DM (246 patients on oral antidiabetic drugs and 115 patients on insulin therapy) and 896 patients had no DM. At 10 years, 477 patients died: 291 nondiabetic patients (35.7%), 111 diabetic patients (49.5%) on oral antidiabetic drugs and 75 diabetic patients (70.0%) on insulin therapy (hazard ratio [HR] = 1.57, 95% confidence interval [1.26–1.96]; p < 0.001 for diabetic patients on oral antidiabetic drugs vs. nondiabetic patients; HR = 2.80 [2.17–3.61]; p < 0.001 for diabetic patients on insulin therapy vs. nondiabetic patients; HR = 1.78 [1.33–2.39]; p <0.001 for diabetic patients on insulin therapy vs. diabetic patients on oral antidiabetic drugs). The 10-year incidence of myocardial infarction was higher in diabetic patients on insulin therapy (10.0%) versus diabetic patients on oral antidiabetic drugs (3.0%). There were no significant differences between the groups regarding the 10-year incidence of definite stent thrombosis, coronary artery bypass graft surgery, repeat PCI or stroke. Conclusions: In patients with LMCA disease undergoing PCI, DM was associated with a higher 10-year incidence of all-cause mortality than patients without DM with the worst outcomes observed in diabetic patients on insulin therapy. Full article

Diabetes mellitus affects over 530 million adults globally, with current therapies limited by frequent dosing, <20% oral bioavailability, and poor long-term glycemic control. Nanomedicine, particularly self-assembled peptide nanostructures (nanofibrils), offers sustained, glucose-responsive drug release and extended peptide bioactivity for several days per dose. This review critically evaluates recent advances in smart antidiabetic nanomedicine, focusing on quantitative improvements in pharmacokinetics, controlled release, and patient compliance compared with conventional treatments. It also outlines remaining challenges in large-scale synthesis, safety validation, and regulatory translation. Collectively, these insights highlight the potential of reversible peptide nanofibrils as long-acting, cost-effective therapeutics for improved diabetes management. Full article

Background: To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. Methods: CAA exhibited reduced lipophilicity and decreased transintestinal transport compared to CBT, as shown in an ex vivo experiment using isolated rat jejunal segments. It also underwent cleavage into CBT and 5-ASA when incubated with cecal contents of rats. Additionally, oral administration of CAA and Sulfasalazine (SSZ), a colon-specific prodrug of 5-ASA currently used for IBD treatment, resulted in similar levels of 5-ASA accumulation in the rat cecal region. Results: In a dinitrobenzene sulfonic acid-triggered colitis model in rats, CAA produced a more pronounced improvement in colon injury and inflammation than SSZ. Furthermore, rectal co-administration of CBT and 5-ASA conferred enhanced protective outcomes compared to monotherapy with either agent alone, suggesting a combined anticolitic action. The two drugs also jointly suppressed valacyclovir uptake via peptide transporter 1 (PepT1) in the distal colon, supporting PepT1 as a target contributing to their combined anticolitic effect. Unlike CBT, which significantly reduced blood glucose following oral administration, equimolar administration of CAA did not alter glycemic levels, consistent with reduced systemic exposure to CBT. Conclusions: In conclusion, CAA functions as a colon-specific mutual prodrug that surpasses SSZ in anticolitic performance while minimizing hypoglycemia risk, thus facilitating the repurposing of CBT as a treatment for IBD. Full article

Background: Annona cherimola Miller (A. cherimola) is traditionally used in Mexico to treat diabetes. Objectives: this study aimed to evaluate the antihyperglycemic activity of the aqueous leaf extracts (AEAcL) and stem (AEAcS) of A. cherimola alone and combined with oral antidiabetic drugs (OADs), as well as to determine their effect on % HbA1c, lipid parameters and toxicity. As well, the study aimed to isolate and identify some of its compounds to propose findings about its mode of action. Methods: Antihyperglycemic activity was evaluated using in vivo models with streptozotocin-induced experimental diabetes in Balb/c mice. Computer tools were used to obtain the pharmacokinetic and toxicological properties of the identified flavonoids; to obtain findings on their potential as α-glucosidase and SGLT1 inhibitors, in vivo and in silico studies were carried out using oral sucrose tolerance (OSTT) and glucose (OGTT) tests and molecular coupling studies. Results: ÇAEs and aSAAcS administered alone at 200 mg/kg showed a significant reduction in hyperglycemia. The best combination was AEAcL + Met (100/500 mg/kg), which significantly reduced hyperglycemic values and the % of HbA1c, TG, and LDL. The flavonoids isolated from AEAcL were identified as rutin, nicotiflorin, and narcissin. The molecular coupling assay and OSTT and OGTT tests showed that the flavonoids could inhibit α-glucosidase and SGLT1. Conclusions: AEAcL shows significant antihyperglycemic and antihyperlipidemic activity in murine models of diabetes, both alone (100 mg/kg) and in combination with metformin (100/500 mg/kg). Isolated flavonoids (rutin, nicotiflorin, and narcissine) appear to be partly responsible for these effects, although they have pharmacokinetic limitations. In silico and in vivo studies suggest a possible mechanism of action by inhibition of α-glucosidase and SGLT1. Full article

Diabetes is a chronic metabolic disorder characterized by persistently high blood glucose levels due to insulin malfunction, defective insulin secretion, or both. Chromen-4-one, known to have diverse biological activity, is a core structure found in many natural products, particularly in the flavonoid and isoflavonoid families. The study aims to explore the potential of Chrome-4-one derivatives as a potential antidiabetic agent through the α-glucosidase inhibition mechanism. The compounds were retrieved from the PubChem database, optimized, and prepared using ChemDraw 12.0, Spartan14, and UCSF Chimera. The post-docking analysis was performed using BIOVIA Discovery Studio. Theoretical oral bioavailability and toxicity predictions were performed using ADMETlab3.0. Molecular docking of the compounds against the α-glucosidase enzyme (PDB ID: 3A4A) was carried out using AutoDock Vina 1.2.5. According to Lipinski’s rule of five (5), all the ligands passed the oral bioavailability and are druggable. The binding score of all the ligands was better than the native ligand (−5.7 Kcal/mol) but slightly lower than that of Acarbose (−9.0 Kcal/mol), except for L7 (Myricetin), which equals the standard drug. The ligands revealed good interaction with the enzyme’s active site residues. The most notable interactions were hydrogen bonding, van der Waals, Pi–anion, Pi–cation, Pi–Pi T-shape, Pi–Sigma, and carbon–hydrogen bonds. The ligands interacted with the key catalytic residues: Asp352, Glu277, Glu411, Trp158, and Arg442, which are responsible for α-glucosidase inhibition. The result of the study suggests that the chrome-4-one derivatives have the potential to be utilized as a lead molecule for orally available α-glucosidase inhibitors. Full article

The complex bidirectional relationship between diabetes mellitus (DM) and oral cancer (OC) denotes that metabolic dysfunction and malignancy intersect at molecular, cellular, and systemic levels. This state-of-the-art review analyzes the most recent literature data on the multiple interconnected pathways linking DM and OC, including hyperinsulinemia/IGF-1 signaling, chronic hyperglycemia-induced cellular damage, persistent inflammation, immune dysfunction, and oral microbiota dysbiosis. These mechanisms create a permissive environment for oral carcinogenesis while simultaneously impairing the body’s natural tumor surveillance systems. Key molecular networks explored include the PI3K/AKT/mTOR pathway, AGE-RAGE interactions, NF-κB signaling, the p53 tumor suppressor pathway, and HIF-mediated responses. Clinical evidence demonstrates that patients with diabetes have higher OC prevalence (250 per 100,000 patients) and significantly increased mortality (HR of 2.09) compared to non-diabetics. The review highlights metformin as the most promising anti-diabetic agent for OC management, showing anti-tumor effects through mTOR inhibition. Novel therapeutics, such as GLP-1 agonists, particularly semaglutide, may be helpful but require further clinical validation. Understanding the shared molecular pathways enables the development of integrated therapeutic strategies that target both conditions simultaneously, and it supports effective screening programs, personalized prevention strategies, and optimized multidisciplinary management approaches for this high-risk patient population. Full article

Diabetes mellitus is largely driven by oxidative stress that disrupts insulin signaling, leading to failure in insulin-mediated glucose absorption. Exploration of natural bioactive compounds is fueled by their promising role in correcting redox imbalance. This study aims to investigate the antidiabetic effect of the methanolic extract of Praecitrullus fistulosus, potentially by transcriptional modulation in streptozotocin–nicotinamide-induced diabetic rats. Male Wistar albino rats (n = 36) were assigned to six groups: normal control; diabetic control; standard drug group; and three treatment groups receiving P. fistulosus extract orally at doses of 200, 400, and 600 mg/kg body weight, respectively, for 30 consecutive days. Diabetes was induced in all groups, except for normal control, by intraperitoneal co-administration of streptozotocin and nicotinamide. Nicotinamide (100 mg/kg) was injected 15 min prior to a single dose of streptozotocin (50 mg/kg). Baseline and endpoint assessments of weight and blood glucose levels were performed. Blood was processed to assess insulin-related indices, lipid profile, and oxidative stress markers. q-PCR and Western blotting were utilized to explore the underlying molecular mechanisms. The diabetic control-group rats exhibited impaired glucose tolerance due to the marked reduction in serum insulin levels, compromised β-cell function, and substantial rise in lipid profile and oxidative stress parameters. Oral administration of P. fistulosus methanolic extract effectively mitigated these alterations in a dose-dependent manner, accompanied by the upregulation of both gene and protein expression involved in the insulin-signaling cascade. Full article