Search Results (769)

Hypertension is among the most important modifiable risk factors associated with heart failure with preserved ejection fraction (HFpEF) development and progression, yet guideline-directed blood pressure (BP) targets (<130/80 mmHg) and sodium–glucose co-transporter 2 inhibitor (SGLT2i) therapies lack dedicated randomized controlled trials (RCTs) in this specific group of patients. This narrative review synthesizes 2024 ESC/ESH and 2025 JSH meta-analyses, discussing the proposed pathophysiological framework linking hypertension-associated remodeling with HFpEF. Post hoc analyses from landmark trials (EMPEROR-Preserved, DELIVER) demonstrate consistent heart failure (HF) event reductions with SGLT2i (pooled HR 0.79, 95% CI 0.67–0.93), complemented by modest systolic BP lowering (−2.3 mmHg) and biomarker insights. Soluble ST2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) may contribute to risk stratification in HFpEF populations when interpreted in conjuction with imaging findings and clinical context; however, neither biomarker is specific for hypertension-mediated remodeling. Critical evidence gaps persist: heterogeneous BP thresholds across international guidelines, limited device therapy data (renal denervation showing −8.5 mmHg sustained reduction), and real-world implementation barriers among elderly/comorbid Europeans (adherence < 50%, polypharmacy risks). Hellenic HF Registry data highlight frailty prevalence (68% in patients > 75 years) complicating aggressive BP management. The review addresses phenotype-specific challenges through precision medicine approaches incorporating phenomapping and multi-biomarker panels (NRI 0.28 improvement). We advocate for dedicated HFpEF RCTs evaluating intensive vs. standard BP targets, SGLT2i sequencing with antihypertensives, and European real-world registries to bridge the translational gap. These strategies aim to transform guideline recommendations into optimized, patient-centered care for the rapidly expanding hypertensive HFpEF population. Full article

Background: Patients with type 2 diabetes mellitus (T2DM) who present with ST-segment elevation myocardial infarction (STEMI) remain at high risk of adverse remodeling after reperfusion. This observational study examined whether pre-admission glucose-lowering therapy class was associated with six-month left ventricular (LV) reverse remodeling and myocardial work recovery. Methods: We analyzed 253 patients with STEMI, baseline LV ejection fraction ≤ 50%, successful primary PCI, and complete baseline and six-month echocardiography. The primary inferential analyses focused on 75 patients with T2DM, grouped according to pre-admission therapy with SGLT-2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or conventional therapy; non-diabetic patients were retained as a descriptive reference group. Clinical outcome, propensity-score, subgroup, and mediation analyses were considered exploratory because of small subgroup and event counts. Results: SGLT-2 inhibitor and GLP-1 receptor agonist exposure was associated with larger improvements in LVEF, LV volumes, and global work efficiency than DPP-4 inhibitors or conventional therapy. Crude MACE rates were highest in the conventional-therapy group, but event estimates were imprecise and confounded by baseline risk, revascularization status, and discharge therapy. Conclusions: In patients with T2DM recovering from STEMI, pre-admission exposure to SGLT-2 inhibitors and, to a lesser extent, GLP-1 receptor agonists was associated with more favorable structural and myocardial work recovery. These hypothesis-generating findings should be interpreted as associations and require confirmation in adequately powered prospective studies. Full article

Age-related hyperphosphatemia is increasingly recognized as a contributing factor in sarcopenia. This work studies the metabolic effects of elevated phosphate on muscle. C2C12 cells were differentiated in the absence or presence of 10 mM β-glycerophosphate (BGP), an exogenous phosphate donor. In addition, quadriceps muscles from four experimental groups of male C57BL/6J mice were analyzed: young (5 months) and old (24 months) fed with standard diet; old mice fed with hypophosphatemic diet or supplemented with the phosphate binder Velphoro^®, for the last three months of life. Mice were stratified according to sarcopenia degree based on muscle mass, strength and physical performance. Protein levels were determined by immunoblotting and mRNA expression by RT-qPCR. ATP levels were measured by luminescence and L-lactate production, citrate synthase and cytochrome c oxidase activities by colorimetric assays. Mitochondrial content, membrane potential and reactive oxygen species (ROS) were determined by fluorescence assay. BGP-treated cells showed increased glucose transporter 1 (GLUT1) and decreased NADH Dehydrogenase (CI-NDUFB8) protein expression, elevated hexokinase II (HK2), phosphoglycerate kinase 1 (PGK1) and lactate dehydrogenase A (LDHA) mRNA levels, reduced ATP levels, increased lactate production, and decreased mitochondrial enzyme activities. Moreover, BGP increased ROS, diminished mitochondrial membrane potential, and altered fusion–fission dynamics and mitophagy. In aged quadriceps, oxidative phosphorylation (OXPHOS) subunits and superoxide dismutase 2 (SOD2) expression were reduced. The hypophosphatemic diet improved all parameters, whereas Velphoro^® selectively increased Mitochondrial cytochrome C oxidase subunit 1 (CIV-MTCO1) expression. Several altered mitochondrial markers are associated with sarcopenia degree. Altogether, hyperphosphatemia induces metabolic changes that scale with the sarcopenic degree. Our findings show a relevant association between hyperphosphatemia and mitochondrial dysfunction, and they support the potential benefit of phosphate reduction as a strategy to prevent or mitigate sarcopenia. Full article

We aimed to investigate the potential antidiabetic effects of an ethanol extract derived from the fruit of Malus floribunda (MF) on insulin resistance, oxidative stress, inflammation, and apoptosis associated with diabetes. In our study, diabetes was induced through the administration of a 10% fructose solution and 40 mg/kg Streptozotocin (STZ). Once diabetes had been induced, metformin (Met) 300 mg/kg and the MF extract (250 mg/kg and 500 mg/kg) were administered orally once daily for 30 days. At the end of the experiment, markers of insulin resistance, oxidative stress, inflammation and apoptosis were evaluated in the serum, muscle and liver tissues of the different groups. The MF extract significantly improved the levels of HOMA-IR, insulin receptor (InR), insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4)—key components of peripheral insulin resistance associated with type 2 diabetes. Fructose/streptozotocin induced oxidative stress, inflammation, and apoptosis were mitigated by increasing Nuclear factor erythroid 2-related factor 2 (NRF2) expression, which restored antioxidant levels (Superoxide dismutase (SOD) and Glutathione (GSH)), significantly improved cytokine levels (Tumor necrosis factor alpha (TNF-α) and Interleukin-1 beta (IL-1β)), and downregulated apoptotic proteins (caspase-3 and caspase-9). We demonstrated the antidiabetic effect of MF extract using a fructose/streptozotocin-induced type 2 diabetes model. MF extract shows promise for future use in herbal medicine. Full article

Background: Sodium glucose-linked transport 2 inhibitors (SGLT2-Is) are well known to exert beneficial effects in chronic heart failure (CHF) independent of left ventricular ejection fraction (LVEF). As inflammation plays a key role in cardiac diseases, data on the association of inflammatory biomarkers and ventricular arrhythmic (VA) burden in SGLT2-I-treated patients is lacking. Methods: This pre-defined subanalysis investigated changes in pre-specified inflammatory biomarkers from baseline to week 52 in response to 5 mg Ertugliflozin compared to placebo and their associations to the incidence of VA burden. Results: A total of 36 patients (18 versus 18) with available biobank samples were included in the analysis. At week 52, leukocyte and neutrophil counts, as well as high-sensitive C-reactive protein (hsCRP) and interleukin-6 (IL-6), were numerically higher in the Ertugliflozin group. In contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were lower in the Ertugliflozin group, although these differences did not reach statistical significance. Notably, lymphocyte counts were significantly higher in Ertugliflozin showing a mean difference of 19.0 ± 10.78% (p = 0.028). Further, a significantly higher incidence of VA burden was observed among Ertugliflozin-treated patients with elevated hsCRP levels (incidence rate ratio [IRR] 3.58; 95% Confidence interval [CI], 1.12–11.40, p = 0.031). Conclusions: In patients with CHF, Ertugliflozin treatment was associated with a higher incidence of VA burden in those with elevated hsCRP levels. This may suggest a potential higher risk for VA in SGLT2-I-treated patients in the setting of heightened inflammatory activity. However, this finding is based on a single interaction analysis in a small sample size, and the results should therefore be considered exploratory and hypothesis-generating, and must be interpreted cautiously. Full article

Background/Objectives: Uncontrolled diabetes and associated comorbidities disproportionately affect African American (AA) adults. Medication adherence is key to diabetes control yet is often suboptimal, particularly among AA adults. This study examined associations between patient characteristics and adherence among AA adults with uncontrolled diabetes and compared two medication adherence instruments for predicting diabetes control. Methods: This cross-sectional analysis used baseline data from the Management of Diabetes in Everyday Life (MODEL) study, a clinical trial to improve diabetes self-care among AA adults with uncontrolled diabetes. Internal consistency of the 12-item Adherence to Medication Refills and Medications Scale for diabetes medications (ARMS-D) was evaluated by comparing its Cronbach α to the standardized Cronbach α calculated from MODEL data. Associations with variables were examined using correlations, t-tests, or ANOVA, as appropriate. Stepwise multiple regression identified predictors of diabetes control assessed by hemoglobin A1c (HbA1c). Results: Among 665 participants (mean age = 54 years, HbA1c = 10.24%; 67% female; 73% high health literacy), 75% reported perfect adherence on the Summary of Diabetes Self-Care Activities Medications Subscale (SDSCA-MS) versus 7.3% on ARMS-D. ARMS-D showed strong internal consistency (α = 0.81). Lower adherence by ARMS-D was associated with younger age, higher social complexity, and depression (all p ≤ 0.001). ARMS-D score, age, depression, and insulin, dipeptidyl peptidase 4 inhibitor, and sodium-glucose co-transporter 2 inhibitor use predicted baseline HbA1c. Conclusions: This study demonstrates that younger age, depression, and high social complexity are associated with lower medication adherence measured using the ARMS-D. Adherence gaps identified by ARMS-D may validly predict diabetes control and help guide interventions to improve diabetes care in AA adults with uncontrolled diabetes. Full article

Diabetes mellitus is a complex metabolic disorder whose management has moved from glycemic control to the control of risk factors through the use of new antihyperglycemic drugs with pleiotropic effects. Despite the multiple cardio–renal benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors, their prescription is often avoided due to concerns regarding side effects. This review aims to discuss the multiple benefits of SGLT2 inhibitors in balance with one of the most concerning side effects, the risk of euglycemic diabetic ketoacidosis (EDKA). A literature search was performed to identify and select articles relevant to this topic. We accessed several databases, including PubMed, Web of Science and Scopus, using appropriate keywords. We selected and evaluated randomized controlled trials, retrospective studies, systematic reviews and meta-analysis published between 2014 and 2024 supporting the multifaceted benefits of SGLT2 inhibitors and the limitations of their recommendations and focusing on the risk of EDKA. Initially designed as antidiabetic agents, SGLT2 inhibitors have demonstrated important cardio–renal benefits, these drugs being the first-line medication in patients with established cardiovascular disease, heart failure and chronic kidney disease. SGLT2 inhibitors are associated with some potential side effects, but with contradictory data concerning their prevalence and clinical relevance. From the possible side effects, EDKA is a life-threatening metabolic emergency whose incidence and recognition has increased, in particular with the use of SGLT2 inhibitors. These drugs can cause this disorder through several mechanisms, including reduced insulin secretion and increased glucagon levels, leading to free fatty acid production, which generally occurs in the presence of some risk factors such as reduced dietary carbohydrates, intercurrent illnesses, surgical stress and alcohol consumption. Through awareness of these risk factors as well as of the clinical symptoms, this condition could be promptly avoided or managed and SGLT2 inhibitors could be safely used. Full article

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD. Full article

Fermentation is widely used to enhance the bioactivity of herbal phytochemicals through microbial bioconversion. Rehmannia glutinosa contains catalpol, an iridoid glycoside with metabolic and immunomodulatory potential; however, its efficacy in the unfermented form is limited. This study investigated whether fermentation enhances catalpol production and improves metabolic and immune-regulating functions via glucagon-like peptide-1 receptor (GLP-1R) signaling. Rehmannia glutinosa extract was fermented under optimized conditions, and catalpol and iridoid precursor levels were quantified to assess bioconversion efficiency. Biological effects were evaluated in intestinal epithelial cells, macrophages, and an Artemia model, focusing on glucose transport, GLP-1 secretion, dipeptidyl peptidase-4 (DPP-4) expression, mucosal defense, and GLP-1R/protein kinase A/cAMP response element-binding protein (PKA/CREB) signaling. Fermentation significantly increased catalpol content while reducing iridoid precursors. The fermented extract suppressed intestinal glucose absorption by downregulating sodium–glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2). It also enhanced GLP-1 secretion and reduced DPP-4 expression, leading to activation of GLP-1R/PKA/CREB signaling. This activation increased mucin 2 (MUC2) expression and promoted anti-inflammatory. Full article

Background: Myocardial fibrosis plays a key role in adverse remodeling after ST-segment-elevated myocardial infarction (STEMI). The effect of sodium–glucose cotransporter 2 inhibitors (SGLT2is) on myocardial fibrosis deposition among patients with STEMI undergoing primary percutaneous coronary intervention (pPCI) is unclear. Objectives: To assess the effects of SGLT2is on myocardial fibrosis among patients with STEMI undergoing pPCI. Methods: Patients with STEMI undergoing pPCI with left ventricular ejection fraction ≤ 50% were randomized to dapagliflozin 10 mg or placebo. The primary endpoint was cardiac magnetic resonance (CMR)-derived 6-month changes in remote myocardium extracellular volume (ECV) fraction from baseline. Secondary endpoints included changes in CMR-derived myocardial volumes, change in serum fibrosis biomarker levels, and adverse events. Multivariable adjustment for infarction location and diabetes status was performed as sensitivity. The study was halted prematurely due to slow recruitment. Results: Fifty-two patients underwent randomization between May 2021 and April 2024 and completed follow-up. At 6 months, dapagliflozin resulted in a non-significant reduction in ECV change compared to placebo (−0.39 [4.7] vs. 1.43 [5.7]; difference: −1.82 [−4.86; 1.23]; p-value = 0.235) while also leding to a higher degree of reduction in N-terminal pro-peptide of type III collagen (−177.0 pg/mL [416.1] vs. 3.6 pg/mL [553.8]; p-value = 0.208). No significant differences in other biomarkers or adverse events were noted in the main analysis. After adjustment, dapagliflozin was associated with increased reduction in left ventricular end-systolic volume (−4.02 mL [7.4] vs. 0.10 mL [10.1]; difference: −4.92 [−9.8; −0.1]; p-value = 0.047). Conclusions: In STEMI patients undergoing pPCI, dapagliflozin did not result in a significant reduction in ECV or biomarkers of fibrosis at 6 months. Full article

Type 2 diabetes mellitus (T2DM) is a major global health challenge that has intensified interest in multi-target nutraceuticals with potential adjunctive benefits. Ganoderma lucidum (Lingzhi/Reishi) is a medicinal mushroom traditionally used in East Asia and is increasingly investigated for its role in glycemic regulation and metabolic disturbances. This review critically synthesizes current evidence on its hypoglycemic effects, focusing on bioactive compounds, molecular mechanisms, and translational limitations. Unlike broader reviews on Ganoderma bioactivity and health-related benefits, this review specifically evaluates the alignment between taxonomic authentication, chemical standardization, preclinical mechanisms, and human clinical evidence in the context of glycemic regulation. This narrative review was based on a targeted literature search conducted in PubMed/MEDLINE, Web of Science, and Scopus for studies published up to October 2025, supplemented by Google Scholar. The included studies comprised in vitro experiments, in vivo animal models, and human clinical trials evaluating glycemic and metabolic outcomes of Ganoderma preparations. In vitro and animal studies indicate that polysaccharides, including β-(1→3)/(1→6)-glucans and proteoglycans such as FYGL, may improve insulin sensitivity via AMPK (AMP-activated protein kinase) and PI3K/Akt pathways, promote GLUT4 (glucose transporter type 4) translocation, suppress hepatic gluconeogenesis, protect pancreatic β-cells, and modulate gut microbiota. In enzyme assays and preclinical models, lanostane-type triterpenoids act primarily by inhibiting α-glucosidase and α-amylase, thereby potentially reducing postprandial glucose excursions. Despite consistent preclinical evidence, clinical findings remain heterogeneous, with the largest randomized controlled trial reporting no significant glycemic benefit. Overall, Ganoderma lucidum shows strong mechanistic plausibility but insufficient clinical evidence for antidiabetic efficacy. Future research should prioritize species authentication, chemical standardization, and adequately powered clinical trials. Full article

Background: Metabolic syndrome is characterized by dysregulated glucose metabolism and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Although glucose-lowering therapies such as glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, their use may be limited by cost, administration route, side effects and tolerability. Bergamot (Citrus bergamia Risso et Poiteau) extract, rich in flavanones, has shown favorable metabolic effects in clinical studies, although its mechanisms of action remain insufficiently defined. This study aimed to investigate the potential glucose-modulating mechanisms of a standardized phospholipid-formulated bergamot extract (BP) (Vazguard™) in vitro. Methods: GLP-1R activation was assessed in a U2OS cell line expressing cyclic adenosine monophosphate (cAMP)-sensitive Nomad Biosensors™. Dipeptidyl peptidase-4 (DPP4) activity was evaluated using a cell-free enzymatic assay, while Glucose transporter type 4 (GLUT4)-mediated glucose uptake was assessed in CHO-K1 cells stably expressing human GLUT4 using an adenosine triphosphate (ATP)-based readout. Cytotoxicity was also using lactate dehydrogenase (LDH), MTT, and nuclei count assays. Results: BP exhibited a dose-dependent (0.31–5 mg/mL) increase in cAMP biosensor fluorescence, consistent with GLP-1R-associated signaling and a maximal response of approximately 60% relative to the positive control (GLP-1R agonist II). No cytotoxic effects were observed. In contrast, BP showed no inhibitory effect on DPP4 activity and did not alter GLUT4-mediated glucose uptake under the experimental conditions tested. Conclusions: These findings provide novel mechanistic evidence that phospholipid-formulated bergamot extract suggests a possible involvement in GLP-1R-associated signaling in vitro, without detectable effects on DPP4 or GLUT4 pathways under the conditions tested. This suggests a mechanism consistent with weak agonist or allosteric modulation of GLP-1R and supports further investigation of bergamot formulated with phospholipids as potential natural adjuncts in metabolic health management. Full article

Brown seaweeds are recognized for their rich content of phlorotannins with promising antidiabetic properties through multi-targeted modulation of glucose metabolism. This study investigated the antidiabetic potential of the ethyl acetate fraction of Ecklonia cava (EC-ETAC) and its major phlorotannin, dieckol, focusing on inhibition of carbohydrate-digesting enzymes, intestinal glucose absorption, dipeptidyl peptidase-IV (DPP-IV) activity, and hepatic glucose metabolism. EC-ETAC potently inhibited α-glucosidase (IC₅₀ = 2.2 ± 0.2 µg/mL) and α-amylase (IC₅₀ = 41.0 ± 1.2 µg/mL), outperforming acarbose by 26-fold and 6-fold, respectively. Pure dieckol showed strong activity with IC₅₀ values of 2.213 ± 0.04 µM (α-glucosidase) and 156.87 ± 0.124 µM (α-amylase). In differentiated Caco-2 cells, both EC-ETAC and dieckol downregulated SGLT1 and GLUT2 protein expression to ~0.5-fold of control and suppressed 2-NBDG glucose uptake by 46–53% over 120 min, effects not seen with acarbose. Dieckol inhibited DPP-IV activity (IC₅₀ = 12.12 ± 0.021 µM), reducing in situ activity to 53.89% at 25 µM without changing DPP-IV protein levels. Molecular docking revealed high-affinity binding of dieckol to DPP-IV (−10.396 kcal/mol), directly occluding the catalytic triad (Ser630, His740). In insulin-resistant HepG2 cells, dieckol restored glucose uptake to 108.97% of control via AMPK activation (1.21-fold), GLUT2 normalization (0.84-fold), and PGC-1α recalibration (0.96-fold), matching or surpassing 1 mM metformin. These results demonstrate dual-inhibition mechanism combined with hepatic AMPK restoration, establishing dieckol as a promising marine-derived multi-targeted agent for T2DM management. Full article

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose co-transporter 2 inhibitors (SGLT2is) have demonstrated protective effects against chronic kidney disease, their impact on acute kidney injury (AKI) remains unclear. AKI and chronic kidney disease share overlapping clinical features but differ in pathogenesis and risk profiles. Previous analyses often grouped diverse agents into single categories, potentially concealing medication-specific renal risks. Given the widespread assumption of renoprotection, particularly among newer agents, there is a need to evaluate the comparative AKI risk of GLP-1RAs and SGLT2is at the individual drug and dose level. We performed a Bayesian network meta-analysis (NMA) following Cochrane-recommended methodology for safety-focused assessments. A systematic literature search across eight databases identified 67 randomized controlled trials (RCTs), including 199,877 participants. Eligible trials reported AKI outcomes or sufficiently explicit acute renal injury-related events associated with GLP-1RA or SGLT2i interventions. The primary outcome was the incidence of AKI; all-cause dropout was analyzed as a general tolerability measure. Odds ratios (ORs) with 95% credible intervals (CrIs) were calculated, and surface under the cumulative ranking curves (SUCRA) were used to estimate relative safety rankings. Only high-dose tirzepatide (10–15 mg/week) was associated with a significantly increased risk of AKI compared to controls (absolute risk difference: 0.28%; number needed to harm: 357). In contrast, lixisenatide, high-dose canagliflozin (300 mg/day), empagliflozin, and dapagliflozin were associated with reduced AKI risk. Risk rankings consistently identified high-dose tirzepatide as the most likely to induce AKI. Subgroup analyses excluding patients with baseline renal impairment yielded consistent results. High-dose tirzepatide may elevate AKI risk despite its metabolic benefits. Clinicians should assess renal vulnerability when prescribing GLP-1RAs or SGLT2is, particularly in patients with preserved kidney function. Further prospective trials are needed to clarify causal mechanisms and inform clinical decision-making. Full article

Type 2 diabetes mellitus (T2DM) represents a significant global health burden. The natural alkaloid, 1-Deoxynojirimycin (DNJ), abundant in mulberry (Morus alba L.), offers a promising bioactive approach to its early management. This review comprehensively summarises the multifaceted roles of DNJ in modulating the core pathophysiological dysfunctions of T2DM, including impaired glucose and lipid metabolism, insulin resistance (IR), and dysbiosis of gut microbiota. Specifically, DNJ exerts its therapeutic effects by regulating various pathways involved in glucose and lipid metabolism (e.g., phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and AMP-activated protein kinase (AMPK) pathways), enhancing insulin sensitivity, modulating the gut microbiota, and upregulating transporter proteins. We highlight emerging methodologies, such as network pharmacology, which underscore the pivotal role of the PI3K/AKT and AMPK signalling pathways as primary targets of DNJ in T2DM management. Although this review elucidates multifaceted mechanisms of DNJ in T2DM management, it also identifies critical research gaps, particularly concerning its effects on pancreatic cells, obesity-related T2DM, and mitochondrial energy metabolism. Further investigation in these areas is crucial for fully understanding DNJ’s preventive and therapeutic potential and for the development of related functional foods. Full article