Elevated branched-chain amino acids (BCAAs; leucine, valine, isoleucine) are linked to type 2 diabetes (T2D) risk, characterised by defective insulin secretion in pancreatic β-cell and peripheral insulin resistance. Causative interaction between BCAA metabolism and these two diabetic pathogenesis remains unclear. Using publicly available datasets from the European population, we conducted a meta-analysis of genome-wide association studies (GWAS), followed by multi-trait analysis of GWAS (MTAG), to identify genetic loci associated with BCAAs and their catabolites. Two-sample bidirectional Mendelian Randomisation (MR) examined putative causal associations of genetically determined BCAAs and their catabolites with 10 traits related to insulin and glucose metabolism. Sensitivity analyses evaluated robustness and specificity of observed associations. MTAG identified 57.14%, 59.09%, and 63.41% novel genetic loci for circulating leucine, valine and isoleucine, respectively. Genetically elevated valine had a significant association with increased insulin fold change during oral glucose challenge test (OGTT) (β [95% CI] = 0.135 [0.045, 0.225]), False discovery rate adjusted p-value (p FDR = 0.022), and suggestive association with fasting glucose level (β [95% CI] = 0.031 [0.004, 0.058], inverse-variance weighted p-value [p IVW] = 0.025). In the reverse direction, genetically determined homeostasis model assessment of β-cell (HOMA-B) exhibited significant inverse associations with BCAAs (Leucine: β [95% CI] = -0.140 [-0.244, -0.036], p FDR = 0.034; Valine: β [95% CI] = -0.147 [-0.255, -0.040], p FDR = 0.030; Isoleucine: β [95% CI] = -0.149 [-0.248, -0.049], p FDR = 0.020). Moreover, β-hydroxyisovalerate, a leucine-derived catabolite, was inversely related to 2-h glucose level after OGTT (β [95% CI] = -0.149 [-0.227, -0.071], p FDR = 0.045). In the reverse direction, genetically predicted peak insulin response was suggestively associated with elevated isoleucine catabolite, 2-hydroxy-3-methylvalerate (β [95% CI] = 0.074 [0.018, 0.130], p IVW = 9.20 × 10-3). Our genetic analysis indicates BCAA catabolism and insulin secretion/action interact with each other; their aberrance might form a vicious cycle promoting T2D progression.

Islet-associated macrophages regulate beta cell function during inflammation and tissue repair, but evidence for their role during metabolic adaptation and its failure is more limited. Our aim was to determine their influence on insulin secretion in models of caloric overload and type 2 diabetes, and to assess how they coordinate with extra-pancreatic macrophages. We conditionally depleted resident macrophages in vivo using CD11b-DTR transgenic mice, which ectopically express the diphtheria toxin receptor under the control of the CD11b myeloid promotor. Conversely, we expanded resident macrophages in wild-type C57Bl6/J mice by chronic exposure to IL-4. Assays included GTTs and ITTs, and ex vivo measurements of insulin secretion and gene expression. Flow cytometry was performed on immune populations in islets and peritoneal exudates. Relevance to type 2 diabetes was assessed using db/db mice. In CD11b-DTR mice on a high-fat diet (but not chow diet), a single i.p. injection of diphtheria toxin impacted biphasically on beta cell function (improved at 1 day, impaired after 7 days). Surprisingly, islet-associated macrophages were not ablated at either time point. Peritoneal myeloid populations were, however, remodelled in a manner consistent with an inflammatory response and its abnormal resolution: complete loss of large peritoneal macrophages at 1 day post toxin, and a supra-physiological rebound at 7 days. The augmented insulin secretion was predominately mediated by extra-pancreatic IL-6 and involved glucagon-like peptide-1 (GLP-1) or glucagon generated locally within the islet. Conversely, expansion of large peritoneal macrophages in response to IL-4 complex was sufficient to impair insulin secretion. The beta cell defect in 7 day CD11b-DTR islets required both islet-associated macrophages and localised cylco-oxygenase-1 (COX1)-mediated generation of prostaglandin E2. Large peritoneal macrophages were also augmented in diabetic db/db mice, and defective insulin secretion was reverted ex vivo by inhibiting the function of COX1/prostaglandin E2 in islets. Islet-associated macrophages coordinate with extra-pancreatic macrophages to regulate glucose homeostasis and insulin secretion. In particular, the remodelling of peritoneal macrophage populations is sufficient to promote the benefits of acute inflammation, and conversely a maladapted inflammatory resolution potentially contributes to the beta cell failure of type 2 diabetes.

Monogenic diabetes arises from pathogenic variants in a single gene that are sufficient to cause disease predisposition. In general, a greater functional impact of genetic abnormalities is associated with an earlier age of onset. Accordingly, monogenic diabetes encompasses a wide clinical spectrum, including neonatal diabetes mellitus presenting within the first six months of life, and maturity-onset diabetes of the young (MODY) typically manifesting from childhood to early adulthood; both diabetic types exhibit impaired insulin secretory capacity. Although MODY is currently classified as diabetes of monogenic defect with impaired insulin secretion, it has become evident that mutations in rare MODY subtypes exhibit reduced pathogenic effects and low penetrance. In addition, observed differences in the clinical phenotypes caused by the same mutation, even in the same family, might be caused by other phenotypic modifying factors. Furthermore, their clinical expression is influenced, at least in part, by environmental factors, such as the intrauterine environment. Nevertheless, identification of the causative genes underlying monogenic diabetes has elucidated previously unrecognized molecular mechanisms responsible for the impaired insulin secretion. These findings have not only revealed novel therapeutic targets but have also provided important insights into the pathophysiology of common type 2 diabetes mellitus in the Japanese population, a multifactorial disease in which defective insulin secretion plays a central role.

Carbohydrate responsive element-binding protein (ChREBP) is a glucose-activated transcription factor implicated in metabolic regulation and β-cell proliferation. Although in vitro studies have suggested that ChREBP promotes glucose-stimulated β-cell proliferation, its in vivo role under physiological and pathophysiological conditions remains unclear. We generated β-cell-specific ChREBP knockout (βChrebp cKO) mice and examined β-cell proliferation and glucose metabolism under three conditions known to induce β-cell expansion: pharmacologically induced insulin resistance using the insulin receptor antagonist S961, high-fat diet (HFD) feeding, and pregnancy. β-cell proliferation was assessed by 5-Bromo-2'-deoxyuridineincorporation; islet gene expression was evaluated by quantitative PCR and RNA sequencing. βChrebp cKO mice displayed significantly impaired β-cell proliferation under both S961 treatment and HFD feeding, accompanied by decreased expression of the ChREBP target gene Rgs16. These mice also exhibited a mild defect in early-phase insulin secretion at 1 year of age and developed age-associated glucose intolerance. In contrast, pregnancy-induced β-cell proliferation and the expression of mitogenic genes (e.g., Tph2, Ccnb1, Ccnb2) were preserved in βChrebp cKO mice, and Rgs16 expression was unaffected. These findings suggest that ChREBP is critical for β-cell adaptation under hyperglycemia and insulin-resistant states, but not during normoglycemic pregnancy. ChREBP plays a context-dependent role in regulating β-cell proliferation, particularly under metabolic stress. The ChREBP-RGS16 axis may mediate adaptive β-cell proliferation in diabetes-related conditions, and this axis represents a potential therapeutic target to preserve or restore β-cell mass in type 2 diabetes.

Diabetes mellitus (DM) is a lifelong metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The global prevalence of DM is increasing at a frightening rate to over 783 million cases projected by 2045. Type 2 diabetes mellitus (T2DM), the most common form, is a companion of insulin resistance, glucose uptake defect, and impaired glycogen metabolism. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase involved in the central regulation of insulin action by its phosphorylation and inhibition of glycogen synthase and, thus, in hyperglycemia. Inhibition of GSK-3 has been viewed as a therapeutic strategy to amplify insulin sensitivity and offer better Glycemic control. The current research focuses on the synthesis and characterization of new imidazolidine-2,4-dione derivatives as prospective GSK-3 inhibitors. Two-step synthesis pathway was chosen starting from benzoyl chloride analogues which were treated with p-hydroxybenzaldehyde to give intermediate products, followed by condensation with hydantoin derivatives. Synthesized compounds were characterized through thin layer chromatography (TLC), melting point measurement, and spectroscopic analysis (IR, NMR, and mass spectrometry). Molecular docking experiments performed by AutoDock Vina were performed to ascertain binding capacity to GSK-3β. Some of the compounds possessed favorable binding scores, such as the o-phenyl, p-phenyl, and m-triethylammonium substituted compound, which shows great promise as GSK-3 inhibitors. These findings point to imidazolidine-2,4-dione derivatives with selective aromatic and heterocyclic substitutions as good lead compounds for anti-diabetic drug research and development. Further studies in vitro and in vivo would be required to ascertain their pharmacological activity and safety profiles

Antidiabetic drugs are extensively used for the management of diabetes mellitus, a chronic metabolic disorder characterized by persistent hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Accurate analytical methods are essential to ensure the quality, safety, and efficacy of these drugs during formulation development and throughout their shelf life. The present study focuses on the development and validation of a stability-indicating reverse phase high-performance liquid chromatography (RP-HPLC) method for the quantitative determination of selected antidiabetic drugs in pharmaceutical dosage forms. Chromatographic separation was achieved using a C18 column with an optimized mobile phase consisting of acetonitrile and phosphate buffer under isocratic conditions. Detection was performed using a UV detector at an optimized wavelength suitable for the selected drug molecules. The developed method was validated according to International Conference on Harmonisation (ICH) guidelines for parameters including linearity, accuracy, precision, specificity, robustness, limit of detection (LOD), limit of quantification (LOQ), and system suitability. Forced degradation studies under acidic, alkaline, oxidative, thermal, and photolytic conditions were conducted to establish the stability-indicating capability of the method. The results demonstrated excellent linearity within the studied concentration range with high correlation coefficients. Recovery values confirmed the accuracy of the method, while low relative standard deviation values indicated high precision. The degradation studies revealed that the method effectively separated degradation products from the parent drug peaks. The validated RP-HPLC method was found to be simple, reliable, reproducible, and suitable for routine quality control analysis of antidiabetic drugs in pharmaceutical formulations and stability studies

We have previously demonstrated that ovarian tumor (Otu) domain-containing ubiquitin aldehyde-binding protein 2 (Otub2), a deubiquitinating enzyme, exerts anti-apoptotic effects in primary human islets. The present study aims to further elucidate the molecular mechanisms underlying the role of Otub2 as a regulator of insulin secretion and β-cell function. Otub2 overexpression or silencing was employed to study its effects on cultured MIN6 cells and dispersed human islets. To evaluate its in vivo effects, Otub2 knockout (KO) mice were employed, as well as a pancreata-specific Otub2 overexpression model. RNA sequencing was performed on pancreatic tissue from Otub2-KO and control mice to study its effects on gene expression patterns. Co-immunoprecipitation followed by mass spectrometry identified Otub2-interacting proteins. Overexpression of Otub2 inhibited NF-κB activity and enhanced glucose-stimulated insulin secretion (GSIS) in cultured MIN6 cells and primary human islets. Otub2 KO mice exhibited impaired glucose tolerance and upregulation of NF-κB target genes. Conversely, selective in vivo overexpression of Otub2 in pancreata of C57BL wild-type mice resulted in significantly lower (~30%) blood glucose levels, post glucose injection, compared to control mice. Transcriptomic analysis of KO pancreata revealed downregulation of K+ transporter-related genes and upregulation of oxidative phosphorylation genes, consistent with defective insulin secretion. Mass spectrometry identified the voltage-gated potassium channel subunit Kv9.3 as a major Otub2 binding partner, along with paternally expressed 3 (Peg3) and calcium/calmodulin dependent protein kinase II delta (Camk2d) proteins known to promote NF-κB signaling and β-cell apoptosis. Otub2 is a critical regulator of β-cell function, acting through modulation of NF-κB signaling and K+ channel-associated complexes. By deubiquitinating components such as Peg3 and Camk2d, Otub2 may protect β-cells from cytokine-induced apoptosis and sustain insulin secretory capacity. These findings position Otub2 as a potential therapeutic target for preserving β-cell function in diabetes.

Type 2 diabetes is a chronic and progressive metabolic disease, with a steadily increasing global incidence and prevalence, representing a major public health concern due to its substantial impact on morbidity and mortality. Type 2 diabetes is characterized by defective insulin secretion and peripheral insulin resistance, resulting in dysregulated glucose homeostasis. Optimal disease management is critical due to its association with multiple systemic complications, including diabetic retinopathy, nephropathy, neuropathy, foot ulcers, cardiomyopathy, and diabetes-related cognitive impairment. The involvement of exosomes in the initiation and progression of type 2 diabetes has recently gained considerable attention. These nanosized vesicles, secreted by virtually all cell types, play a pivotal role in mediating intercellular communication. This review highlights the potential of exosomes and their molecular cargo, particularly microRNAs, as endogenous biomarkers for the detection and monitoring of type 2 diabetes and its associated complications, while also exploring their emerging therapeutic applications.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated blood glucose levels resulting from defects in insulin secretion, insulin action, or both. Persistent hyperglycemia in diabetes leads to disturbances in carbohydrate, fat, and protein metabolism. It is mainly classified into type I and type II DM. Type I Diabetes Mellitus (DM) is primarily managed through insulin replacement therapy, as pancreatic β-cell destruction results in absolute insulin deficiency. In contrast, Type II DM is typically treated with oral hypoglycaemic agents and, when necessary, insulin therapy. Combination therapy is often employed to achieve optimal glycaemic control and minimize complications. Globally, Diabetes Mellitus represents a major public health challenge, with an estimated 589 million adults projected to be affected by 2025, reflecting the increasing prevalence linked to sedentary lifestyles, obesity, and aging populations.

The pathophysiology of cystic fibrosis-related diabetes (CFRD) remains poorly understood, with uncertainty whether the insulin secretion defect progresses over time, characterized by a decline in C-peptide and an increase in proinsulin-to-C-peptide ratio. CFRD is often compared to type 1 diabetes (T1D), which is associated with complete beta-cell exhaustion. Similarly, insulin is the sole therapy recommended for CFRD. We aimed to examine beta-cell function over time in adults with CFRD and compare it with T1D. This retrospective cross-sectional study compared fasting C-peptide measurements between 59 adults (≥18 years) with CFRD (PwCFRD) and 1185 people with T1D (PwT1D). The fasting and stimulated proinsulin-to-C-peptide ratio after a mixed meal tolerance test was quantified in a subset of 18 PwCFRD and 75 PwT1D. Fasting C-peptide was higher in PwCFRD (0.27 [0.34]) than in PwT1D (0.00 [0.04], P < .001). The duration of CFRD did not correlate with C-peptide secretion (P = .736), even after adjustment for glycated hemoglobin and insulin therapy (P = .714). Proinsulin-to-C-peptide ratio was lower in PwCFRD than in PwT1D at baseline (P < .001) and 2 h (P = .001) after a mixed meal tolerance test. PwCFRD who required intravenous antibiotics the previous year showed a significantly lower C-peptide secretion (P = .042), but there was no difference between patients receiving or not receiving cystic fibrosis transmembrane conductance regulator modulator therapy. C-peptide levels in our cohort of PwCFRD were independent of diabetes duration, in contrast to PwT1D. A lower proinsulin-to-C-peptide ratio in PwCFRD compared to PwT1D suggested lower beta-cell dysfunction at fasting and stimulated evaluation. This supports the use of non-insulin therapies for adults with CFRD.

Diabetes mellitus is a multifaceted metabolic disorder characterized by chronic hyperglycemia, arising from defects in insulin secretion, insulin action, or both. Beyond its well-documented metabolic underpinnings, emerging evidence has illuminated a pivotal role of inflammation in the pathogenesis of diabetes. Pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), disrupt insulin signaling, impair β-cell function, and exacerbate insulin resistance. Chronic low-grade inflammation serves as a unifying mechanism linking obesity, metabolic dysfunction, and diabetes progression. The interplay between inflammatory pathways and diabetes extends to both type 1 and type 2 diabetes. In type 1 diabetes, autoimmune-mediated β-cell destruction is driven by inflammatory cytokines and dysregulated immune responses, while in type 2 diabetes, systemic and adipose tissue inflammation perpetuate insulin resistance and β-cell stress. Key molecular players, including toll-like receptors, the NLRP3 inflammasome, and the c-Jun N-terminal kinase (JNK) pathway, act as mediators between metabolic stress and inflammatory responses, emphasizing the bidirectional relationship between inflammation and hyperglycemia.

Diabetes mellitus can be considered as a chronic metabolic disorder categorized by the level of blood glucose which resulting from the defects of insulin secretion, insulin action, or both. Therefore, it is a known as a primary cause of morbidity and mortality in the worldwide, because its prevalence continues to rise, mainly in developing countries. Understanding the changes of biochemical associated with diabetes is crucial for disease management and the prevention of complications. This research aims to examine the relationship between, the serum of diabetes mellitus and calcium level. The research has conducted on 100 diabetic patients at the Endocrinology and Diabetes center in Emsallata, and ran on 48 males and 52 females. The research showed no statistically significant relationship between the levels of calcium, and the presence of diabetes mellitus.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to defects in insulin secretion, insulin action, or both. As a major global health concern, diabetes is associated with multiple systemic complications. In recent years, the bidirectional relationship between DM and periodontal diseases has gained increasing attention. This review aims to highlight the classification, pathophysiology, and complications of diabetes, while emphasizing the reciprocal interactions between DM and periodontal diseases. Moreover, the prevalence, pathogenesis, and clinical manifestations of periodontal diseases in diabetic individuals are discussed, along with dental treatment approaches tailored for these patients. The bilateral association between DM and periodontal disease highlights the necessity for clinicians to incorporate periodontal evaluations into the standard care of diabetic patients. Timely diagnosis, stringent glycemic management, and consistent periodontal treatment are critical measures to mitigate disease progression and enhance clinical results. Enhancing collaboration between medical and dental experts can improve patient education, facilitate preventative care, and ultimately preserve both systemic and periodontal health.

Background/Objectives: Diabetes mellitus is a serious global disease characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. It represents a major health concern affecting millions of people worldwide. This condition can lead to severe complications significantly affecting patients’ quality of life. Due to the limitations and side effects of current therapies, the search for safer and more effective antidiabetic agents, particularly from natural sources, has gained considerable attention. This study investigates the antidiabetic potential of seaweed-derived compounds through structure-based virtual screening targeting α-glucosidase. Methods: A library of compounds derived from the Seaweed Metabolite Database was subjected to a hierarchical molecular docking protocol against α-glucosidase. Extra Precision (XP) docking was employed to identify the top-ranked ligands based on their binding affinities. Drug-likeness was assessed according to Lipinski’s Rule of Five, followed by pharmacokinetic and toxicity predictions to evaluate ADMET properties. Density Functional Theory (DFT) calculations were performed to analyze the electronic properties and chemical reactivity of the selected compounds. Furthermore, molecular dynamics simulations were carried out to examine the stability and dynamic behavior of the ligand–enzyme complexes. Results: Following XP docking and ADMET prediction, four promising compounds were selected: Colensolide A, Rhodomelol, Callophycin A, and 7-(2,3-dibromo-4,5-dihydroxybenzyl)-3,7-dihydro-1H-purine-2,6-dione. Molecular dynamics simulations further confirmed the structural stability and strong binding interactions of these compounds within the α-glucosidase active site. Conclusions: This investigation demonstrated the important role of seaweed-derived compounds in inhibiting α-glucosidase activity. Further experimental validation is warranted to confirm their biological activity and therapeutic potential.

The c-Jun N-terminal kinases (JNKs) regulate diverse physiological processes. Whereas JNK1 and JNK2 are broadly expressed and associated with insulin resistance, inflammation, and stress responses, JNK3 is largely restricted to central nervous system neurons and pancreatic β cells, and its physiological role in β cells remains poorly defined. To investigate its function, we generated mice lacking JNK3 specifically in β cells (βJNK3-KO). These mice displayed glucose intolerance and defective insulin secretion, particularly after oral glucose challenge, indicating impaired incretin responses. Consistently, Exendin-4–stimulated (Ex4-stimulated) insulin secretion was blunted in βJNK3-KO islets, accompanied by reduced GLP-1R expression. Similar findings were observed in human islets treated with a selective JNK3 inhibitor (iJNK3). Downstream of GLP-1R, Ex4-induced CREB phosphorylation was diminished in βJNK3-KO islets, indicating impaired canonical signaling. Moreover, activation of the GLP-1R/CREB/IRS2 pathway, a key regulator of β cell survival, was reduced in βJNK3-KO islets and iJNK3-treated human islets. As a consequence, the protective effects of Ex4 were lost in cytokine-treated βJNK3-KO and human islets, and Ex4-mediated protection was partially attenuated in βJNK3-KO mice exposed to multiple low-dose streptozotocin. These findings identify JNK3 as a regulator of β cell function and survival and suggest that targeting this pathway may enhance incretin-based therapies.

Rapid protein carbonylation and decreased insulin secretion induced by inflammatory oxidative stress compounds.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to defects in insulin secretion, insulin action, or both. 1 In children and adolescents, type 1 diabetes mellitus (T1D) is the most common form and results from autoimmune destruction of pancreatic -cells, leading to absolute insulin deficiency. 2 However, the increasing prevalence of type 2 diabetes mellitus (T2D) in youth, particularly in South Asia, has introduced diagnostic challenges due to overlapping clinical features. 3e presence of diabetes-associated autoantibodies (DAAs), such as those against glutamic acid decarboxylase (GADA), insulin (IAA), serves as a hallmark of autoimmune T1D and plays a critical role in differentiating it from T2Dat diagnosis.Diabetes-associated autoantibodies (DAAs), notably glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA) and islet antigen-2 (IA2A) are key markers of autoimmune T1D and assist in distinguishing T1D from T2D at diagnosis. 4,5Western cohorts report >90% antibody positivity in T1D at

Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca2+ oscillations are critical for the stimulation of insulin secretion, though the mechanisms through which these propagate across the islet are poorly understood. Here, we use beta cell-targeted GCaMP6f to explore the role of endoplasmic reticulum (ER) Ca2+ mobilization in response to submaximal (11 mM) or hyperglycemic (25 mM) glucose, mimicking diabetes. Inhibition of inositol 1,4,5-trisphosphate (IP3) receptors, and other ion channels, with 2-aminoethoxydiphenyl borate (2-APB), had minimal effects on the initial peak or intercellular connectivity provoked by 11 mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic Ca2+increases and connectivity at both 11 and 25 mM glucose. Unexpectedly, the activation of IP3 receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca2+ waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca2+ waves we next blocked sarco(endo)plasmic Ca2+ ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the KATP-channel opener, diazoxide. Under these conditions, an initial cytosolic Ca2+increase was followed by secondary Ca2+ waves that subsided slowly. The application of carbachol alongside diazoxide still enhanced Ca2+dynamics, though activity was uncoordinated. After genetic deletion of SERCA2 in beta cells, Ca2+wave frequency, but not connectivity, were lowered. Our results show that ER Ca2+ mobilization plays a relatively minor role in the initiation and propagation of Ca2+ waves in response to glucose but is needed for sustained Ca2+waves.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia resulting from defects in insulin action or secretion. The synthesized bis-Schiff base derivatives of ibuprofen were evaluated for their in vitro α-amylase and α-glucosidase inhibitory activities using acarbose as a standard. Six compounds (13, 12, 14, 10, 9, and 11) exhibited superior dual inhibitory potency compared to acarbose, with IC50 values ranging from 3.85 ± 0.05 µM to 14.47 ± 0.14 µM (α-amylase) and 4.36 ± 0.12 µM to 16.18 ± 0.12 µM (α-glucosidase), representing 1.1- to 4.2-fold enhanced activity. Compound 13 (3,4,5-trimethoxyphenyl) was the most potent, showing 4.2-fold (α-amylase) and 3.8-fold (α-glucosidase) improvement compared to acarbose. Molecular docking and DFT analyses revealed that compound 13's superior binding affinity (ΔG = -7.033 kcal mol-1 vs. -5.868 kcal mol-1 (acarbose)) arose from optimized π-π stacking with Trp59 and hydrogen bonding with Gln63/Ser108, facilitated by electron-donating methoxy groups. The FMO analysis showed a low HOMO-LUMO gap (ε = 1.840 eV) and a high electrophilicity index (ω = 2.094), correlating with enhanced charge-transfer interactions. Cytotoxicity assessments suggested no toxicity up to 1000 µg mL-1. These findings position ibuprofen-based bis-Schiff bases as promising leads with enhanced potency and potentially improved drug-like properties compared to acarbose.

In Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage. Thrombin-Activatable Fibrinolysis Inhibitor(TAFI) is a protein that plays a major role in regulating the analysis of blood clots, It is involved in the fibrinolysis process. The study was designed to study the change concentration of TAFI, Insulin, HOMA-IR, and lipid profile in the T2DM patient in addition to studying the TAFI 1040C&gt;T SNP (rs1926447) gene polymorphism with the development of T2DM complication. Genome study doing by restriction fragment length polymorphism PCR (RFLP-PCR). These parameters included the evaluated of glucose metabolic characteristics (FSG, insulin, HbA1C, HOMA-IR, lipid profile). The expected frequencies, calculated under the assumption of no association, were 47.61for CC, 60.03, CT, and 9.61for TT. TC genotype does not appear a statistically significant linkage to the rise risk of thrombosis, OR(3.272) is and CI (0.4173 to 1.4498), p-value &lt;0.0002 was associated with an increased danger of the thrombosis to three times. frequency of C allele among cases is 43.5%, but it is 69% among controls. Frequency T allele was among cases is 56.5%, whereas it is 31% among controls. The findings of this investigation revealed that there was significant link between the TAFI 1040C&gt;T polymorphism and T2DM complication in Iraqi patients. However, we recommend conducting the study in a larger sample and different sexes to confirm our findings.