Search Results (94)

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s potential as a therapeutic agent, functioning not only to control blood sugar levels but also to enhance vascular health and strengthen cardiac resilience in diabetes. The investigation focused on alterations in the vascular endothelial growth factor (VEGF) and its receptor-1 (FLT-1) signaling pathways, as well as its potential to suppress inflammation and oxidative stress. A number of rats received a single dose of streptozotocin (STZ) 55 mg/kg (i.p.) to induce DM. Sitagliptin was administered orally (100 mg/kg/90 days) to normal and diabetic rats, after which samples were collected for investigation. Sitagliptin significantly mitigated weight loss in diabetic rats. Its administration significantly reduced blood glucose levels and improved serum troponin I and CK-MB levels. Heart sections from diabetic rats showed a marked increase in mTOR, VEGF, and FLT-1 immune reaction, while sitagliptin-treated diabetic rats’ heart sections showed moderate immune reactions. Sitagliptin’s protective effect was also associated with reduced inflammation, and apoptotic markers. In conclusion, Sitagliptin is suggested to offer beneficial effects on the vascular health of cardiac blood vessels, thereby potentially reducing myocardial stress in diabetic patients. Full article

Sitagliptin is an orally bioavailable selective DPP4 inhibitor that reduces blood glucose levels without significant increases in hypoglycemia. The aim of this study was to design and validate an innovative, rapid, and highly sensitive LC–MS/MS assay for the precise measurement of sitagliptin concentrations in human plasma. This analytical method, utilizing sitagliptin-d4 as the internal standard, is performed using only 100 μL of plasma and a liquid–liquid extraction procedure based on methyl tert-butyl ether (MTBE). Chromatographic separation is expertly achieved with a Kinetex^® C18 column under isocratic elution, employing a perfect 1:1 blend of 5 mM ammonium acetate (with 0.04% formic acid) and acetonitrile, and maintaining an efficient flow rate of 0.2 mL/min. Detection occurs in positive ionization mode through multiple reaction monitoring, precisely targeting transitions of m/z 408.2 → 193.0 for sitagliptin and 412.2 → 239.1 for the IS. The total runtime of this assay is under 2 min. Comprehensive validation in line with MFDS and FDA criteria demonstrates outstanding linearity (5–1000 ng/mL, r² > 0.998), alongside impressive levels of accuracy, precision, recovery and sample stability. Due to its minimal sample requirement and high-throughput capability, the validated approach is highly appropriate for pharmacokinetic and bioequivalence assessments involving sitagliptin. Full article

Recent studies have demonstrated the efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in enhancing glycemic control, regulating body weight, and modulating lipid metabolism. However, their effects on lipoprotein subfractions have not been clarified. The objective of this 52-week, single-center, randomized trial was to compare the effects of subcutaneous semaglutide administered once weekly and oral sitagliptin administered once daily on anthropometric measurements and lipoprotein subfractions measured by Lipoprint gelelectrophoresis in patients with type 2 diabetes mellitus (T2DM). A total of 34 obese individuals with T2DM were enrolled in the study and randomly assigned to receive semaglutide (n = 18) or sitagliptin (n = 16). Thirty-one age- and body weight-matched non-diabetic obese individuals served as controls. Semaglutide treatment resulted in significant reductions in body mass index (BMI), waist circumference, and Hb_A1c, along with improvements in lipid parameters, including reductions in LDL cholesterol and non-HDL cholesterol levels, and redistribution of LDL and HDL subfractions toward a less atherogenic profile. Conversely, sitagliptin elicited modest glycemic improvements without substantial alterations in lipid composition. Multivariate regression analysis demonstrated that fluctuations in lipoprotein subfractions were not influenced by changes in BMI or HbA1c. These results support the pleiotropic metabolic benefits of semaglutide and its potential role in managing the cardiometabolic risk of T2DM. Full article

Background: The gut microbiota plays a critical role in metabolic health and type 2 diabetes mellitus (T2DM). Alterations in microbial composition may influence glycemic control and systemic inflammation. Materials and methods: In this single-center, randomized study, 60 adults with T2DM receiving metformin were evaluated biologically and received either empagliflozin or sitagliptin. Demographic, metabolic, and lifestyle data were collected. Gut microbiota profiling was conducted at two timepoints to assess changes in bacterial and fungal taxa. Blood glucose, HbA1c, and inflammation markers were analyzed longitudinally. Results: Both treatment groups showed significant improvements in glycemic control. Median fasting glucose decreased from 132 to 123 mg/dL (p = 0.046) in the sitagliptin group and from 131 to 114 mg/dL (p = 0.025) in the empagliflozin group. Median HbA1c levels declined significantly in both groups, with a greater reduction in the empagliflozin group (p = 0.001 vs. p = 0.049). The microbiota analysis revealed an increase in beneficial bacteria (e.g., Bifidobacterium spp. and Lactobacillus spp.) and a decrease in pro-inflammatory taxa (Escherichia coli and Streptococcus spp.). Notably, empagliflozin was associated with a more pronounced microbiota rebalancing and a significant decline in fungal overgrowth (e.g., Candida spp.; p = 0.034). Conclusions: Treatment with sitagliptin and empagliflozin led to improved glycemic outcomes and partial restoration of gut microbial balance in T2DM patients. Empagliflozin showed superior efficacy in modulating both glycemia and dysbiosis. Full article

ω-Transaminases are biocatalysts capable of asymmetrically synthesizing high-value chiral amines through the reductive amination of carbonyl compounds, and they are ubiquitously distributed across diverse microorganisms. Despite their broad natural occurrence, the industrial utility of naturally occurring ω-transaminases remains constrained by their limited catalytic efficiency toward sterically bulky substrates. Over recent decades, the use of structure-guided molecular modifications, leveraging three-dimensional structures, catalytic mechanisms, and machine learning-driven predictions, has emerged as a transformative strategy to address this limitation. Notably, these advancements have unlocked unprecedented progress in the asymmetric synthesis of bulky chiral amines, which is exemplified by the industrial-scale production of sitagliptin using engineered ω-transaminases. This review systematically explores the structural and mechanistic foundations of ω-transaminase engineering. We first delineate the substrate binding regions of these enzymes, focusing on their defining features such as substrate tunnels and dual pockets. These structural elements serve as critical targets for rational design to enhance substrate promiscuity. Next, we dissect the catalytic and substrate recognition mechanisms of (S)- and (R)-ω-transaminases. Drawing on these insights, we consolidate recent advances in engineering ω-transaminases to highlight their performance in synthesizing bulky chiral amines and aim to guide future research and the industrial implementation of tailored ω-transaminases. Full article

Sitagliptin, an important anti-diabetic drug, can be obtained using transaminase (TA) enzymes, which are known to be promising biocatalysts for the production of highly enantiopure amines under mild reaction conditions. In an industrial context, the use of immobilized enzymes can provide several advantages, such as the improved stability of the biocatalyst and easy product recovery. In this study, a new commercially available transaminase enzyme to produce sitagliptin was immobilized on inorganic and organic supports using two different approaches: adsorption and covalent bond formation. Among the inorganic media, non-functionalized silica gel was chosen for its stability and competitive cost. A range of commercially available resins with different functionalities have also been selected for their characteristics that can meet industrial standards. The immobilized biocatalysts were first tested in the transamination of acetophenone as a model substrate, which obtains, in most cases, higher conversions with respect to soluble enzymes. The best results in the enantioselective synthesis of sitagliptin were achieved with the sample immobilized on the epoxy- and octadecyl-functionalized methacrylic resin, which allowed the complete conversion of the corresponding ketone and high enantioselectivity (>99% ee). Moreover, the recycling of the supported enzyme could be performed in a continuous flow system without loss of activity for five consecutive runs. Full article

Background: Chronic inflammation and immune dysregulation are key drivers of diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies for thromboembolism and glycemic control, respectively. This study evaluated the novel therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin (SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-induced diabetic rats. Methods: Type 2 diabetes was induced in rats using a single injection of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RX-treated (5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg). After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was conducted. Immunohistochemistry was used to assess hepatic NF-κB expression. Results: STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression and histopathological abnormalities in immune organs. NRX significantly reduced inflammatory cytokines, improved histopathological changes in organs, and decreased hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB expression, and near-complete histopathological normalization. Conclusions: This study underscores the promise of combining nanoparticle-based drug delivery with established therapies like sitagliptin to achieve superior immune modulation and inflammation control, presenting a potential therapeutic strategy for managing diabetes complications. Full article

Diabetes mellitus is a chronic, degenerative, and multifactorial disease characterized by hyperglycemia, and at least 537 million people suffered from diabetes in 2021. Agave durangensis Gentry, a species of agave native to the state of Durango, reports phenolic compounds, flavonols, flavonoids, and saponins and could be an alternative for the treatment of diabetes. The aim of this work was to identify the compounds in the leaves of Agave durangensis Gentry and their potential activity in diabetes. The leaf extract of Agave durangensis Gentry (EAD) was characterized by ultra-performance liquid chromatography–mass spectrometry (UPLC-MS), and different families of bioactive compounds were quantified by analytical methods. Probable pharmacological targets were identified in silico, and the inhibition of dipeptidyl peptidase-4 (DPP4) was validated in vitro. A model of hyperglycemia was established with streptozotocin in male Wistar rats, and we administered EAD intragastrically at a dose of 300 mg/kg, as well as combinations of the extract with metformin and sitagliptin over 30 days. Biochemical and histological parameters were analyzed. We identified thirty-six major compounds, where triterpenes represented 30% of the extract. Molecular docking showed that the extract could interact with α-glucosidases and DPP4 since a large number of compounds in the extract have a Δ G lower than that reported for the controls, and DPP4 inhibition was confirmed by in vitro assays. In vivo assays demonstrated that the administration of the extract was able to significantly decrease glucose levels by 56.75% and glycosylated hemoglobin by 52.28%, which is higher than that reported for sitagliptin with a decrease of 35.22%. In addition, the extract decreased triglycerides by 59.28% and very-low-density lipoprotein (VLDL) cholesterol by 60.27%, and when administered in combination with metformin, it decreased them more than when metformin was administered alone. For all the above reasons, Agave durangensis Gentry extract could be used for the development of phytomedicine for the treatment of diabetes. Full article

Background/Objectives: DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. Methods: In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. Results: Twelve compounds exhibited IC₅₀ values at the nM range with the best showing IC₅₀ = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC₅₀ with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. Conclusions: Potent inhibitors with IC₅₀ at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors. Full article

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article

Background/Objectives: Early stages of diabetic retinopathy are currently considered an unmet medical need due to the lack of effective treatments beyond proper monitoring and control of glycemia and blood pressure. Sitagliptin eye drops have emerged as a new therapeutic approach against early stages of the disease, as they can prevent its main hallmarks, including both neurodegeneration and microvascular impairment. Interestingly, all of these effects occur without any glycemic systemic improvement. In the present study, we aimed to investigate the pharmacokinetics and distribution of the drug within the eye and plasma. Methods: A total of 48 male New Zealand rabbits were treated with topical administration (eye drops) of sitagliptin at two concentrations: 5 mg/mL and 10 mg/mL. Blood, iris/ciliary body, retina/choroid, aqueous humor, and vitreous humor samples were collected at specific intervals post-administration (10 and 30 min and 1, 3, 6, 15, and 24 h), processed, and analyzed using an LC-MS/MS method. The pharmacokinetics of sitagliptin were then calculated, and statistical comparisons were performed. Results: Our findings indicate that sitagliptin reaches the retina prior to the aqueous and vitreous humors, suggesting that its absorption follows the transscleral route. Additionally, systemic absorption was minimal and below pharmacologically active concentrations. Conclusions: These results support the use of an eye drop formulation for the treatment of diabetic retinopathy and other retinal diseases. Full article

Due to the increased prevalence of diabetes, the consumption of anti-diabetic drugs for its treatment has likewise increased. Metformin is an anti-diabetic drug that is commonly prescribed for patients with type 2 diabetes and has been frequently detected in surface water and wastewaters, thus representing an emerging contaminant. Metformin can be prescribed in combination with other classes of anti-diabetic drugs; however, these drugs are not sufficiently investigated in environmental samples. Fabric phase sorptive extraction (FPSE) has emerged as a simple and green method for the extraction of analytes in environmental samples. In this study, FPSE coupled with a high-performance liquid chromatography diode array detector (HPLC-DAD) was employed for the simultaneous analysis of different classes of anti-diabetic drugs (metformin, dapagliflozin, liraglutide, pioglitazone, gliclazide, glimepiride, glargine, repaglinide, sitagliptin, and vildagliptin) in environmental water samples. Four different fabric membranes were synthesized but the microfiber glass filter coated with sol-gel polyethylene glycol (PEG 300) was observed to be the best FPSE membrane. The parameters affecting the FPSE process were optimized using a combination of one-factor-at-a-time processes and the design of experiments. The FPSE was evaluated as a green extraction method, based on green sample preparation criteria. The FPSE-HPLC-DAD method achieved acceptable validation results and was applied for the simultaneous analysis of anti-diabetic drugs in surface and wastewater samples. Glimepiride was detected below the quantification limit in both lake and river water samples. Dapagliflozin, liraglutide, and glimepiride were detected at 69.0 ± 1.0 μg·L⁻¹, 71.9 ± 0.4 μg·L⁻¹, and 93.9 ± 1.3 μg·L⁻¹, respectively, in the city wastewater influent. Dapagliflozin and glimepiride were still detected below the quantification limit in city wastewater effluent. For the hospital wastewater influent, metformin and glimepiride were detected at 1158 ± 21 μg·L⁻¹ and 28 ± 0.8 μg·L⁻¹, respectively, while only metformin (392.6 ± 7.7 μg·L⁻¹) was detected in hospital wastewater effluent. Full article

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a—known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities. Full article

Hypoglycemic medications are widely used in managing diabetes mellitus, with emerging evidence suggesting their role in cardiac reverse remodeling. This systematic review aims to quantitatively synthesize data regarding the impact of these medications on left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), and to evaluate the clinical relevance of these changes in promoting favorable cardiac outcomes. We conducted a comprehensive search across PubMed, Scopus, and the Web of Science up to 22 April 2024, selecting studies based on inclusion criteria that focused on the impact of hypoglycemic medications on LVEDD and LVESD in patients with diabetes. Studies were selected through a rigorous process, adhering to PRISMA guidelines, and involving various designs including randomized controlled trials and observational studies. The main outcomes were changes in LVEDD and LVESD measured by validated cardiac imaging techniques. A total of ten studies met the inclusion criteria, involving a total of 1180 patients. Treatment durations ranged from 3 to 24 months. Significant improvements in cardiac dimensions were noted with some medications. For instance, Liraglutide treatment over three months significantly improved LVEF from 47.2% to 57.2% and reduced LVEDD and LVESD from 46.5 mm to 45.2 mm and 35.2 mm to 32.7 mm, respectively. In contrast, other medications like Sitagliptin showed minimal impact over 24 months. On average, hypoglycemic medications reduced LVEDD from 58.2 mm to 55.0 mm and LVESD from 48.3 mm to 44.3 mm, with a mean improvement in LVEF from 38.9% to 43.8%. Hypoglycemic medications contribute variably to cardiac reverse remodeling. Medications such as Liraglutide and Dapagliflozin demonstrate significant potential in improving cardiac dimensions and function, indicating their utility beyond glycemic control. This review highlights the need for tailored treatment approaches to maximize cardiac outcomes in patients with diabetes, suggesting a broader therapeutic role for these agents. Full article