Antidiabetic Research Articles

Mechanisms of action of fungal polysaccharides and their therapeutic effect.

The purpose of this article is to discuss the relationship between the therapeutic bioactivity of basidial fungal polysaccharides (BFPs) BFPs and their structural characteristics and conformational features, as well as to characterize the mechanisms of action of BFPs in diseases of various origins. The review was conducted using the PubMed (Medline), Scopus, Web of Science and the Russian Science Citation Index databases. 8645 records were identified, of which 5250 were studies (86 were randomized controlled trials). The period covered is from 1960 to the present. The most significant studies conducted mainly in Southeast Asian countries were selected for the review. Based on clinical studies, as well as the results obtained on in vivo, in vitro and ex vivo models, it has been proven that BFPs have diverse and highly effective biological activity in the human body in various diseases. The production of BFPs-based vaccines is an innovative strategy from a clinical and biochemical point of view, since as potential immunoprotective and low-toxic biopolymers they have innate immune receptors in the body. Promising results have been obtained in the development of antidiabetic drugs, probiotic, renoprotective and neurodegenerative dietary supplements. The biological activity, mechanism of action and specific therapeutic effect of BFPs largely depend on their structural and physicochemical characteristics. BFPs as multifunctional macromolecular complexes with low toxicity and high safety are ideal as new powerful pharmaceuticals for the treatment and prevention of many diseases.

Recent Advances in the Drugs and Glucose-Responsive Drug Delivery Systems for the Treatment of Diabetes: A Systematic Review.

Diabetes is a common chronic metabolic disease. Different types of drugs play important roles in controlling diabetes and its complications, but there are some limitations. The glucose-responsive drug delivery system is a novel technology with potential in diabetes treatment. It could automatically release drugs in response to changes in glucose levels in the body to maintain blood glucose within a normal range. The emergence of a glucose-sensitive drug delivery system provides a more intelligent and precise way to treat diabetes. The review is carried out according to the Preferred Reporting Items for Systematic Reviews (PRISMA 2020) guidelines This review focuses on the recent advances in the drugs and different systems of glucose-sensitive drug delivery, including glucose oxidase, phenylboronic acid, Concanavalin A, and other glucose-reactive systems. Furthermore, the glucose-responsive drug delivery system combined with the application applied in hydrogels, microneedles, and nanoparticles is also explored and summarized. The new platforms to sustain the release of anti-diabetic drugs could be desirable for patients. It could lead to increased adherence and glycemic outcomes for the detection and treatment of diabetes. Furthermore, given the limitations of glucose-responsive drug delivery systems, solutions and perspectives are proposed to help the understanding and application of these systems. This review will be helpful for drug discovery and treatment of diabetes from a new perspective.

Serum interleukin-10 level is increased and correlated positively with disease severity in patients with dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with a linear deposit of autoantibodies at the epidermal basement membrane zone. It was reported that diabetes patients who took a dipeptidyl peptidase-4 inhibitor (DPP4i), an oral antidiabetic drug, had an increased incidence of BP. However, data on DPP4i-related BP are limited. In our study, we measured serum levels of various cytokines using LEGENDplex and assessed correlations of these serum levels with clinical severity and laboratory data. Serum samples obtained from BP patients who visited our hospital from June 2016 to February 2023 were collected in this study. Patients' background, characteristics, and clinical data were retrospectively collected from their charts. Serum samples from 27 patients with DPP4i-unrelated BP, 17 patients with DPP4i-related BP, and 13 healthy controls were analyzed. Patients with DPP4i-related BP had lower score of Bullous Pemphigoid Disease Area Index (BPDAI)-erythema/urticaria, lower number of circulating eosinophils, and lower titer of anti-BP180 antibody than patients with DPP4i-unrelated BP. The serum interleukin (IL)-6 level was significantly higher in patients with DPP4i-related BP than in healthy controls (P = 0.0037). The serum IL-10 level was significantly higher in patients with DPP4i-related BP than in patients with DPP4i-unrelated BP and in healthy controls (P = 0.0006, P = 0.0448), and was positively correlated with the BPDAI-blister/erosions score (r = 0.757, P = 0.001), BPDAI-erythema/urticaria score (r = 0.616, P = 0.013), and BPDAI-total score (r = 0.833, P < 0.001) in patients with DPP4i-related BP. In conclusion, patients with DPP4i-related BP had increased serum levels of IL-6 and IL-10 compared with healthy controls and positive correlations between the serum IL-10 level and BPDAI scores reflecting clinical severity, indicating that the serum IL-10 level is a potential objective biomarker of disease severity in patients with DPP4i-related BP.

Multifunctional mesoporous nanoselenium delivery of metformin breaks the vicious cycle of neuroinflammation and ROS, promotes microglia regulation and alleviates Alzheimer's disease

Clinical trials based on a single molecular target continue to fail, and the adverse effects of Aβ protein aggregation and neuroinflammation need to be solved and treatment of Alzheimer's disease. Herein, by designed a nano-sized flower mesoporous selenium transport carrier (Met@MSe@Tf) with high enzyme-like activity, metformin (Met) was loaded, and transferrin (Tf) was modified to bind to transferrin receptor to promote receptor-mediated transport across the BBB. In the AD lesion environment, with the acidic environment response dissociation, promote the release of metformin by nanoflower to achieve therapeutic effect in the brain lesion site. Metformin, a major anti-diabetic drug in diabetic metabolism, has been found to be a promising new therapeutic target in neurodegenerative diseases. Further studies showed that the metformin drug release from the designed and synthesized transport nanoparticles showed high intrinsic activity and the ability to degrade the substrate involved, especially the degradation of Aβ deposition in the cortex and hippocampus, increased the phagocytosis of microglia, thus relieving neuroinflammation simultaneously. Collectively, in vivo experiments demonstrated that Met@MSe@Tf significantly increased the number of NeuN-positive neurons in the hippocampus of AD mice, promoted neurovascular normalization in the brain, and improved cognitive dysfunction in AD transgenic AD mice. Thus, it provides a preclinical proof of concept for the construction of a highly modular accurate drug delivery platform for Alzheimer's disease.

Comparative Analysis of ARIMA, SARIMA and Prophet Model in Forecasting

Machine learning has become a powerful tool in forecasting, offering greater accuracy than traditional human predictions in today’s data-driven world. The capability of machine learning to predict future trends has significant implications for key sectors such as finance, healthcare, and supply chain management. In this study, ARIMA/SARIMA (AutoRegressive Integrated Moving Average/Seasonal AutoRegressive Integrated Moving Average), alongside Prophet, a scalable forecasting tool developed by Facebook based on a generalized additive model, are considered. These models are applied to predict the demand for antidiabetic drugs. The records were collected by the Australian Health Insurance Commission. This dataset was sourced from Medicare Australia. The study evaluates the performance of these models based on their Mean Absolute Error (MAE), a key metric for assessing forecast accuracy. Root Mean Squared Error (RMSE) and Mean Absolute Percentage Error (MAPE) are also considered. The outcome of the comparative analysis shows that the Prophet model outperformed both ARIMA and SARIMA models, achieving an MAE of 0.74, which is significantly lower than the MAE values of 2.18 and 3.02 obtained by SARIMA and ARIMA, respectively. Prophet&amp;apos;s superior performance shows its effectiveness in handling complex, non-linear trends and seasonal patterns often observed in real-world time series data. This research contributes to the growing knowledge of machine learning-based forecasting and shows the importance of advanced models like Prophet in optimizing business operations and driving innovation. The findings from this research offer valuable guidance for data experts, analysts, and researchers in selecting the best forecasting methods for reliable predictions.

Exploring the 3,5-Dibromo-4,6-dimethoxychalcones and Their Flavone Derivatives as Dual α-Glucosidase and α-Amylase Inhibitors with Antioxidant and Anticancer Potential.

The rising levels of type 2 diabetes mellitus (T2DM) and the poor medical effects of the commercially available antidiabetic drugs necessitate the development of potent analogs to treat this multifactorial metabolic disorder. It has been demonstrated that targeting two or more biochemical targets associated with the onset and progression of diabetes along with oxidative stress and/or cancer could be a significant strategy for treating complications related to this metabolic disorder. The 3,5-dibromo-4,6-dimethoxychalcones (2a-f) and the corresponding flavone derivatives (3a-f) were synthesized and characterized using spectroscopic (NMR, HR-MS and FT-IR) techniques. The inhibitory effect of both series of compounds against α-glucosidase and α-amylase was evaluated in vitro through enzymatic assays. Selected compounds were also evaluated for potential to activate or inhibit superoxide dismutase. Compound 3c was selected as a representative model for the flavone series and evaluated spectrophotometrically for potential to coordinate Cu(II) and/or Zn(II) ions implicated in the metal-catalyzed free radical generation. A plausible mechanism for metal-chelation of the test compounds is presented. Furthermore, the most active compounds from each series against the test carbohydrate-hydrolyzing enzymes were selected and evaluated for their antigrowth effect on the human breast (MCF-7) and lung (A549) cancer cell lines and for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The parent chalcone 2a and flavone derivatives 3a, 3c and 3e exhibited relatively high inhibitory activity against the MCF-7 cells with IC50 values of 4.12 ± 0.55, 8.50 ± 0.82, 5.10 ± 0.61 and 6.96 ± 0.66 μM, respectively. The chalcones 2a and 2c exhibited significant cytotoxicity against the A549 cells with IC50 values of 7.40 ± 0.67 and 9.68 ± 0.80 μM, respectively. Only flavone 3c exhibited relatively strong and comparable cytotoxicity against the MCF-7 and A549 cell lines with IC50 values of 6.96 ± 0.66 and 6.42 ± 0.79 μM, respectively. Both series of compounds exhibited strong activity against the MCF-7 and A549 cell lines compared to the analogous quercetin (IC50 = 35.40 ± 1.78 and 35.38 ± 1.78 μM, respectively) though moderate compared to nintedanib (IC50 = 0.53 ± 0.11 and 0.74 ± 0.15 μM, respectively). The test compounds generally exhibited reduced cytotoxicity against the Vero cells compared to this anticancer drug. Molecular docking revealed strong alignment of the test compounds with the enzyme backbone to engage in hydrogen bonding interaction/s and hydrophobic contacts with the residues in the active sites of α-glucosidase and α-amylase. The test compounds possess favorable drug-likeness properties, supporting their potential as therapeutic candidates against T2DM.

The effect of antidiabetic drugs on bone metabolism: a concise review.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.

Trends in Antidiabetic Drug Use and Safety of Metformin in Diabetic Patients with Varying Degrees of Chronic Kidney Disease from 2010 to 2021 in Korea: Retrospective Cohort Study Using the Common Data Model.

This study aimed to investigate trends in antidiabetic drug use and assess the risk of metformin-associated lactic acidosis (MALA) in patients with chronic kidney disease (CKD). A retrospective observational analysis based on the common data model was conducted using electronic medical records from 2010 to 2021. The patients included were aged ≥18, diagnosed with CKD and type 2 diabetes, and had received antidiabetic medications for ≥30 days. MALA was defined as pH ≤ 7.35 and arterial lactate ≥4 mmol/L. A total of 8318 patients were included, with 6185 in CKD stages 1-2 and 2133 in stages 3a-5. Metformin monotherapy was the most prescribed regimen, except in stage 5 CKD. As CKD progressed, metformin use significantly declined; insulin and meglitinides were most frequently prescribed in end-stage renal disease. Over the study period, the use of SGLT2 inhibitors (13.3%) and DPP-4 inhibitors (24.5%) increased significantly, while sulfonylurea use decreased (p < 0.05). Metformin use remained stable in earlier CKD stages but significantly decreased in stage 3b or worse. The incidence rate (IR) of MALA was 1.22 per 1000 patient-years, with a significantly increased IR in stage 4 or worse CKD (p < 0.001). Metformin was the most prescribed antidiabetic drug in CKD patients in Korea with a low risk of MALA. Antidiabetic drug use patterns varied across CKD stages, with a notable decline in metformin use in advanced CKD and a rise in SGLT2 inhibitor prescriptions, underscoring the need for further optimized therapy.

Method Development and Validation Studies of Anti-diabetic Drug Lobeglitazone from Pharmaceutical Formulation and Human Plasma by HPLC-DAD

Method Development and Validation Studies of Anti-diabetic Drug Lobeglitazone from Pharmaceutical Formulation and Human Plasma by HPLC-DAD

Renoprotective effect of liraglutide on diabetic nephropathy by modulation of Krüppel-like transcription factor 5 expression in rats.

Diabetic nephropathy (DN) is a serious consequence of diabetes that can develop through the lysophosphatidic acid axis. The purpose of this study was to determine whether the antidiabetic drug liraglutide can slow the development of diabetic kidney damage by altering the lysophosphatidic acid axis via KLF5. Wistar albino rats were divided into nondiabetic and diabetic rats (resulting from an intraperitoneal streptozotocin dose of 30mg/kg and a high-fat diet). These rats were further divided into four groups: nondiabetic control, liraglutide-treated nondiabetic, diabetic control, and liraglutide-treated diabetic. The nondiabetic and diabetic control groups received normal saline for 42 days, while the liraglutide-treated nondiabetic and diabetic groups received normal saline for 21 days, followed by a subcutaneous dose of liraglutide (200 μg/kg/day) for 21 days. Subsequently, serum levels of DN biomarkers were evaluated, and kidney tissues were histologically examined. The protein expression of PCNA, autotaxin, and KLF5 was detected. Liraglutide treatment in diabetic rats decreased DN biomarkers, histological abnormalities in kidney tissues, and the protein expression of PCNA, autotaxin, and KLF5. Liraglutide can slow the progression of DN by modulating KLF5-related lysophosphatidic acid axis. Thus, liraglutide may be an effective treatment for preventing or mitigating diabetes-related kidney damage.

Application of Fabric Phase Sorptive Extraction as a Green Method for the Analysis of 10 Anti-Diabetic Drugs in Environmental Water Samples

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.

Epidemiology And Biological Mechanisms Of Cardiovascular Disease And Diabetes

The risk of CVDs in T2DM patients in LMICs is higher than in developed nations. It is essential to make an evaluation of the current situation of CVDs among people with T2DM. These CVDs are easily preventable through intervention especially in T2DM patients and this should be done in a comprehensive manner. The following targets and principles should be considered: individual targets of HbA1c for patients, a rigorous control of cardiovascular risk factors such as blood pressure and lipids, and incorporation of newer anti-diabetic, lipid-lowering and anti-hypertensive agents. It is, therefore, crucial to design a stepped-wedge approach that bundles a patient-level intervention, lifestyle, and pharmacological interventions to reduce the risk of CVD in LMIC T2DM populations. When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: It should be noted that the choice of anti-diabetic drugs should take into consideration cardiovascular safety. SGLT2 inhibitors and GLP-1 agonists are newer agents for managing diabetes and have been found to have cardiorenal benefits. The choice of lipid-lowering should be targeted to lower LDL cholesterol and triglycerides as effectively as possible. If the intensity of statin is high; it is considered first-line therapy, and other optional medication includes ezetimibe and PCSK9 inhibitors. To maintain the best pressure level that is suitable for an individual, and as a result control hypertension, the use of antihypertensive drugs is necessary. This makes ACE inhibitors or ARBs the preferred first-line antihypertensive agents because of their cardiovascular benefits. For the purpose of secondary prevention in individuals who have experienced a cardiovascular event, the antiplatelet drug aspirin in a dosage of between 75 to 150 milligrams per day should be administered. This is to minimize the probability of such difficulties re-emerging by influencing platelet activity. In general, adequate blood pressure management and antiplatelet aggregation therapy are key interventions with specific antiplatelet medication needs in this setting.

Identification and in vitro genotoxicity assessment of forced degradation products of glimepiride and glyburide using HEK cell-based COMET assay.

This study focuses on characterizing the forced degradation products of antidiabetic drugs glimepiride (GMD) and glyburide (GBD), with previously unexplored genotoxicity. Drugs underwent stress induced by acid, base, and hydrogen peroxide. For GMD, impurities were profiled and isolated using Hypersil Gold C8 (250 × 10 mm, 5μ) through semi-preparative HPLC with a fraction collector. For GBD, impurity profiling was performed using semi-preparative HPLC (Hypersil GOLD C18, 250 × 10 mm, 5μ), and reverse-phase flash chromatography (FP ECOFLEX C18 4g column) for isolation. Although five GMD and three GBD impurities were detected, only three GMD and two GBD impurities were separated and assessed for purity using analytical RP-HPLC with the purity percentages ranging from 96.6% to 99.9%. LC-Orbitrap MS was used to identify these three GMD impurities (m/z: 408.122, 338.340, 381.160) and two GBD impurities (m/z: 369.065, 325.283). ProTox-II in silico predictions classified all impurities as class 4 and 5, with no positive genotoxicity indications. In vitro comet assays, using HEK cells, indicated that for GMD, impurity 2 and impurity 5 were less genotoxic, whereas impurity 4 exhibited genotoxicity. For GBD, both impurities 1 and 3 were found to be genotoxic, with impurity 3 showing a higher level of genotoxicity than impurity 1.

Click Reaction Inspired Enzyme Inhibitors in Diabetes Care: An Update in the Field of Chronic Metabolic Disorder.

Diabetes is a chronic metabolic disorder that impacts all age groups and affects a large population worldwide. Humans receive glucose from almost every food source, and after absorption from the gut, it reaches the liver, which functions as the distribution center for it. The insulin-responsive glucose transporter type 4 (GLUT-4) is a major carrier of glucose to the various cells (majorly expressed in myocytes, adipocytes, and cardiomyocytes) in a well-fed state. In fasting periods, the glucose supply is maintained by glycogenolysis and gluconeogenesis. In diabetes, the distribution of glucose is hampered due to several reasons. Furthermore, to treat this disorder, several drugs have been synthesized, and click chemistry plays an important role. A more recent concept for producing pharmaceuticals with a click chemistry approach makes any reaction more practical and stereospecific, along with a higher yield of products and a smaller number of by-products. This approach comprises a compiled study of the activity of numerous compelling antidiabetic drugs containing 1, 2, 3-triazole derivatives supported by click chemistry. In this review, we discuss the synthetic antidiabetic drugs made via click chemistry and their commendable role in improving diabetes care.

A new bicyclo [3.3.1]nonadienemethanol-type lignan from the leaves of Taxus wallichiana Zucc.

Following an α-glucosidase inhibitory activity-guided phytochemical study, a rare new bicyclo[3.3.1]nonadienemethanol-type lignan named 9,9′-oxidolanceolatanin B (1) and four known lignans, lanceolatanin B (2), pinoresinol (3), syringaresinol (4), and medioresinol (5), were isolated from a CHCl3-soluble fraction of Taxus wallichiana Zucc. leaves. The absolute configuration of 9,9′-oxidolanceolatanin B was elucidated based on NMR spectroscopic interpretation and ECD data. All isolated compounds 1–5 showed stronger α-glucosidase inhibitory potency than the positive control, acarbose. This data could support the conceit that Taxus wallichiana leaves could be a promising source for plant-based anti-diabetic drug discovery.

Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.

Computational Drug Design Approaches for the Identification of Novel Antidiabetic Compounds from Natural Resources through Molecular Docking, ADMET, and Toxicological Studies.

Type 2 diabetes mellitus (T2DM) is usually depicted by relative insulin deficiency, raised blood glucose levels, and the predominant risk factor, insulin resistance. Hence, the development of insulin sensitizer drugs targeting PPAR-γ receptors has expanded enormous interest as an attractive choice for T2DM treatment. Thiazolidinediones (TZD) enhance insulin sensitivity either by directly functioning on gene transcription of the PPARγ receptor related to glucose homeostasis or by systemic sensitization of insulin and, therefore, improved hyperglycemia in a wide range of patients. However, severe complications and adverse effects of TZDs necessitate the development of an efficacious and reliable insulin sensitizer from alternative resources. On the contrary, Nature is a rich source of anticipated effective and safer medicine; more than fifty percent of drugs on the market are developed from natural products. Hence, searching for a new PPAR-γ agonist from bioactive secondary compounds of medicinal plants along with greater efficacy and safety is a recognized and consistent tactic for developing novel antidiabetic agents. Pulicaria jaubertii is a fragrant perennial aromatic plant with anti-inflammatory, antidiabetic, antimicrobial, antimalarial, and insecticidal properties. The current study was designed to use a computer-aided drug design to explore the best antidiabetic compounds from P. jaubertii. Herein, the molecular docking study of 80 investigated ligands against the PPAR-γ receptor identifies the highest docking score for five ligands ranging from -8.9 kcal/mol to 8.0 kcal/mol, which is also more significant than the standard drug pioglitazone (-7.7 kcal/mol) determined by the PyRx 8.0 virtual screening software. GLN286, CYS285, SER289, TYR473, MET364, ARG288, ILE341, and LEU333 residues are found to be significant contributors to the non-bonded interaction between ligands and receptors. Molecular electrostatic potential (MEP), DFT, molecular orbital (MO), ADMET, and toxicological analyses were performed on the selected five high-scored ligands of P. jaubertii. Results documented that all investigated ligands, especially L4, show considerably excellent profiles in molecular docking, MEP, DFT, MO, ADMET, and toxicological predictions, suggesting our drug-designing approaches may contribute to the development of a novel antidiabetic drug for the treatment of T2DM from natural resources.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

&lt;p&gt;Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. &lt;/p&gt;&lt;p&gt; Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. &lt;/p&gt;&lt;p&gt; This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.&lt;/p&gt;

In vitro Anti-Diabetic and Antioxidant Potential of the Siddha formulation Mega Sanjeevi Chooranam

Background: The increasing prevalence of type 2 diabetes mellitus (T2DM) presents a significant public health challenge due to its long-term complications and its role as a primary risk factor for cardiovascular diseases, which have both economic and social implications. Plant-derived antidiabetic drugs are being extensively studied due to their safety and efficacy. The main objective of the present study is to evaluate the anti-diabetic and anti-oxidant potential of the formulation Mega Sanjeevi Chooranam (MSC) through in-vitro investigation. Materials and Methods: The in vitro investigation of traditional siddha formulation MSC were performed to ascertain its inhibitory potential against α-amylase and α-glucosidase enzymes along with antioxidant analysis. Results: The MSC displayed the highest activity against α-amylase enzyme, with a percentage inhibition of 73.44 ± 6.87% (IC50, 299.4 ± 27.27 μg/ml), followed by a moderate level of α-glucosidase inhibition at 48.89 ± 13.38% (IC50, 402.2 ± 86 μg/ml). Furthermore, the MSC exhibited the strongest antioxidant activity in quenching ABTS● radicals (IC50, 110.1 ± 18.6 μg/ml), followed by DPPH● (IC50, 144.4 ± 36.8 μg/ml), H2O2● (IC50, 172.7 ± 39.3 μg/ml), and NO● radicals (IC50, 238.4 ± 58.56 μg/ml). Conclusion: In conclusion the formulation MSC demonstrated the significant antioxidant activity and effectively inhibited α-amylase and α-glucosidase enzyme activities. Further study is needed to isolate bioactive phytoconstituents and determine the molecular mechanism behind their antidiabetic effect.

8336 Glycemic Control and Associated Factors During Transition in Youths with Childhood-onset Type 2 Diabetes Mellitus

Abstract Disclosure: J. Yoo: None. H. Woo: None. M. Gu: None. J. Kim: None. Y. Lee: None. C. Shin: None. Y. Lee: None. Background: Childhood-onset type 2 diabetes has increased risk of early diabetes-related complications due to accelerated loss of pancreatic beta cell function. However, no second-choice anti-diabetic drug(such as GLP1 receptor agonists and SGLT2 inhibitors), other than metformin and insulin, is approved to be administered in pediatric patients with type 2 diabetes in South Korea. This study aimed to describe microvascular complications (nephropathy and eye disease) of youths with childhood-onset type 2 diabetes, investigate trends of glycemic control of patients and associated factors across transition period, and analyze change in glycemic control after adding 2nd-choice drug. Method: Among the patients who were treated for type 2 diabetes at Seoul National University Hospital since 2001, 84 patients who were diagnosed under age 18 and reached at age 20 or more on July, 2023 were included. Data of HbA1c, diabetes duration, administered medication, and diabetic complications were collected. Changes in HbA1c from 19 to 22 years of age (transition period) were investigated, and sex, age at diagnosis, and glycemic control at age 19 were analyzed as associated factors. Result: The average age of diagnosis and last follow-up was 14 years and 24.9 years respectively, and the median duration of diabetes was 9.6 years. At the last follow-up, complications developed in 28 patients (33.7%), and the prevalence was 25.3% for nephropathy and 20.6% for eye disease. At the occurrence of complications, the median diabetes duration was 6.2 years for microalbuminuria and 11.3 years for ophthalmic complications. During the transition period, HbA1c showed a significant decline from 8.3% to 7.7% (p=0.007). During this phase HbA1c decreased more significantly in the female (vs. male), in the patients with diagnostic age &amp;lt;15 years (vs. &amp;gt;15 years old), and patients with HbA1c 7% or above at 19-year-old visit(vs. &amp;lt; 7%). During entire follow-up, 59 patients (70%) received diabetes drugs other than metformin and insulin. At diagnosis, the proportion of patients treated with insulin accounted for 55%. At last visit, only few patients were maintained with metformin alone, and most patients required insulin or 2nd-choice antidiabetic drug. Analysis of HbA1c changes in 59 patients with the addition of 2nd-choice drug showed a decrease to 8.5% after 1 year (p=0.006) and to 8.1% at the last visit(p=0.017). Conclusion: Diabetic complications were observed in one-thirds of youths with type 2 diabetes at last follow-up in this study. Glycemic control during transition period to adulthood showed improvement, and factors that influence HbA1c improvement included female, younger age at diagnosis, and better glycemic control at age 19. There is a need to lower the insurance age criteria of South Korea for 2nd-choice antidiabetic drugs, considering that glycemic control significantly improved after adding the 2nd-choice drugs. Presentation: 6/1/2024