Antidiabetic Agents Research Articles

Drug Discovery Based on Oxygen and Nitrogen (Non-)Heterocyclic Compounds Developed @LAQV-REQUIMTE/Aveiro.

Artur Silva's research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades.

HPTLC Quantification of α-Glucosidase Inhibitor Mangiferin in Hydro-alcoholic extract of Salacia Species and Antidiabetic Poly-herbal Formulation

Salacia oblonga Wall. and Salacia reticulata Wight. (Family Celastraceae) are commonly known as Saptarangi and used in Ayurvedic medicine as potent antidiabetic agent. It is a woody climber, mainly habitat in Sri Lanka and Southern India. A large number of chemical constituents such as salacinol, neosalacinol, kotalanol, neokotalanol, and mangiferin were isolated from stem and root of saptarangi which shows various therapeutics activities. Chemical constituent presents in both species of Salacia are working as α-glucosidase inhibitor for diabetes management. Among them mangiferin is a plant natural polyphenol of C-glycosylxanthone structure and found in many plant species. Many chromatography techniques like LC-MS, HPLC are available to quantify mangiferin but no proper data available for simple, rapid, precise, economic HPTLC method. So, HPTLC method was developed with mobile phase ethyl acetate: formic acid: water (4:0.5:0.5 v/v/v) which confirmed the presence of mangiferin at 0.38±0.01 Rf value observed under 254nm. Mangiferin was present in 1.02% in Salacia oblonga root extract, 0.94% in Salacia reticulata stem extract and 0.42% in polyherbal formulation. The validated HPTLC method will be useful in standardization of different Ayurvedic formulations using mangiferin as a marker.

Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease

BackgroundMetformin (MET) treatment prior to stroke might have neuroprotective effects other than hypoglycemic effects. This study evaluated whether MET treatment prior to stroke is associated with neurological severity and functional outcome in patients with stroke who were not indicated for endovascular treatment and whether the effects of MET differ for each ischemic stroke subtype. MethodsWe investigated 160 type 2 diabetes mellitus patients with ischemic stroke without endovascular treatment who were taking some oral antidiabetic agents prior to stroke in two tertiary hospitals. Lower neurological severity was defined as a National Institutes of Health Stroke Scale score of 3 or lower on admission, and favorable functional outcome was defined as a modified Rankin Scale score = 0–2 at discharge. We analyzed the effects of MET on the neurological severity and functional outcome in each ischemic stroke subtype on logistic regression analysis with adjustments for multiple confounding factors. ResultsMET treatment prior to stroke was associated with lower stroke severity and favorable functional outcome. In the stroke subtypes, MET use affected both neurological severity (P = 0.037) and functional outcome (P = 0.041) in only patients with small-vessel disease (SVD). ConclusionsMET may be useful to improve the outcome of patients with SVD.

Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor use among adults with diabetes mellitus by cardiovascular-kidney disease risk: National Health and Nutrition Examination Surveys, 2015–2020

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear. MethodsWe performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015–2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker). ResultsOverall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9–11.0): 4.8 % (95 % CI 3.6–6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3–7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98–1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25–1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82–0.86). ConclusionAmong US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization.

Central insulin dysregulation in antipsychotic-naïve first-episode psychosis: In silico exploration of gene expression signatures

Antipsychotic drug (AP)-naïve first-episode psychosis (FEP) patients display premorbid cognitive dysfunctions and dysglycemia. Brain insulin resistance may link metabolic and cognitive disorders in humans. This suggests that central insulin dysregulation represents a component of the pathophysiology of psychosis spectrum disorders (PSDs). Nonetheless, the links between central insulin dysregulation, dysglycemia, and cognitive deficits in PSDs are poorly understood. We investigated whether AP-naïve FEP patients share overlapping brain gene expression signatures with central insulin perturbation (CIP) in rodent models. We systematically compiled and meta-analyzed peripheral transcriptomic datasets of AP-naïve FEP patients along with hypothalamic and hippocampal datasets of CIP rodent models to identify common transcriptomic signatures. The common signatures were used for pathway analysis and to identify potential drug treatments with discordant (reverse) signatures. AP-naïve FEP and CIP (hypothalamus and hippocampus) shared 111 and 346 common signatures respectively, which were associated with pathways related to inflammation, endoplasmic reticulum stress, and neuroplasticity. Twenty-two potential drug treatments were identified, including antidiabetic agents. The pathobiology of PSDs may include central insulin dysregulation, which contribute to dysglycemia and cognitive dysfunction independently of AP treatment. The identified treatments may be tested in early psychosis patients to determine if dysglycemia and cognitive deficits can be mitigated.

Phytochemical profiling and antidiabetic evaluation of Peperomia pellucida as a potential alpha glucosidase inhibitor

Abstract. Hidayati S, Agustin AT, Sari EK, Sari SM, Destiawan RA, Silvana WA. 2023. Phytochemical profiling and antidiabetic evaluation of Peperomia pellucida as a potential alpha glucosidase inhibitor. Biodiversitas 24: 5972-5978. One strategy in post-prandial hyperglycemic control can be done by inhibiting the digestion of dietary carbohydrates through the inhibition of alpha glucosidase enzymes. This study was conducted to determine the antidiabetic activity of Peperomia pellucida in inhibiting the alpha glucosidase. An inhibitory activity analysis test was carried out on alpha glucosidase in vitro and in silico using alpha glucosidase. Molecular docking between receptors and ligands was performed using Hex 8.0 software. The setting column is set in Shape+Electro+DARS mode. The results showed ethanol extract and ethyl acetate fraction in vitro showed the ability to inhibit the activity of alpha glucosidase enzyme with C50 values of 13.43 mg/mL and 9.73 mg/mL respectively with IC50 positive control acarbose values of 8.11 mg/mL. The results of in silico analysis showed that the Patuloside A component was able to bind to the binding site of alpha glucosidase and gave the smallest binding energy value with a value of -321.4 kcal/mol compared to isovitexin, isoswertisin, pellucidatin, and caryatin-7-O-?-rhamnoside compounds. P. pellucida has the potential to be developed as an antidiabetic agent that has activity in inhibiting the work of the enzyme alpha glucosidase so that it can reduce blood glucose levels.

Polyhydroquinoline derivatives for diabetic management: synthesis, in vitro and in silico approaches.

Background: Medication used to treat Type 2 diabetes by decreasing the absorption of carbohydrates in the intestine consists of α-glucosidase inhibitors. Polyhydroquinoline derivatives have attracted interest as excellent antidiabetic agents. Methods: Polyhydroquinoline derivatives (1-17) were synthesized and tested for in vitro α-glucosidase inhibitory activity. Results: All the synthesized compounds exhibited excellent to good inhibitory activity, having IC50 values from 1.23±0.03 to 73.85±0.61μM, compared with the standard drug, acarbose. The binding mechanism of these derivatives with α-glucosidase was deduced by docking studies and indicated that a slight variation in the orientation of compounds, affects their binding capability. Conclusion: In order to find new antidiabetic drugs, this study has discovered prospective lead candidates.

Synthesis, in vitro Α-Glucosidase, and acetylcholinesterase inhibitory activities of novel Indol-Fused Pyrano[2,3-D]Pyrimidine compounds

In this study, new indol-fused pyrano[2,3-d]pyrimidines were designed and synthesized. These products were obtained in moderate to good yields and their structures were assigned by NMR, MS, and IR analysis. Afterwards, the biological important of the products was highlighted by evaluating in vitro for α-glucosidase inhibitory activity as well as acetylcholinesterase (AChE) inhibitory activity. Eleven products revealed substantial inhibitory activity against α-glucosidase enzyme, among which, two most potent products 11d,e were approximately 93-fold more potent than acarbose as a standard antidiabetic drug. Besides that, product 11k exhibited good AChE inhibition. The substituents on the 5-phenyl ring, attached to the pyran ring, played a critical role in inhibitory activities. The biological potencies have provided an opportunity to further investigations of indol-fused pyrano[2,3-d]pyrimidines as potential anti-diabetic agents.

Antidiabetic Activity, Molecular Docking, and ADMET Properties of Compounds Isolated from Bioactive Ethyl Acetate Fraction of Ficus lutea Leaf Extract

Diabetes contributes to the rising global death rate. Despite scientific advancements in understanding and managing diabetes, no single therapeutic agent has been identified to effectively treat and prevent its progression. Consequently, the exploration for new antidiabetic therapeutics continues. This study aimed to investigate the antidiabetic bioactive ethyl acetate fraction of F. lutea at the molecular level to understand the molecular interactions and ligand-protein binding. To do this, the fraction underwent column chromatography fractionation to yield five compounds: lupeol, stigmasterol, α-amyrin acetate, epicatechin, and epiafzelechin. These compounds were evaluated in vitro through α-glucosidase inhibition and glucose utilization assays in C2C12 muscle and H-4-11-E liver cells using standard methods. In silico analysis was conducted using molecular docking and ADMET studies. Epicatechin exhibited the most potent α-glucosidase inhibition (IC50 = 5.72 ± 2.7 µg/mL), while epiafzelechin stimulated superior glucose utilization in C2C12 muscle cells (33.35 ± 1.8%) and H-4-11-E liver cells (46.7 ± 1.2%) at a concentration of 250 µg/mL. The binding energies of the isolated compounds for glycogen phosphorylase (1NOI) and α-amylase (1OSE) were stronger (<−8.1) than those of the positive controls. Overall, all tested compounds exhibited characteristics indicative of their potential as antidiabetic agents; however, toxicity profiling predicted epiafzelechin and epicatechin as better alternatives. The ethyl acetate fraction and its compounds, particularly epiafzelechin, showed promise as antidiabetic agents. However, further comprehensive studies are necessary to validate these findings.

Is Metformin Associated with a Lower Prevalence of Polyps, Adenomas, and Colorectal Carcinoma in Patients with Diabetes Mellitus?

Recent studies suggested a protective role of metformin in the development of colorectal cancer (CRC) and its precursors. We aimed to investigate if metformin was associated with a lower prevalence and number of colorectal polyps in diabetic patients and also adenomas, high-risk adenomas, and CRC. Retrospective study on adult patients with diabetes mellitus followed in our hospital with a total colonoscopy between 2015 and 2019, treated with either metformin for > 5years or other antidiabetic agent (control group). We assessed the number, size, and histopathology examination of proliferative lesions detected on colonoscopy. We included 401 patients aged 69 ± 9years, 57% males, divided into two groups: treated with metformin (n = 260) and without (n = 141). The number of polyps detected was significantly lower in patients under metformin (p = 0.014). There was a nonsignificant trend towards lower polyp detection rates in the metformin compared to the control group both in unadjusted analysis (50% vs 60%, p = 0.058) and multivariable adjusted analysis (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.43-1.09, p = 0.111). In the latter, we identified male gender (OR 2.24, 95%CI 1.44-3.49, p < 0.001), age (OR 1.35 for every 10years, 95%CI 1.07-1.71, p = 0.012), glycated hemoglobin value (OR 1.20 for every 1% increase, 95%CI 1.06-1.37, p = 0.005), and hypertension (OR 1.76, 95%CI 1.01-3.08, p = 0.046) as factors associated with a higher prevalence of polyps. We saw no statistically significant differences regarding adenoma (p = 0.231), high-risk adenoma (p = 0.810), and CRC (p = 0.705) diagnoses between groups. In our study, metformin was associated with less colorectal polyps in diabetic patients compared to other treatment modalities. We observed a nonsignificant trend towards lower polyp detection rates in the metformin group both in unadjusted and adjusted analyses.

GLP-1 RAs and SGLT2i: two antidiabetic agents associated with immune and inflammation modulatory properties through the common AMPK pathway.

Immune cells and other cells respond to nutrient deprivation by the classic catabolic pathway of AMPK (Adenosine monophosphate kinase). This kinase is a pivotal regulator of glucose and fatty acids metabolism, although current evidence highlights its role in immune regulation. Indeed AMPK, through activation of Foxo1 (Forkhead box O1) and Foxo3 (Forkhead box O3), can regulate FOXP3, the key gene for differentiation and homeostasis of Tregs (T regulators lymphocytes). The relevance of Tregs in the onset of T1D (Type 1 diabetes) is well-known, while their role in the pathogenesis of T2D (Type 2 diabetes) is not fully understood yet. However, several studies seem to indicate that Tregs may oppose the progression of diabetic complications by mitigating insulin resistance, atherosclerosis, and damage to target organs (as in kidney disease). Hence, AMPK and AMPK-activating agents may play a role in the regulation of the immune system. The connection between metformin and AMPK is historically known; however, this link and the possible related immune effects are less studied about SGLT2i (Sodium-glucose co-transport 2 inhibitors) and GLP1-RAs (Glucagon-like peptide-1 receptor agonists). Actual evidence shows that the negative caloric balance, induced by SGLT2i, can activate AMPK. Conversely and surprisingly, an anabolizing agent like GLP-1RAs can also upregulate this kinase through cAMP (Cyclic adenosine monophosphate) accumulation. Therefore, both these drugs can likely lead to the activation of the AMPK pathway and consequential proliferation of Tregs. These observations seem to confirm not only the metabolic but also the immunoregulatory effects of these new antidiabetic agents.

Potential Endophytic Fungi from the Leaves of Syzygium zeylanicum (L.) and Their Secondary Metabolite

Endophytic fungi coexist without harms in the host in some parts or all parts of its lifecycle. Endophytic fungi excrete specialized bioactive compounds beneficial for of its host; the compound itself can be different from what can be found on their host. Endophytic fungi are capable to excrete biologically significant secondary metabolites acting as antidiabetic, antioxidant, antimicrobial, and cytostatic agents. Endophytic fungi existence are common across different plants; including Syzygium zeylanicum that can be found in Indonesia. This study aims to isolate endophytic fungi found in leaves of Syzygium zeylanicum, L., to elucidate their characterized morphologically, and to examine its antimicrobial and antioxidant properties in addition to their chemical structures. Characterization of endophytic fungi was conducted by their macroscopic and microscopic features, followed by molecular characterization of highly bioactive metabolites. Antimicrobial activities were measured by disc diffusion method. Antioxidant properties were measured with DPPH. Secondary metabolites were chromatographically isolated and identified with spectroscopy techniques (NMR ID and 2D). Four endophytic fungi isolates were obtained: Penicillium citrinum (SZ1), Colletotrichum lindemuthianum (SZ2), Aspergillus nidulan (SZ3), Scopulariopsis asperula (SZ4). Penicillium citrinum (SZ1) showed antimicrobial activities against four different bacteria (71.3% against E. coli; 74.1% against S. aureus; 76.2% against S. typhi; and dan76.9% against B. subtilis). Antioxidant activity ini all ekstrak of endophytic fungi showed very activity (IC50 SZ3 extract = 3.85 µg/mL). Potential endophytic fungi SZ1 was molecularly identified as Penicillium citrinum. Extracts from SZ1 fungi contains bioactive 4-hydroxy-2-(4-hydroxyphenyl)-ɣ-butyrolactone-3-yl) methyl acetate. The newly obtained substance could be developed into antimicrobial and antioxidant agents in further studies.

The association between alcohol drinking and glycemic management among people with type 2 diabetes in China.

To investigate the association between alcohol drinking and glycemic management among adult patients with type 2 diabetes in regional China. In this cross-sectional survey conducted in Nanjing Municipality of China in 2018, adult type 2 diabetes patients were randomly selected from urban and rural communities. The outcome variable was the glycemic management status. The explanatory measure was alcohol drinking. Mixed-effects regression models were employed to estimate odds ratios (ORs) and 95% confidence interval (95% CI) for examining the associations of alcohol drinking with glycemic management among type 2 diabetes patients. Among the overall 5,663 participants, the glycemic management rate was 39.8% (95% CI = 38.5, 41.1), with 41.2% (95% CI = 39.7, 42.7), 43.9% (95% CI = 38.9, 48.8), and 34.1% (95% CI = 31.5, 36.7) for non-drinkers, mild/moderate drinkers, and heavy drinkers, respectively. After adjustment for potential confounders and community-level clustering effect, heavy and mild/moderate alcohol drinkers were at 0.76 (95% CI = 0.66, 0.89) and 1.04 (95% CI = 0.87, 1.28) times odds to have glycemia under control than non-drinkers among the overall participants. Furthermore, when stratified separately by gender and use of anti-diabetes agents, the scenario within men, either regular or irregular users of anti-diabetes agents was the same as that for overall participants, while the association between alcohol drinking and glycemic management became non-significant among women. Heavy alcohol drinking might have a negative effect on glycemic management among patients with type 2 diabetes irrespective of the use of anti-diabetes agents in regional China. This study has important public health implications regarding precision intervention on patients' glycemia control for type 2 diabetes management.

Tigecycline and Hypoglycemia, When and How?

Objective: To describe the clinical characteristics of hypoglycemia that develop with tigecycline therapy and to review and summarize the current evidence of this uncommonly occurring metabolic adverse effect of tigecycline therapy. Underlying risk factors and potential mechanisms are also discussed. Data source: A 3-phase literature search was performed. In phase 1, the Cochrane Central Register of Controlled Trials (CENTRAL) Library, MEDLINE, and Embase electronic databases were searched for hypoglycemia and tigecycline, published from inception until August 2023. In phase 2, MEDLINE was searched for tigecycline randomized controlled trials and results were manually screened for hypoglycemia. In phase 3, the US Food and Drug Administration Adverse Event Reporting System public dashboard was searched for reports on tigecycline and hypoglycemia from June 2005 until July 2023. Study selection and data extraction: Relevant English-language citations and those conducted in humans were considered. Relevance to patient care and clinical practice: Hypoglycemia of various causes is an independent mortality risk. This review raises awareness among clinicians about the possibility of hypoglycemia with tigecycline therapy. Conclusion: Data on tigecycline-related hypoglycemia are scarce. Hypoglycemia may occur at any time during tigecycline therapy and can be severe and persist for days after tigecycline cessation. Renal dysfunction or renal replacement therapy may predispose to severe hypoglycemia during tigecycline therapy. Tigecycline-related hypoglycemia may develop in patients with or without diabetes mellitus and appears independent of insulin or antidiabetic agents. Intravenous dextrose showed efficacy in the restoration of euglycemia. Studies are needed to determine whether tigecycline-related hypoglycemia is iatrogenic or spontaneous.

The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful?

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.

Polysaccharides (pectin, mucilage, and fructan inulin) and their fermented products: A critical analysis of their biochemical, gut interactions, and biological functions as antidiabetic agents.

Diabetes mellitus is a globally metabolic endocrine syndrome marked by a deficiency of insulin secretion (type-1 DM) or glucose intolerance arising from insulin response impairment (type-2 DM) leading to abnormal glucose metabolism. With an increasing interest in natural dietary components for diabetes management, the identification of novel agents witnessed major discoveries. Plant-derived mucilage, pectin, and inulin are important non-starch polysaccharides that exhibit effective antidiabetic properties often termed soluble dietary fiber (SDF). SDF affects sugar metabolism through multiple mechanisms affecting glucose absorption and diffusion, modulation of carbohydrate metabolizing enzymes (α-amylase and α-glucosidase), ameliorating β-pancreatic cell dysfunction, and improving insulin release or sensitivity. Certain SDFs inhibit dipeptidyl peptidase-4 and influence the expression levels of genes related to glucose metabolism. This review is designed to discuss holistically and critically the antidiabetic effects of major SDF and their underlying mechanisms of action. This review should aid drug discovery approaches in developing novel natural antidiabetic drugs from SDF.

Use of Monoterpenes as Potential Therapeutics in Diabetes Mellitus: A Prospective Review.

Monoterpenes are secondary metabolites of plants belonging to the terpenoid class of natural products. They are the most abundant components of essential oils that are generally considered to have various pharmacological properties. These compounds are reported to have antidiabetic effects in recent years. Due to nature's complex biosynthetic machinery, they also exhibit a reasonable degree of structural complexity/diversity for further analysis in structure-activity studies. Therefore, monoterpenes as antidiabetic agents have been investigated by recent in vitro and in vivo studies extensively reported in the scientific literature and claimed by patent documents. The purpose of this survey is to provide a comprehensive and prospective review concerning the potential applications of monoterpenes in the treatment of diabetes. The data for this research were collected through the specialized databases PubMed, Scopus, Web of Science, and ScienceDirect between the years 2014 and 2022, as well as the patent databases EPO, WIPO, and USPTO. The research used 76 articles published in the leading journals in the field. The main effect observed was the antidiabetic activity of monoterpenes. This review showed that monoterpenes can be considered promising agents for prevention and/or treatment of diabetes as well as have a marked pharmaceutical potential for the development of bioproducts for therapeutics applications.

Concise review on anti-diabetic agents: Traditional to modern

Diabetes is one of the major challenging diseases as it is associated with other health complications including Atherosclerosis (narrowing of blood vessels), Heart diseases, Neuropathy (nerve damage in limbs), and Hypertension (high blood pressure). Its prevalence has been precarious since the last decade. Researchers have been trying hard to find the best remedy for diabetes since the last century and have developed a whole range of drugs of various chemical classes to control the mortality rate. Antidiabetic drugs synthesized during the last century are classified into three stages in the present review article and certain examples with their structure, mode of action, and applications are briefly discussed in the article. The future aspect, drug of choice, and success rate have been discussed as well.

Biogenic synthesis of ZnO nanoparticles using Polystichum squarrosum extract and its applications as anti-oxidant, anti-diabetic agent and industrial waste water treatment

Biogenic synthesis of ZnO nanoparticles using Polystichum squarrosum extract and its applications as anti-oxidant, anti-diabetic agent and industrial waste water treatment

Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment

Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from β-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one’s moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (−13.9 kcal/mol and −86.2 kcal/mol), A1 (−11.1 kcal/mol and −79.5 kcal/mol), A13 (−11.3 kcal/mol and −91.4 kcal/mol), and the co-crystal itself (−9.8 kcal/mol and −76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and β-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein. Communicated by Ramaswamy H. Sarma