Antidiabetic Drug Discovery Research Articles

Oral glucose tolerance test with methanol extract of leaves of Ocimum minimum L. (Lamiaceae) in Swiss albino mice

Background: Diabetes is a metabolic disorder characterized by high blood sugar caused due to either insufficient production of insulin from the pancreas or development of insulin resistance, which causes polyuria, polydipsia, and polyphagia. In recent years, the disorder is increasing at a rapid rate in virtually all countries of the world. Existing conventional drugs suffer from problems of non-affordability, adverse effects, and non-availability in particularly rural and remote areas of developing countries like Bangladesh. As a result scientists are continually striving for discovery of new anti-diabetic drugs, which can fulfill the needs of all diabetic patients. Methods and Findings: The Ocimum genera within the Lamiaceae family contains a number of plants reported to possess anti-diabetic properties. However, very little is known about the pharmacological including anti-diabetic properties of Ocimum minimum L., the leaves of which are chewed by the indigenous people in the Chittagong Hill Tracts region in the south-eastern part of Bangladesh to control diabetes. Oral glucose tolerance test (OGTT) was conducted with Swiss albino mice and methanol extract of Ocimum minimum, using glibenclamide (a standard anti-diabetic drug) as the comparison drug. The methanolic extract of Ocimum minimum (MEOM) showed only significant anti-hyperglycemic activity at a dose of 400 mg/kg body weight; at that dose blood glucose was lowered by nearly 19%. By comparison, glibenclamide at a dose of 10 mg/kg lowered blood glucose by 37%.Conclusions: Methanol extract of Ocimum minimum leaves did not show any remarkable lowering of blood glucose in OGTT except at high doses. However, the plant has an advantage of growing profusely in the Chittagong Hill Tracts region, which is mountainous, forested, and inhabited by a number of indigenous communities with little contact with modern medical facilities. As such, the inhabitants of this region can chew, if necessary, as much as possible of the leaves of Ocimum minimum and bring their blood glucose under control.

α-Glucosidase and α-Amylase Inhibition Activities of Sarcococca coriacea Hook. And Sarcococca wallichii Staph. of Nepalese Origin

Diabetes mellitus is being severe health problem globally with an increasing number of patients every day. Due to the lack of effective and non-toxic medicine to cure diabetes, plants that are used in ethnomedicine may be a good source for antidiabetic drug discovery. Plants of the Sarcococca genus are medicinally important and are used by local people for managing many diseases including diabetes. In the course of our continuous search of antidiabetic plants and pure compounds, in vitro α-glucosidase, and α-amylase inhibition activity along with the antioxidant activity of methanolic extract of S. coriacea leaf ( Sc-A), S. coriacea stem (Sc-B), and dichloromethane fraction of methanolic extract of Sarcococca wallichi (Sw-D) were carried out. The research revealed dicholoromethane fraction of S. wallichii (Sw-D) with good inhibition of α- amylase enzyme (IC50= 53.79 ± 2.50), whereas Sc-B inhibits α-glucosidase (20.97±2.37) effectively. Similarly, Sc-A showed significant antioxidant activity with IC50=24.56±3.3. The total phenolic content on Sc-A and Sc-B was calculated as 151.35±4.42 mg GAE/g and 86.22±1.59 mg GAE/g whereas the total flavonoid content on Sc-A and Sc-B was found to be 21.61±4.88 mg QE/g and 24.09±4.02 mg QE/g respectively. Similarly, total phenolic and total flavonoid content on Sw-D were found to be 85.26±3.16 mg GAE/g and 21.57±1.26 mg QE/g. To the best of our knowledge, this is the first report of α-glucosidase and α-amylase inhibition activity in these plants. This research work has scientifically supported the use of these plants to manage diabetes by local people and has explored new plants for antidiabetic drug discovery research.

StackDPPIV: A novel computational approach for accurate prediction of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides.

The development of efficient and effective bioinformatics tools and pipelines for identifying peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activities from large-scale protein datasets is of great importance for the discovery and development of potential and promising antidiabetic drugs. In this study, we present a novel stacking-based ensemble learning predictor (termed StackDPPIV) designed for identification of DPP-IV inhibitory peptides. Unlike the existing method, which is based on single-feature-based methods, we combined five popular machine learning algorithms in conjunction with ten different feature encodings from multiple perspectives to generate a pool of various baseline models. Subsequently, the probabilistic features derived from these baseline models were systematically integrated and deemed as new feature representations. Finally, in order to improve the predictive performance, the genetic algorithm based on the self-assessment-report was utilized to determine a set of informative probabilistic features and then used the optimal one for developing the final meta-predictor (StackDPPIV). Experiment results demonstrated that StackDPPIV could outperform its constituent baseline models on both the training and independent datasets. Furthermore, StackDPPIV achieved an accuracy of 0.891, MCC of 0.784 and AUC of 0.961, which were 9.4%, 19.0% and 11.4%, respectively, higher than that of the existing method on the independent test. Feature analysis demonstrated that our feature representations had more discriminative ability as compared to conventional feature descriptors, which highlights the combination of different features was essential for the performance improvement. In order to implement the proposed predictor, we had built a user-friendly online web server at http://pmlabstack.pythonanywhere.com/StackDPPIV.

Citrullus lanatus natural product library: A hoard of viable potential inhibitor candidates for diabetes mellitus type II therapeutic target enzymes

The ethnomedicinal function of several cucurbit species (cucumber, squash, melon, gourd, etc.) on diseases (i.e. diabetes, microbial infections, cancer, etc.), and as free radical scavengers have been reported. However, there remains infinitesimal record on citron watermelon broad use, which reflects the reason for wide oversight of underutilization, from lack of recognition for functional food crop development and commercialization. The objective of this study focus towards identifying the natural phytochemicals of C. lanatus on water melon molecules online database for insilico computational approach to screened for suitable antidiabetic lead, and construction of phylogenetic relatedness of target Type 2 Diabetes Mellitus proteins was conducted to predict reoccurrence of insilico analysis output with other homologous target proteins. The T2DM protein targets, phytochemical and standard inhibitory drugs are mined from different databases. Insilico docking analysis, and adme/toxicity profiling was virtually screened for the best fit. In additionally, phylogenetic relationship of the target proteins was aligned and construction with other homologous protein targets to predict the reoccurrence confidence of results on compounds. Seventeen phytochemicals out of the nineteen potential drug candidates substantially passed the profiling test. Also, homologous protein targets with > 90% bootstrap confidence are likely to produce a reoccurring insilico result. Thus, these phytochemicals fulfil all the enlisted criteria and it is suggestively determined to be suitable for the development of potent antidiabetic drugs. It is evident that phytochemicals from Citrullus lanatus produced satisfactory insilico output, and this reflect it to be a probable reservoir containing other potential therapeutic drug candidates for antidiabetic drug discovery and development. Additionally, derivatives can be developed for further effective screening result.

Direct visualization of glucagon‐like peptide‐1 secretion by fluorescent fusion proteins

Live‐cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon‐like peptide‐1 (GLP‐1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP‐1 synthesis through the post‐translational processing from proglucagon. Here, we have developed FP‐tagged GLP‐1 by inserting FPs into the middle of GLP‐1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP‐1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP‐tagged GLP‐1 enables direct visualization of stimulation‐dependent exocytosis of GLP‐1 at a single granule resolution with total internal reflection fluorescence microscopy. FP‐tagged GLP‐1 might facilitate the screening of GLP‐1 secretagogues and the discovery of new antidiabetic drugs.

Antidiabetic Phytochemicals From Medicinal Plants: Prospective Candidates for New Drug Discovery and Development.

Diabetes, a chronic physiological dysfunction affecting people of different age groups and severely impairs the harmony of peoples’ normal life worldwide. Despite the availability of insulin preparations and several synthetic oral antidiabetic drugs, there is a crucial need for the discovery and development of novel antidiabetic drugs because of the development of resistance and side effects of those drugs in long-term use. On the contrary, plants or herbal sources are getting popular day by day to the scientists, researchers, and pharmaceutical companies all over the world to search for potential bioactive compound(s) for the discovery and development of targeted novel antidiabetic drugs that may control diabetes with the least unwanted effects of conventional antidiabetic drugs. In this review, we have presented the prospective candidates comprised of either isolated phytochemical(s) and/or extract(s) containing bioactive phytoconstituents which have been reported in several in vitro, in vivo, and clinical studies possessing noteworthy antidiabetic potential. The mode of actions, attributed to antidiabetic activities of the reported phytochemicals and/or plant extracts have also been described to focus on the prospective phytochemicals and phytosources for further studies in the discovery and development of novel antidiabetic therapeutics.

Effects of alcoholic extract of Terminalia Chebula dried fruit on blood biochemical profile in diabetic rats.

A considerable amount of attention has been recently paid to the discovery of effective natural antidiabetic drugs. Terminalia chebula is considered as the mother of herbs, with reported antidiabetic activity. This study aims to evaluate the renal and hepatic protective profile of its antidiabetic therapeutic doses. To achieve the aim of the study, a total of 66 adult male rats of Sprague-Dawley species weighing about 180-200 g (weighed using a digital scale) were used. Type 2 diabetes mellitus (T2DM) was induced in using streptozotocin (STZ), rats were given a 5% dextrose solution for the next 24h. Subjects received oral treatment of Terminalia chebula ethanolic extract at different doses (200, 400, and 600mg/kg body weight) for 28days. Measurements of fasting blood glucose level, change in body weight, lipid profile, serum liver enzymes, serum renal parameter, and histopathology of liver and kidney were carried out. Higher doses of Terminalia chebula (600mg/Kg) were shown to have a potential therapeutic effect as well as the most prominent antidiabetic, antilipidemic activity, hepatoprotective and renoprotective profiles when compared to lower doses. The use of Terminalia chebula alone or in combination with conventional antidiabetic drugs may be beneficial as a new advent therapy for diabetes. The online version contains supplementary material available at 10.1007/s40200-021-00951-8.

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales.

Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

Research progress of indole compounds with potential antidiabetic activity.

New types of antidiabetic agents are continually needed with diabetes becoming the epidemic in the world. Indole alkaloids play an important role in natural products owing to their variable structures and versatile biological activities like anticonvulsant, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, which are a promising source of novel antidiabetic drugs discovery. The synthesized indole derivatives possess similar properties to natural indole alkaloids. In the last two decades, more and more indole derivatives have been designed and synthesized for searching their bioactivities. This present review describes comprehensive structures of indole compounds with the potential antidiabetic activity including natural indole alkaloids and the synthetic indole derivatives based on the structure classification, summarizes their approaches isolated from natural sources or by synthetic methods, and discusses the antidiabetic effects and the mechanisms of action. Furthermore, this review also provides briefly synthetic procedures of some important indole derivatives.

Peptide conjugates of 18β-glycyrrhetinic acid as potent inhibitors of α-glucosidase and AGEs-induced oxidation

18β-Glycyrrhetinic acid (18β-GA) is known for several biological activities, and has been the focus of extensive research for the development of therapeutic agents. In the current study, 18β-GA-peptide conjugates 2-11 were evaluated for their in vitro α-glucosidase inhibitory and antiglycation activities. Structure-activity relationship (SAR) established and molecular interactions of active bioconjugates with the enzyme's binding sites were predicted through molecular modeling approach. In tripeptide moiety of conjugates 2−11, peptide residue at position 1 was found to have a significant role on α-glucosidase inhibition. The most active 18β-GA-peptide conjugates 5 (18β-GA-Cys1-Tyr2-Gly3), and 8 (18β-GA-Pro1-Tyr2-Gly3) exhibited several-fold potent α-glucosidase inhibition (IC50 values 20–28 μM), as compared to standard drug acarbose (IC50 = 875.8 ± 2.10 µM). Kinetic studies of potent compounds, 4–8 revealed that conjugate 5 exhibits competitive-type of inhibition, while conjugates 6–8 showed a non-competitive type of inhibition. The simulation studies also supported the kinetic results that conjugate 5 (18β-GA-Cys1-Tyr2-Gly3) inhibits the α-glucosidase enzyme by blocking its substrate binding site. AGEs-induced NO• inhibitors play an important role in controlling the inflammation associated with diabetes mellitus. The peptide conjugates 2–11 were also evaluated in vitro for AGEs-induced NO• inhibition using RAW 264.7 macrophage cell line. Our data revealed that conjugates 7–10 were the more potent AGEs-induced NO• inhibitors, comparable to standards rutin, and PDTC. The peptide conjugate 5 (a competitive inhibitor of α-glucosidase) also exhibited a strong inhibitory activity against AGEs-induced NO• production. Furthermore, peptide conjugates 2–11 were found non-cytotoxic to mouse fibroblast NIH-3T3, and murine macrophages RAW 264.7 cell lines. In conclusion, our data demonstrates that besides possessing strong α-glucosidase inhibition, the newly synthesized peptide conjugates also alleviated the AGEs-induced NO• production in RAW macrophages. Dual inhibition of α-glucosidase enzyme, and AGEs-induced NO• production by 18β-GA-peptide conjugates qualify them for further research in anti-diabetic drug discovery.

Anti-diabetic drug discovery using bioactive compounds: Molecular docking insights

Diabetes mellitus is a metabolic disorder that has become a global health problem. About 500 million people were estimated to be living with diabetes in 2018 with about 20 million in Africa and 2 million cases in Nigeria. Bioactive compounds offer an advanced starting point in the search for highly specific and potent modulator of bimolecular function as well as novel drugs, which can be studied with more precision by using computer aided drug design (CADD). Molecular docking employed for predicting the interactions between receptor and ligands is an integral aspect in drug discovery. The main objective is to attain ligand-receptor complex with optimized conformation and with the intention of possessing less binding free energy. Several studies have used this method to explore the potency of bioactive compounds to predict better alternatives in the search for an anti-diabetic drug with very effective therapeutic role and minimal side effects. This has been carried out by using several compounds such as Quercetin, against endogenous targets such as Glycogen phosphorylase, Peroxisome Proliferator-activated Receptor (PPAR)-y, Glucokinase, Protein Tyrosine Phosphatase 1-beta (PTP-1B), GLUT4, etc. In Silico tools such as Protein Database (PDB), GenBank and softwares such as Autodock and modeller are of major importance to these studies. The paper seeks to examine bioactive compounds basically quercetin that have been successfully identified through molecular docking and their molecular targets as well as recent advances in the use of molecular docking in the novel discovery and explanation of mechanisms of actions of some bioactive compounds in anti-diabetic drug discovery.

Anti-diabetic drug discovery using bioactive compounds: Molecular docking insights

Anti-diabetic drug discovery using bioactive compounds: Molecular docking insights

SODIUM-GLUCOSE LINKED COTRANSPORTER 2 INHIBITOR: A NEW HORIZON IN THE TREATMENT OF TYPE-2 DIABETES

Hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes (T2D) mellitus. The various therapeutic classes of antidiabetic drugs presently existing in the market are not sufficiently effective in maintaining long-term glycemic control in most of the diabetic patients, even when used in combination. The undesirable adverse effects of these drugs, such as hypoglycemia, weight gain, and hepatic and renal toxicity, have escalated the demand for the discovery of new and safer antidiabetic drugs. The progressive nature of T2D requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. Sodium-glucose cotransporter 2 inhibitors (SGLT2-is) are the new class of antidiabetic medications that are approved (2013) by the Food and Drug Administration recently for treating diabetes. These inhibitors block the SGLT2 protein involved in glucose reabsorption from the proximal renal tubule resulting in escalated glucose excretion and lower blood glucose levels. These inhibitors exhibit favorable effects beyond glucose control, such as consistent body weight, blood pressure, and serum uric acid reductions. This review highlighted the brief updates of SGLT2-i, their benefits, and adverse effects.

2,4-Dinitrophenyl hydrazone derivatives as potent alpha amylase inhibitors

In our current study thirteen new 2,4-dinitrophenyl hydrazone derivatives 1–13 have been evaluated for alpha amylase activity. The molecular docking results indicate that compounds potentially bind in the catalytic site of the enzyme with excellent result. Molecular Operating Environment (MOE) software was used for docking study. 2,4-Dinitrophenyl hydrazone 1-13 have been obtained under reflux conditions by reacting dinitrophenyl hydrazine in methanol with different aromatic as well as aliphatic aldehydes in the presence of acetic acid act as a catalyst. The current results have shown that compounds 5 (IC50 =12.16µg/mL), 6 (IC50 =15.03µg/mL), and 12 (IC50 =16.42 µg/mL) have been found to be the more potent alpha amylase inhibitors as compared to the standard acarbose (IC50 = 42.47µg/mL). These compounds may provide better leads for alpha amylase inhibitor and further assessment of these compounds can be of great help in the discovery of new antidiabetic drugs.

Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties

Protein tyrosine phosphatase 1B (PTP1B) is a well-validated target in therapeutic interventions for type 2 diabetes mellitus (T2DM), however, PTP1B inhibitors containing negatively charged nonhydrolyzable pTyr mimetics are difficult to convert to the corresponding in vivo efficacy owing to poor cell permeability and oral bioavailability. In this work, molecules bearing less acidic heterocycle 2,4-thiazolidinedione and hydantoin were designed, synthesized and evaluated for PTP1B inhibitory potency, selectivity and in vivo antidiabetic efficacy. Among them, compound 5a was identified as a potent PTP1B inhibitor (IC50 = 0.86 μM) with 5-fold selectivity over the highly homologous TCPTP. Long-term oral administration of 5a at a dose of 50 mg/kg not only significantly reduced blood glucose levels, triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels but also ameliorated insulin sensitivity in diabetic BKS db mice. Moreover, 5a enhanced the insulin-stimulated phosphorylation of IRβ, IRS-1 and Akt in C2C12 myotubes. A histopathological evaluation of liver and pancreas demonstrated that 5a increased liver glycogen storage and improved islet architecture with more β-cells and fewer α-cells in diabetic mice. Thus, our work demonstrated that compound 5a could serve as a lead compound for the discovery of new antidiabetic drugs.

Wild-Type Zebrafish (Danio rerio) Larvae as a Vertebrate Model for Diabetes and Comorbidities: A Review.

Simple SummaryDiabetes is predicted to become a major global pandemic in the not too distant future; subsequently, there is an urgent need to develop new drugs to treat this disease and its associated complications. Animal studies form an integral component of drug development, as they provide information concerning safety and efficacy of new drugs in an experimental setting reflecting the complexity of human physiology. Over the past decade, research has firmly established that zebrafish represent a convenient preclinical animal model. While genetic manipulation has given rise to numerous target specific models, these mutant zebrafish are unfortunately also associated with serious disadvantages. Therefore, wild-type zebrafish may be a preferred option for many researchers; however, information relating to their use in diabetes research remains scattered. This review collates existing scientific literature specifically pertaining to wild-type zebrafish and highlights the value of wild-type zebrafish larvae as a suitable animal model. Details regarding organ development, including similarities to mammalian counterparts, are discussed to indicate relevance. In addition, information covering experimental design and endpoint analysis provides an overview of the technical aspects when using wild-type zebrafish larvae as an experimental tool to mimic diabetes and its associated complications.Zebrafish have become a popular alternative to higher animals in biomedical and pharmaceutical research. The development of stable mutant lines to model target specific aspects of many diseases, including diabetes, is well reported. However, these mutant lines are much more costly and challenging to maintain than wild-type zebrafish and are simply not an option for many research facilities. As an alternative to address the disadvantages of advanced mutant lines, wild-type larvae may represent a suitable option. In this review, we evaluate organ development in zebrafish larvae and discuss established methods that use wild-type zebrafish larvae up to seven days post fertilization to test for potential drug candidates for diabetes and its commonly associated conditions of oxidative stress and inflammation. This provides an up to date overview of the relevance of wild-type zebrafish larvae as a vertebrate antidiabetic model and confidence as an alternative tool for preclinical studies. We highlight the advantages and disadvantages of established methods and suggest recommendations for future developments to promote the use of zebrafish, specifically larvae, rather than higher animals in the early phase of antidiabetic drug discovery.

Target recognition and network pharmacology for revealing anti-diabetes mechanisms of natural product

Diabetes is a metabolic disease characterized by persistent hyperglycemia, which results in serious complications such as cardiovascular disorder, neuropathy, renal failure, and retinopathy. Various anti-diabetic drugs have been developed, however, their therapeutic effect is far from satisfactory. Therefore, increasing attention has been paid to natural products, whose multi-targets characteristics might contribute to treating polygenetic disease like diabetes. Indeed, valuable implications for anti-diabetic drug discovery can be obtained through exploring the molecular mechanism of these natural products, however, it could be a formidable task with traditional experimental approaches. As such, computational approaches are applied in predicting the compound-target interactions, including molecular docking, molecular dynamics (MD) simulations, and other computer aided drug design (CADD) methods. Furthermore, network pharmacology strategy is introduced for exploring natural products with anti-diabetic activities, including the general workflow of network pharmacology, its application in anti-diabetic traditional Chinese medicine formula research, and the application of natural products in diabetic complications. In particular, a promising prospective insight of combining computational methods and network pharmacology in anti-diabetic drug discovery is discussed. In summary, the combination of computational approaches and network pharmacology has already produced fruitful natural products with anti-diabetic effect, and will hopefully initiate novel anti-diabetic drug development with advanced therapeutic effect and less side effect.

Morusalisins A-F, six new Diels-Alder type adducts, as potential PTP1B inhibitors from cell cultures of Morus alba

Six new Diels-Alder type adducts, morusalisins A-F (1–6), were isolated from Morus alba cell cultures. The structures of 1–6 were determined by extensive spectroscopic data analysis, including HRESIMS, NMR, and ECD experiments. Furthermore, compounds 1–6 exhibited potent protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values ranging from 1.14 to 2.24 μM, making them promising as bioactive compounds for anti-diabetic drug discovery.

The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus

Diabetes mellitus (DM) is a chronic metabolic disorder affecting a vast number of people all around the world. Diabetes is mainly characterized by chronic hyperglycemia, resulting from defects in insulin secretion or insulin action, or both. To date, several glucose-lowering drugs have been used clinically. These drugs exert their anti-diabetic effect by stimulating insulin secretion, increasing peripheral absorption of glucose, delaying the absorption of carbohydrates from the intestine and reducing hepatic gluconeogenesis. The concern over effectiveness and side effects of currently available therapies in the treatment of Type 2 DM (T2DM) has promoted interest in discovery and development of natural antidiabetic drugs. Plants used in folk medicine to treat DM represent a viable alternative for the control of this disease. Several plants with antidiabetic properties exert their effects by inhibiting ATP-sensitive potassium (KATP) channels in the β-cell plasma membrane, resulting in membrane depolarization and stimulation of insulin release from insulin stores by exocytosis. In this article, we examined the results of earlier studies on the actions of natural compounds on pancreatic KATP channels. It is likely that these natural compounds can be employed as lead structures for the synthesis of therapeutic agents to treat T2DM in future clinical studies

Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery.

Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.