ABSTRACT
Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune syndrome induced by carbimazole in a middle-aged Chinese man with underlying Graves' disease, which was managed conservatively with a combination of dietary modification and alpha-glucosidase inhibitor.
Subject(s)
Antithyroid Agents , Autoimmune Diseases , Carbimazole , Graves Disease , Humans , Male , Autoimmune Diseases/chemically induced , Graves Disease/drug therapy , Graves Disease/immunology , Carbimazole/therapeutic use , Antithyroid Agents/adverse effects , Antithyroid Agents/therapeutic use , Middle Aged , Insulin , Insulin Antibodies/blood , Syndrome , Glycoside Hydrolase Inhibitors/therapeutic use , Glycoside Hydrolase Inhibitors/adverse effectsABSTRACT
The coronavirus disease (COVID-19) pandemic has continued for 5 years. Sporadic cases continue to occur in different locations. Type 2 diabetes mellitus (T2DM) is associated with a high risk of a poor prognosis in patients with COVID-19. Successful control of blood glucose levels can effectively decrease the risks of severe infections and mortality. However, the effects of different treatments were reported differently and even adversely. This retrospective study included 4,922 patients who have been diagnosed as COVID-19 and T2DM from 138 Hubei hospitals. The clinical characteristics and outcomes were compared and calculated their risk for death using multivariate Cox regression and Kaplan-Meier curves. After adjustment of age, sex, comorbidities, and in-hospital medications, metformin and alpha-glucosidase inhibitor (AGI) use performed lower all-cause mortality (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.24-0.71; p = 0.001 for metformin; 0.53, 0.35-0.80, p = 0.002 for AGIs), while insulin use was associated with increased all-cause mortality (adjusted HR, 2.07, 95% CI, 1.61-2.67, p < 0.001). After propensity score-matched (PSM) analysis, adjusted HRs for insulin, metformin, and AGIs associated with all-cause mortality were 1.32 (95% CI, 1.03-1.81; p = 0.012), 0.48 (95% CI, 0.23-0.83, p = 0.014), and 0.59 (95% CI, 0.35-0.98, p = 0.05). Therefore, metformin and AGIs might be more suitable for patients with COVID-19 and T2DM while insulin might be used with caution.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Metformin , Humans , Diabetes Mellitus, Type 2/mortality , Diabetes Mellitus, Type 2/drug therapy , COVID-19/mortality , Male , Female , Retrospective Studies , Middle Aged , China/epidemiology , Aged , Metformin/therapeutic use , Hypoglycemic Agents/therapeutic use , SARS-CoV-2 , Insulin/therapeutic use , Glycoside Hydrolase Inhibitors/therapeutic use , AdultABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus, a widespread chronic illness, affects millions worldwide, and its incidence is increasing alarmingly, especially in developing nations. Current pharmacological treatments can be costly and have undesirable side effects. To address this, medicinal plants with antidiabetic effects, particularly targeting α-glucosidase for controlling hyperglycaemia in type-2 diabetes mellitus (T2DM), hold promise for drug development with reduced toxicity and adverse reactions. AIM OF THIS REVIEW: This review aims to succinctly collect information about medicinal plant extracts that exhibit antidiabetic potential through α-glucosidase inhibition using acarbose as a standard reference in Southeast Asia. The characteristics of this inhibition are based on in vitro studies. MATERIALS AND METHODS: Relevant information on medicinal plants in Southeast Asia, along with α-glucosidase inhibition studies using acarbose as a positive control, was gathered from various scientific databases, including Scopus, PubMed, Web of Science, and Google Scholar. RESULTS: About 49 papers were found from specific counties in Southeast Asia demonstrated notable α-glucosidase inhibitory potential of their medicinal plants, with several plant extracts showcasing activity comparable to or surpassing that of acarbose. Notably, 19 active constituents were identified for their α-glucosidase inhibitory effects. CONCLUSIONS: The findings underscore the antidiabetic potential of the tested medicinal plant extracts, indicating their promise as alternative treatments for T2DM. This review can aid in the development of potent therapeutic medicines with increased effectiveness and safety for the treatment of T2DM.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents , Plant Extracts , Plants, Medicinal , Diabetes Mellitus, Type 2/drug therapy , Humans , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Plants, Medicinal/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Asia, Southeastern , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Animals , alpha-Glucosidases/metabolism , PhytotherapyABSTRACT
One of the most effective therapeutic decencies in the treatment of Type 2 Diabetes Mellitus is the inhibition of α-glucosidase enzyme, which is present at the brush border of the intestine and plays an important role in carbohydrate digestion to form mono-, di-, and polysaccharides. Acarbose, Voglibose, Miglitol, and Erniglitate have been well-known α-glucosidase inhibitors in science since 1990. However, the long synthetic route and side effects of these inhibitors forced the researchers to move their focus to innovate simple and small heterocyclic scaffolds that work as excellent α-glucosidase inhibitors. Moreover, they are also effective against the postprandial hyperglycemic condition in Type 2 Diabetes Mellitus. In this aspect, this review summarizes recent progress in the discovery and development of heterocyclic molecules that have been appraised to show outstanding inhibition of α-glucosidase to yield positive effects against diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Heterocyclic Compounds , Hypoglycemic Agents , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Humans , alpha-Glucosidases/metabolism , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/chemical synthesis , Animals , Molecular Structure , Structure-Activity RelationshipABSTRACT
Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).
Subject(s)
Glycogen Storage Disease Type I , Glycoside Hydrolase Inhibitors , Humans , Glycogen Storage Disease Type I/complications , Glycogen Storage Disease Type I/diagnosis , Glycoside Hydrolase Inhibitors/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Male , Blood Glucose/metabolism , Female , Hypoglycemic Agents/therapeutic use , Adult , Hyperglycemia/complications , Hyperglycemia/diagnosisABSTRACT
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.
Subject(s)
Diabetes Mellitus, Type 2 , Nitroimidazoles , Rats , Animals , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , alpha-Glucosidases/metabolism , Acarbose/pharmacology , Acarbose/therapeutic use , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Molecular Docking Simulation , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Imidazoles/pharmacology , Imidazoles/therapeutic use , Nitroimidazoles/therapeutic use , Structure-Activity Relationship , Molecular StructureABSTRACT
Existing drugs that are being used to treat type-2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been explored as antidiabetic agents. In this study, a series of new indenoquinoxaline-phenylacrylohydrazide hybrids (1-30) were synthesized, structurally characterized, and evaluated for α-amylase and α-glucosidase inhibitory activities, as well as for their antioxidant properties. All scaffolds exhibited varying degrees of inhibitory activity against both enzymes, with IC50 values ranging from 2.34 to 61.12 µM for α-amylase and 0.42 to 54.72 µM for α-glucosidase. Particularly, compounds 10, 16, 17, 18, 24, and 25 demonstrated the highest efficacy in inhibiting α-amylase, while compounds 6, 7, 8, 10, 12, 14, 13, 16, 17, 18, 24, and 25 were the most effective α-glucosidase inhibitors, compared to standard acarbose. Moreover, most of these compounds displayed substantial antioxidant potential compared to standard butylated hydroxytoluene (BHT). Kinetics studies revealed competitive inhibition modes by compounds. Furthermore, a comprehensive in silico study and toxicity prediction were also conducted, further validating these analogs as potential drug candidates. The structured compounds demonstrated enhanced profiles, underscoring their potential as primary candidates in drug discovery.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/drug therapy , Antioxidants/pharmacology , Antioxidants/therapeutic use , alpha-Glucosidases/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , alpha-Amylases/metabolism , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
α-Amylase is a generally acknowledged molecular target of a distinct class of antidiabetic drugs named α-glucosidase inhibitors. This class of medications is scarce and rather underutilized, and treatment with current commercial drugs is accompanied by unpleasant adverse effects. However, mammalian α-amylase inhibitors are abundant in nature and form an extensive pool of high-affinity ligands that are available for drug discovery. Individual compounds and natural extracts and preparations are promising therapeutic agents for conditions associated with impaired starch metabolism, e.g., diabetes mellitus, obesity, and other metabolic disorders. This review focuses on the structural diversity and action mechanisms of active natural products with inhibitory activity toward mammalian α-amylases, and emphasizes proteinaceous inhibitors as more effective compounds with significant potential for clinical use.
Subject(s)
Metabolic Diseases , alpha-Amylases , Animals , Humans , alpha-Amylases/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Glycoside Hydrolase Inhibitors/chemistry , Metabolic Diseases/drug therapy , alpha-Glucosidases/chemistry , Plant Extracts/therapeutic use , Mammals/metabolismABSTRACT
Among antihyperglycemic drugs used for treating diabetes, α-glucosidase inhibitors generate the least adverse effects. This contribution aimed to evaluate the potential antidiabetic activity of Rumex crispus L. by testing its in vitro α-glucosidase inhibition and in vivo antihyperglycemic effects on rats with streptozotocin (STZ)-induced diabetes. Better inhibition of α-glucosidase was found with the methanol extract versus the n-hexane and dichloromethane extracts. The methanol extract of the flowers (RCFM) was more effective than that of the leaves (RCHM), with an IC50 of 7.3 ± 0.17 µg/mL for RCFM and 112.0 ± 1.23 µg/mL for RCHM. A bioactive fraction (F89s) also showed good α-glucosidase inhibition (IC50 = 3.8 ± 0.11 µg/mL). In a preliminary study, RCHM and RCFM at 150 mg/kg and F89s at 75 mg/kg after 30 days showed a significant effect on hyperglycemia, reducing glucose levels (82.2, 80.1, and 84.1%, respectively), and improved the lipid, renal, and hepatic profiles of the rats, comparable with the effects of metformin and acarbose. According to the results, the activity of R. crispus L. may be mediated by a diminished rate of disaccharide hydrolysis, associated with the inhibition of α-glucosidase. Thus, R. crispus L. holds promise for the development of auxiliary drugs to treat diabetes mellitus.
Subject(s)
Diabetes Mellitus, Experimental , Rumex , Rats , Animals , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , alpha-Glucosidases , Methanol , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Plant Leaves , Diabetes Mellitus, Experimental/drug therapy , FlowersABSTRACT
Diabetes is one of the most common metabolic diseases in humans and the use of herbal medicines is of great clinical importance to inhibit carbohydrate-hydrolyzing enzymes and reduce blood glucose levels in diabetic patients. Inhibition of glycosidase activity is an effective way to treat and prevent diabetes. Therefore, in this study, curcumin-based benzaldehyde derivatives were synthesized and used as influential agents in the treatment of diabetes with inhibitory properties against two carbohydrate-hydrolyzing enzymes α-glucosidase (α-Glu) and α-amylase (α-Amy) as significant therapeutic targets for reducing postprandial hyperglycemia. Overall, the findings showed that due to the specific inhibitory activity against α-Glu in comparison with α-Amy, as well as more stability and antioxidant activity than curcumin, C5 and C8 derivatives are potentially important anti-diabetic drugs, not only to decrease glycemic index but also to limit the activity of the main production pathways of reactive oxygen species (ROS) in diabetic patients.Communicated by Ramaswamy H. Sarma.
Subject(s)
Curcumin , Diabetes Mellitus , Humans , Curcumin/pharmacology , Hypoglycemic Agents/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Glycoside Hydrolases , alpha-Glucosidases/metabolism , alpha-Amylases , Diabetes Mellitus/drug therapy , CarbohydratesABSTRACT
Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. It is a well-recognized multifactorial health problem contributes significantly to high mortality rates by causing serious health complications mainly related to cardiovascular diseases, kidney damage and neuropathy. The inhibition of α-glucosidase (enzyme that catalyses starch hydrolysis in the intestine) is an effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes. However, the presently approved drugs/inhibitors such as acarbose, miglitol and voglibose have several undesirable gastrointestinal side effects impeding their applications. Therefore, search for novel and more effective inhibitors with reduced side effects and less cost remains a fascinating area of research. In this context, a large variety of α-glucosidase inhibitors have been identified in recent years that demands attention from drug development community. This review is therefore an effort to summarize and highlight the promising α-glucosidase inhibitors especially those which are primarily based on aromatic heterocyclic scaffolds such as coumarin, imidazole, isatin, pyrimidine, quinazoline, triazine, thiazole etc, having improved safety and pharmacological profiles.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Humans , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Acarbose/pharmacology , Acarbose/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , alpha-GlucosidasesABSTRACT
Medicinal plants (MPs) are natural sources of active compounds with potential therapeutic benefits in alleviating various illnesses for decades. Fijian people also are using these MPs for the management/prevention of Type 2 diabetes mellitus (T2DM) and associated complications. However, till date, none of these Fijian MP's antidiabetic potential have been explored or evaluated. Here, we investigated the antidiabetic potential of Fijian MPs scientifically. Phytochemicals such as polyphenols were detected to inhibit the activity of α-amylase and α-glucosidase, the two key carbohydrate enzymes linked to T2DM. Therefore, in the present study, the total phenolic content (TPC), α-amylase and α-glucosidase inhibitory activity of five Fijian MPs: Vobo (Mussaenda raiateensis, MR), Vula walu (Blechnum orientale, BO), Gasau (Miscanthus floridulus, MF), Molikaro (Citrus limon, CL) and Beki ni sina (Dicranopteris caudate, DC) collected from mainland region of Vitilevu, Fiji Islands, were evaluated in vitro. The hydromethanolic (ME) and dichloromethane (DM) extracts of these selected MPs were investigated. The ME extracts of BO (0.102 ± 0.009 mM CE) and DC (0.098 ± 0.09 mM Catechin Equivalence [CE]) showed a higher TPC compared with the control [vanillic acid (0.052 ± 0.003 mM CE, *P value < 0.05)]. However, the TPC of MF, MR and CL were found in the range of 0.020 ± 0.009 to 0.009 ± 0.01 mM CE. The ME extracts of MF and MR inhibited α-glucosidase significantly in comparison with acarbose as evidenced from the IC50 values (IC50 of MF = 1.58 ± 0.03 ng/µl; IC50 of MR = 1.87 ± 0.43 ng/µl and IC50 of acarbose = 3.34 ± 0.15 ng/µl). Moreover, DM extracts of MR (IC50 = 1.31 ± 0.29 ng/µl) also showed significantly higher α-glucosidase inhibitory activity. In contrary, MR (IC50 = 16.18 ± 0.16 ng/µl) and CL (IC50 = 9.21 ± 0.51 ng/µl) also showed significant α-amylase inhibitory activity in ME and DM extracts, respectively. These, results suggest that Fijian MPs could be a potential source of natural inhibitors of enzymes involved in carbohydrate digestion and thus may possibly be used in managing T2DM.
Subject(s)
Diabetes Mellitus, Type 2 , Plants, Medicinal , Plants, Medicinal/chemistry , Diabetes Mellitus, Type 2/drug therapy , alpha-Glucosidases/therapeutic use , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/therapeutic use , Acarbose/therapeutic use , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Extracts/chemistry , alpha-Amylases , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/chemistry , Phenols/pharmacologyABSTRACT
Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.
Subject(s)
Glucuronidase , Glycoside Hydrolase Inhibitors , Neoplasm Metastasis , Animals , Cell Proliferation/drug effects , Glucuronidase/antagonists & inhibitors , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Heparan Sulfate Proteoglycans/metabolism , Heparitin Sulfate/metabolism , Humans , Mice , Neoplasm Metastasis/drug therapyABSTRACT
AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.
Subject(s)
Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors/adverse effects , Hypoglycemic Agents/adverse effects , Cardiovascular Diseases/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Glycoside Hydrolase Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels and can lead to serious complications such as nephropathy, neuropathy, retinopathy and cardiovascular disease. The aim of this work is to identify and investigate the inhibition mechanism of natural flavonoids and phenolics acids against, the α-amylase (αA) and α-glucosidase (αG). Therefore, we used different approaches; such as conceptual DFT and pharmacophore mapping in addition to molecular mechanics, dynamics and docking simulations. Whereas, a close agreement was found out to decide that Linarin (Flavones) provides more optimized inhibition of αA and αG enzymes. Our results have shown that Linarin could be useful as preventative agent, and possibly therapeutic modality for the treatment of metabolic diseases.Communicated by Ramaswamy H. Sarma.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Diabetes Mellitus, Type 2/drug therapy , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Humans , Molecular Docking Simulation , alpha-Amylases/metabolism , alpha-Glucosidases/metabolismABSTRACT
Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.
Subject(s)
Diabetes Mellitus, Type 2/enzymology , Hypoglycemic Agents/pharmacology , Plants, Medicinal/chemistry , Polyphenols/pharmacology , alpha-Amylases/metabolism , alpha-Glucosidases/metabolism , Computer Simulation , Diabetes Mellitus, Type 2/drug therapy , Drug Evaluation, Preclinical , Gene Expression Regulation, Enzymologic/drug effects , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Humans , Hydrogen Bonding , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Molecular Docking Simulation , Polyphenols/chemistry , Polyphenols/therapeutic use , alpha-Amylases/chemistry , alpha-Glucosidases/chemistrySubject(s)
Enzyme Replacement Therapy/methods , Gangliosidoses, GM2/therapy , Genetic Therapy/methods , beta-Hexosaminidase alpha Chain/genetics , beta-Hexosaminidase beta Chain/genetics , Age of Onset , Animals , Cerebellum/pathology , Disease Models, Animal , G(M2) Ganglioside/antagonists & inhibitors , G(M2) Ganglioside/metabolism , Gangliosidoses, GM2/genetics , Gangliosidoses, GM2/pathology , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/therapeutic use , Gray Matter/pathology , Humans , Mutation , Retina/pathology , Spinal Cord/pathology , White Matter/pathology , beta-Hexosaminidase alpha Chain/metabolism , beta-Hexosaminidase beta Chain/metabolismABSTRACT
Phellodendron chinense Schneid. was widely used as a medicinal herb for the treatment of diabetic osteoporosis in China. In this study, an arabinogalactan, named as PPCP-1, was isolated from the bark of Phellodendron chinense Schneid., and purified by DEAE-cellulose DE52 and Sephacryl S-200 HR column chromatography. The structure of PPCP-1 was characterized as a repeating unit consisting of â3)-ß-d-Galp-(1â, â3,6)-ß-d-Galp-(1â, â5)-α-l-Araf-(1â, â4)-α-d-Glcp-(1â, â3)-α-d-Glcp-(1â, â4)-α-d-Manp-(1â with branches of â5)-α-l-Araf-(1â, â3,5)-α-l-Araf-(1â and terminal α-l-Araf. Pharmacologically, the oral administration of PPCP-1 preserved osteoporosis associated with hyperglycemia by inhibiting α-glucosidase activity, improving glucose tolerance, decreasing the accumulation of advanced glycation end products (AGEs), as well as down-regulating the expression of receptor for AGEs in tibias of streptozotocin-induced diabetic rats. Collectively, the present study suggested that the arabinogalactan PPCP-1 from Phellodendron chinense Schneid. might potentially be used as functional foods for bone health and/or developed for drug discovery for alleviating diabetic osteoporosis.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Galactans/therapeutic use , Hypoglycemic Agents/therapeutic use , Osteoporosis/prevention & control , Phellodendron/chemistry , Animals , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/isolation & purification , Diabetes Mellitus, Experimental/complications , Galactans/chemistry , Galactans/isolation & purification , Glycation End Products, Advanced/metabolism , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/isolation & purification , Glycoside Hydrolase Inhibitors/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/isolation & purification , Lysine/analogs & derivatives , Lysine/metabolism , Male , Osteoporosis/etiology , Rats, Wistar , Receptor for Advanced Glycation End Products/metabolismABSTRACT
5-C-Alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives have been designed and synthesized efficiently from an l-sorbose-derived cyclic nitrone. The DNJ and l-ido-DNJ derivatives with C-5 alkyl chains ranging from methyl to dodecyl were assayed against various glycosidases to study the effect of chain length on enzyme inhibition. Glycosidase inhibition study of DNJ derivatives showed potent and selective inhibitions of α-glucosidase; DNJ derivatives with methyl, pentyl to octyl, undecyl and dodecyl as C-5 branched chains showed significantly improved rat intestinal maltase inhibition. In contrast, most 5-C-alkyl-l-ido-DNJ derivatives were weak or moderate inhibitors of the enzymes tested, with only three compounds found to be potent α-glucosidase inhibitors. Docking studies showed different interaction modes of 5-C-ethyl-DNJ and 5-C-octyl-DNJ with ntMGAM and also different binding modes of 5-C-alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives; the importance of the degree of accommodation of the C-5 substituent in the hydrophobic groove and pocket may account for the variation of glycosidase inhibition in the two series of derivatives. The results reported herein are helpful in the design and development of α-glucosidase inhibitors; this may lead to novel agents for the treatment of viral infection and type II diabetes.
Subject(s)
Glycoside Hydrolase Inhibitors/therapeutic use , Glycoside Hydrolases/metabolism , Molecular Docking Simulation/methods , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.