The findings in pertinent reported studies are reviewed, and the efficacy of various interventions for management of impaired glucose tolerance and type 2 diabetes in slowing the progression of IMT is analyzed.
Enzymatic subsite mapping earlier predicted 10 binding subsites in the active site substrate binding cleft of barley alpha-amylase isozymes. The three-dimensional structures of the oligosaccharide complexes with barley alpha-amylase isozyme 1 (AMY1) described here give for the first time a thorough insight into the substrate binding by describing residues defining 9 subsites, namely -7 through +2. These structures support that the pseudotetrasaccharide inhibitor acarbose is hydrolyzed by the active enzymes. Moreover, sugar binding was observed to the starch granule-binding site previously determined in barley alpha-amylase isozyme 2 (AMY2), and the sugar binding modes are compared between the two isozymes. The "sugar tongs" surface binding site discovered in the AMY1-thio-DP4 complex is confirmed in the present work. A site that putatively serves as an entrance for the substrate to the active site was proposed at the glycone part of the binding cleft, and the crystal structures of the catalytic nucleophile mutant (AMY1D180A) complexed with acarbose and maltoheptaose, respectively, suggest an additional role for the nucleophile in the stabilization of the Michaelis complex. Furthermore, probable roles are outlined for the surface binding sites. Our data support a model in which the two surface sites in AMY1 can interact with amylose chains in their naturally folded form. Because of the specificities of these two sites, they may locate/orient the enzyme in order to facilitate access to the active site for polysaccharide chains. Moreover, the sugar tongs surface site could also perform the unraveling of amylose chains, with the aid of Tyr-380 acting as "molecular tweezers."
The public health burden of type 2 diabetes mellitus has been dramatically increased worldwide. Not only its prevalence rate at present but the increase of its incidence in the near future can create a global health problem. The rapid increase of the total number of newly diagnosed diabetic patients proved to be associated with the increasing prevalence rate of obesity. The metabolic syndrome and type 2 diabetes can contribute to accelerated atherosclerosis and, therefore, the target organ damages can carry a serious problem for the individuals and also for the whole society. It is obvious, that the primary prevention of type 2 diabetes mellitus is of great importance. There is now substantial evidence that type 2 diabetes can be prevented or delayed by lifestyle interventions, i.e. diet and exercise should be the first choice in order to avoid weight gain when preventing diabetes. Pharmacological intervention should not be routinely used to prevent diabetes although results of large clinical trials with metformin and acarbose in subjects with impaired glucose tolerance are available. It is noteworthy that a decrease in the number of newly diagnosed diabetes was observed in prospective, double blind clinical studies evaluating the effect of new antihypertensive drugs (captopril, ramipril, lisinopril, nifedipine GITS, amlodipine, losartan) or lipid-lowering agents (pravastatin) on the cardiovascular morbidity and mortality in high risk patients. In these studies the relative risk reduction of newly diagnosed diabetes was evaluated in comparison to placebo or other drugs in a subgroup of non-diabetic patients at baseline. In addition, the incidence of newly diagnosed type 2 diabetes decreased parallel with weight loss in clinical trials with orlistat, an anti-obesity drug. Although new results were provided by evidence based clinical trials a lot of questions remained to be solved. Further research is necessary to understand better how to facilitate effective primary prevention of type 2 diabetes. Further data are needed to evaluate the clinical significance of currently used antidiabetic drugs and, in addition, the possible role of other drugs (antihypertensives, lipid lowering agents, anti-obesity drugs) should also be investigated in order to identify the optimal primary prevention policy of type 2 diabetes.
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The physiological functions of dietary fiber and its role in health promotion and risk reduction of some chronic diseases has been well documented. In the present investigation, the effect of three dietary fiber sources, oats (OA), barley (BA) and psyllium husk (PH) on glucose adsorption, diffusion and starch hydrolysis were studied using in vitro techniques by simulating gastrointestinal conditions and compared with the commercial dietary fiber sources wheat bran (WB), acarbose (ACB) and guar gum (GG). The glucose binding capacity of all the samples was higher than WB and ACB at 5 mM concentration. In all the samples, the diffusion of glucose was directly proportional to the time and diffusion rate was significantly lower (p ≤ 0.01) in the system containing various samples compared to control. Glucose dialysis retardation index (GDRI) was 100 for OA, BA and PH at 60 min, at 120 min the maximal GDRI was in PH. Whereas; WB and ACB exhibited maximal GDRI at 180 and 240 min. All of these mechanisms might create a concerted function in lowering the rate of glucose absorption and as a result, decrease the postprandial hyperglycemia.
We have a limited understanding of the details of molecular recognition of carbohydrates by proteins, which is critical to a multitude of biological processes. Furthermore, carbohydrate-modifying proteins such as glycosyl hydrolases and phosphorylases are of growing importance as potential drug targets. Interactions between proteins and carbohydrates have complex thermodynamics, and in general the specific positioning of only a few hydroxyl groups determines their binding affinities. A thorough understanding of both carbohydrate and protein structures is thus essential to predict these interactions. An atomic-level view of carbohydrate recognition through structures of carbohydrate-active enzymes complexed with transition-state inhibitors reveals some of the distinctive molecular features unique to protein-carbohydrate complexes. However, the inherent flexibility of carbohydrates and their often water-mediated hydrogen bonding to proteins makes simulation of their complexes difficult. Nonetheless, recent developments such as the parameterization of specific force fields and docking scoring functions have greatly improved our ability to predict protein-carbohydrate interactions. We review protein-carbohydrate complexes having defined molecular requirements for specific carbohydrate recognition by proteins, providing an overview of the different computational techniques available to model them.
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Our findings suggest chlorpropamide, glipizide, glyburide, insulin, and rosiglitazone increased severity-adjusted mortality in veterans with type 2 diabetes. A decision aid that could optimize selection of hypoglycemic medications based on patients' comorbidities might increase patients' survival.
Inhibitors of intestinal alpha-glucosidases are used therapeutically to treat type 2 diabetes mellitus. Bacteria such as Actinoplanes sp. naturally produce potent alpha-glucosidase inhibitor compounds, including the most widely available drug acarbose. It is not known whether lactic acid bacteria (LAB) colonising the human gut possess inhibitory potential against glucosidases. Hence, the study was undertaken to screen LABs having inherent alpha- and beta-glucosidase inhibitory potential.
A simple and rapid CZE method was established for the simultaneous determination of valienamine, acarbose and validamycin A, using a 20-kV CZE with the detection wavelength of 193 nm and 50 mM phosphoric acid-20 mM Tris (pH 5.3) as a running buffer. The calibration curves of valienamine, acarbose, and validamycin A showed a good linear relationship at a concentration range of 5-1000 microg/mL. The detection limits of valienamine, acarbose, and validamycin A were 0.3, 0.6, and 0.6 microg/mL, respectively, and the average recoveries of each of the above were 99.9, 99.5, and 100.3%. The method has been successfully applied for simultaneous determination of substrate and product in the process of preparation of valienamine.
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The α-glucosidase inhibitory effects of five bioactive components, namely 1-deoxynojirimycin, cyanidin-3-glucoside, cyanidin-3-rutinoside, resveratrol and oxyresveratrol contained in mulberry (Morus, Moraceae) plants have been compared. Spectroscopy methods were employed to compare their α-glucosidase inhibitory mechanisms. The results revealed that 1-deoxynojirimycin (competitive), resveratrol and oxyresveratrol (noncompetitive) were stronger inhibitors than acarbose, while cyanidin-3-glucoside and cyanidin-3-rutinoside (mix competitive and noncompetitive) showed modest activities. 1-Deoxynojirimycin, resveratrol and oxyresveratrol could quench the fluorescence spectra statically by forming stable complexes, while the quenching of cyanidin-3-rutinoside and cyanidin-3-glucoside belonged to dynamic quenching by the collision of molecules. The interactions between ligands and α-glucosidase were mainly driven by hydrophobic force, or hydrogen bonding consequently induced conformational changes and reduced surface hydrophobicity. Docking results suggested that they could bind to α-glucosidase at different sites. This work provides useful information for the understanding of the ligands-α-glucosidase interactions and identifies oxyresveratrol as a potent α-glucosidase inhibitor.
The diabetic patients had a significantly higher probability of receiving potential detection examinations (6.38% vs. 5.83%, P<0.0001). After multivariable-adjustment, the OR (95% CI) for diabetes status was 0.816 (0.652-1.021); and for diabetes duration <1 year, 1-3 years, 3-5 years and ≥ 5 years vs. non-diabetes was 0.071 (0.010-0.507), 0.450 (0.250-0.813), 0.374 (0.203-0.689) and 1.159 (0.914-1.470), respectively. Among the anti-diabetic agents, only sulfonylurea was significantly associated with thyroid cancer, OR (95% CI): 1.882 (1.202-2.947). The OR (95% CI) for insulin, metformin, acarbose, pioglitazone and rosiglitazone was 1.701 (0.860-3.364), 0.696 (0.419-1.155), 0.581 (0.202-1.674), 0.522 (0.069-3.926) and 0.669 (0.230-1.948), respectively. Furthermore, patients with benign thyroid disease or other cancer, living in Kao-Ping/Eastern regions, or receiving potential detection examinations might have a significantly higher risk; and male sex, hypertension, dyslipidemia, chronic obstructive pulmonary disease, vascular complications or use of statin, aspirin or non-steroidal anti-inflammatory drugs might be associated with a significantly lower risk.
Postprandial glucose and insulin levels were similar in the 3 groups. Postprandial endothelial dysfunction was similar in the 3 groups before treatment. After 12 weeks of intervention, postprandial FMD was significantly improved in the acarbose group compared with the control group (6.8 +/- 1.3% vs 5.2 +/- 1.1%, p = 0.0022). Area under the curve (AUC) for insulin response was significantly increased in the nateglinide and control groups; however, no significant change was observed in the acarbose group.
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The present investigation was undertaken to explore the possible antiparasitic potential and α-glucosidase inhibition by compounds derived from the Panamanian mangrove Pelliciera rhizophorae. Bioassay-guided fractionation of the crude extract led to the isolation of ten chemical compounds: α-amyrine (1), β-amyrine (2), ursolic acid (3), oleanolic acid (4), betulinic acid (5), brugierol (6) iso-brugierol (7), kaempferol (8), quercetin (9), and quercetrin (10). The structures of these compounds were established by spectroscopic analyses including APCI-HR-MS and NMR. Compounds 4 (IC50 = 5.3 µM), 8 (IC50 = 22.9 µM) and 10 (IC50 = 3.4 µM) showed selective antiparasitic activity against Leishmania donovani, while compounds 1 (IC50 = 19.0 µM) and 5 (IC50 = 18.0 µM) exhibited selectivity against Tripanosoma cruzi and Plasmodium falciparum, respectively. Moreover, compounds 1-5 inhibited α-glucosidase enzyme in a concentration-dependent manner with IC50 values of 1.45, 0.02, 1.08, 0.98 and 2.37 µM, respectively. Their inhibitory activity was higher than that of antidiabetic drug acarbose (IC50 217.7 µM), used as a positive control. Kinetic analysis established that the five compounds acted as competitive inhibitors. Docking analysis predicted that all triterpenes bind at the same site that acarbose in the human intestinal α-glucosidase (PDB: 3TOP).
Between Feb 7, 2011, and Nov 7, 2012, 402 patients were enrolled (199 in the premix group, 203 in the basal-bolus group) and 399 were included in the primary analysis (197 in the premix group, 202 in the basal-bolus group). HbA1c change at week 24 was -1.1% for both treatment groups. The least squares mean difference between groups in HbA1c change from baseline was 0% (95% CI -0.1 to 0.2). Insulin lispro mix was non-inferior to basal-bolus therapy based on the prespecified margin of 0.4%. The frequency of adverse events, and the incidences and 30-day rates of nocturnal and overall hypoglycaemia were comparable between groups. No severe hypoglycaemia was reported.
To evaluate the effect of acarbose on glycemic control and glycemic variability, using a continuous glucose-monitoring system, in patients with type 2 diabetes mellitus who were not well controlled on metformin and vildagliptin therapy.
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Pharmacological intervention with a variety of agents (thiazolidinediones, metformin, acarbose, glucagon-like peptide-1 analogs) consistently reduces the rate of conversion of IGT to T2DM.
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Acarbose reduced excessive blood glucose fluctuations.
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Terminalia sericea extract (IC(50)=92mg/ml) exhibited a considerable alpha-glucosidase inhibitory activity which was better than acarbose (IC(50)=131mg/ml) under our assay conditions. In the reverse transcriptase assay, T. sericea also showed good inhibitory activity (IC(50)=43mg/ml), which was higher than that of the reference drug, Adriamycin (IC(50)=100mg/ml). The ethyl acetate extract of Elaeodendron transvaalense exhibited the most potent inhibitory activity in both the NF-kappaB and Tat assays with inhibitory activity of 76% and 75% respectively at a concentration of 15mg/ml. The acetone and chloroform extracts of E. transvaalense and Zanthoxylum davyi also showed good activity in the NF-kappaB and Tat assays.
There were significantly more responders in the acarbose-treated group compared with the placebo group (20/24 patients vs. 10/19 patients; p < 0.05). The mean daily insulin dose after 24 weeks of treatment was 16.4 +/- 10.1 IU in the acarbose group and 22.4 +/- 12.2 IU in the placebo group (mean +/- s.d.; p < 0.07). Postprandial increases in blood glucose, insulin and C-peptide were consistently lower in the acarbose-treated group than in the placebo group. For example, the mean increase in 2-h postprandial serum insulin remained almost unchanged in the acarbose group at the end of 24 weeks of treatment compared to an increase to 43 +/- 29 microU/ml (mean +/- s.d.) at the end of the study period for the placebo group.