Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes mellitus is associated with clustering of cardiovascular risk factors that may greatly increase individuals' risk of developing coronary artery disease. Type 2 diabetes is believed to impair coronary function. However, its impact on the vasomotor function of coronary resistance vessels in humans is still debated. Reduced, preserved or even augmented dilations of coronary arterioles have been reported in subjects with type 2 diabetes. Interestingly, recent studies have suggested that reactive oxygen species (ROS), particularly hydrogen peroxide, may compensate for the loss of the vasodilatory function of coronary microvessels during disease development. Recent interventional clinical trials have yielded largely negative results, and there has even been some suggestion of harm caused by attempts to reduce ROS. Thus, it is possible that interference with ROS-related signaling might paradoxically temper the function of coronary microvessels, predisposing patients to myocardial ischemia. In this review, we aim to highlight current findings supporting a potential role for ROS in preserving coronary arteriolar dilation in type 2 diabetes mellitus.
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PMID:Preserved coronary arteriolar dilatation in patients with type 2 diabetes mellitus: implications for reactive oxygen species. 1930 97

The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7h post-intragastric administration.
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PMID:Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity. 1936 87

Advanced glycation end products (AGEs) contribute to the pathogenesis of diabetes-associated complications. Previously, we reported the possible effect of pyridoxamine (K-163), an AGE inhibitor, on improvement of glucose intolerance in type 2 diabetes mellitus KK-A(y)/Ta mice. Recently, AGEs and oxidative stress have been shown to induce insulin resistance. The objective of the present study is to examine the effect of pyridoxamine on glucose intolerance and oxidative stress. C57BL/6J mice were divided into 3 groups as follows: low-fat diet, high-fat diet, and high-fat diet with pyridoxamine treatment. Body and adipose tissue weight, serum insulin, hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2'-deoxyguanosine levels were measured. Nicotinamide adenine dinucleotide phosphate subunits, antioxidant enzymes, and adipocytokine messenger RNA expressions in the adipose tissues were evaluated. Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle were also evaluated. Body and adipose tissue weights of the pyridoxamine treatment group were significantly decreased compared with those of the high-fat diet group. Pyridoxamine attenuated serum hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2'-deoxyguanosine and nicotinamide adenine dinucleotide phosphate oxidase expression; increased antioxidant enzyme expression; and improved dysregulation of adipocytokines in adipose tissues. Pyridoxamine improved blood glucose levels after glucose injection and fasting hyperinsulinemia. Suppressed Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle in high-fat diet mice were improved by pyridoxamine treatment. It appears that the antioxidative effect of pyridoxamine is associated with improvement of glucose intolerance and obesity in C57BL/6J mice fed a high-fat diet. We assume that pyridoxamine may be useful in the treatment of the obesity-associated metabolic syndrome.
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PMID:Effects of pyridoxamine (K-163) on glucose intolerance and obesity in high-fat diet C57BL/6J mice. 1942 56

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPAR gamma that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPAR gamma. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPAR gamma target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPAR gamma responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPAR gamma through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes.
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PMID:INT131: a selective modulator of PPAR gamma. 1945 30

Three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried out to explore the binding of 73 inhibitors to dipeptidyl peptidase IV (DPP-IV), and to construct highly predictive 3D-QSAR models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The negative logarithm of IC(50) (pIC(50)) was used as the biological activity in the 3D-QSAR study. The CoMFA model was developed by steric and electrostatic field methods, and leave-one-out cross-validated partial least squares analysis yielded a cross-validated value (r(2)(cv)) of 0.759. Three CoMSIA models developed by different combinations of steric, electrostatic, hydrophobic and hydrogen-bond fields yielded significant r(2)(cv) values of 0.750, 0.708 and 0.694, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified test set of 18 compounds. All of the test compounds were predicted accurately using these models. The mean and standard deviation of prediction errors were within 0.33 and 0.26 for all models. Analysis of CoMFA and CoMSIA contour maps helped identify the structural requirements of inhibitors, with implications for the design of the next generation of DPP-IV inhibitors for the treatment of type 2 diabetes.
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PMID:Molecular docking and 3D-QSAR studies on beta-phenylalanine derivatives as dipeptidyl peptidase IV inhibitors. 2006 22

Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20A away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.
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PMID:Comparative docking assessment of glucokinase interactions with its allosteric activators. 2016 45

Genipin is aglycone of geniposide, one of the active compounds of Gardenia gasminoides Ellis. The gardenia fruit extract has been used in traditional Chinese medicine to relieve the symptoms of type 2 diabetes that is accompanied with extensive oxidative stress and endothelial dysfunction of NO production. Besides, genipin was shown to inhibit UCP-depended proton leak through the inner mitochondrial membrane that leads to increased membrane potential and ATP production. We studied the effects of genipin at ischemia/reperfusion-induced oxidative stress and activity of NOS isozymes using Langendorfperfused old rat heart model. Ischemia/reperfusion is well-known oxidative agent, and showed significant increasing of superoxide radical, hydrogen peroxide and hydroxyl radical. Genipin application in doze 10-5 mol/L for 15 min before prolonged ischemia exerted powerful antiradical and antilipoperoxidative effects. Heart ischemia/reperfusion was supported with peroxynitrite generation and nitrozative stress. We demonstrated the inhibitory property of genipin on INOS expression that possibly occurs via protein kinase A inhibition and stabilization of I-kappaB-NF-kappaB complex. Genipin stimulated cNOS activity seemingly activating PI3K/Akt signaling pathway. Although, post-ischemic recovery ofcardiodynamic parameters of old rat hearts were depressed due to "switching off" the NO production by inducible NOS which is important in early period of reperfusion. Thus, we conclude that genipin is powerfull antioxidant and posses insulin-like activity due to its property of managing the NO production at intracellular signal transduction cascade level.
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PMID:[Effects of uncoupling proteins on nitric oxide synthesis and oxidative stress development in ishemia-reperfusion of old rat hearts]. 2020 83

Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (GLP-1R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 and the long-acting agonist exendin-4 stimulated cell proliferation and increased cell viability by 2-fold at 24 h at physiologically relevant concentrations. This GLP-1R-dependent action was mediated via the protein kinase A and phosphoinositide 3-kinase signaling pathways, with the MAPK pathway playing a minor role. GLP-1 and exendin-4 pretreatment dose-dependently protected SH-hGLP-1R#9 cells from hydrogen peroxide (H(2)O(2))- and 6-hydroxydopamine-induced cell death. This involved amelioration of elevated caspase 3 activity, down-regulation of pro-apoptotic Bax and up-regulation of anti-apoptotic Bcl-2 protein. In the presence of 6-hydroxydopamine, GLP-1's ability to lower caspase-3 activity was abolished with the phosphoinositide 3-kinase inhibitor, LY2940002, and partly reduced with the protein kinase A inhibitor, H89. Hence, GLP-1R mediated neurotrophic and anti-apoptotic actions co-contribute to the neuroprotective property of GLP-1 in neuronal cell cultures, and reinforce the potential therapeutic value of GLP-1R agonists in neurodegenerative disorders involving oxidative stress.
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PMID:Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. 2037 30

Scavenging of the vasodilator nitric oxide by myeloperoxidase activity in the vasculature may contribute to hypertension. Because hydrogen peroxide is a cosubstrate of myeloperoxidase, hyperglycemia-induced oxidative stress may strengthen the relationship between myeloperoxidase and blood pressure. We investigated this relationship and its modification by hyperglycemia and oxidative stress in a population-based cohort of elderly subjects with normal glucose metabolism (n=267), impaired glucose metabolism (n=189), and type 2 diabetes (n=290). In an age- and sex-adjusted linear regression model, plasma myeloperoxidase was positively associated with systolic blood pressure (2.10 mm Hg per 1 SD increment of myeloperoxidase [95% CI: 0.66 to 3.54]), and this association was stronger at higher levels of fasting glucose (0.61 [-1.70 to 2.93], 1.33 [-1.43 to 4.10], and 3.42 [1.01 to 5.82] for increasing tertiles of glucose) and higher plasma levels of oxidized low-density lipoprotein (0.92 [-1.31 to 3.14], 2.00 [-0.71 to 4.70], and 3.58 [0.98 to 6.19] for increasing tertiles of oxidized low-density lipoprotein). Likewise, the relationship between myeloperoxidase and blood pressure was strongest under conditions associated with oxidative stress, like obesity, low high-density lipoprotein cholesterol, metabolic syndrome, and type 2 diabetes. The strength of these associations was only marginally attenuated by adjustment for other cardiovascular risk factors. Our data demonstrate that myeloperoxidase is positively and independently associated with blood pressure, and this association is strongest in subjects with (hyperglycemia-induced) oxidative stress. These observations, together with emerging evidence that myeloperoxidase-derived oxidants contribute to the initiation and propagation of cardiovascular disease, identify myeloperoxidase as a promising target for drug development.
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PMID:Hyperglycemia and oxidative stress strengthen the association between myeloperoxidase and blood pressure. 2038 72

Design of inhibitors of glycogen phosphorylase (GP) with pharmaceutical applications in improving glycaemic control in type 2 diabetes is a promising therapeutic strategy. The catalytic site of muscle glycogen phosphorylase b (GPb) has been probed with five deoxy-fluro-glucose derivatives. These inhibitors had fluorine instead of hydroxyl at the 3' position of the glucose moiety and a variety of pyrimidine derivatives at the 1' position. The best of this carbohydrate-based family of five inhibitors displays a K(i) value of 46muM. To elucidate the mechanism of inhibition for these compounds, the crystal structures of GPb in complex with each ligand were determined and refined to high resolution. The structures demonstrated that the inhibitors bind preferentially at the catalytic site and promote the less active T state conformation of the enzyme by making several favorable contacts with residues of the 280s loop. Fluorine is engaged in hydrogen bond interactions but does not improve glucose potency. The pyrimidine groups are located between residues 284-286 of the 280s loop, Ala383 of the 380s loop, and His341 of the beta-pocket. These interactions appear important in stabilizing the inactive quaternary T state of the enzyme. As a follow up to recent computations performed on beta-d-glucose pyrimidine derivatives, tautomeric forms of ligands 1-5 were considered as potential binding states. Using Glide-XP docking and QM/MM calculations, the ligands 2 and 5 are predicted to bind in different tautomeric states in their respective GPb complexes. Also, using alpha-d-glucose as a benchmark model, a series of substitutions for glucose -OH at the 3' (equatorial) position were investigated for their potential to improve the binding affinity of glucose-based GPb catalytic site inhibitors. Glide-XP and quantum mechanics polarized ligand (QPLD-SP/XP) docking calculations revealed favorable binding at this position to be dominated by hydrogen bond contributions; none of the substitutions (including fluorine) out-performed the native -OH substituent which can act both as hydrogen bond donor and acceptor. The structural analyses of these compounds can be exploited towards the development of better inhibitors.
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PMID:1-(3-Deoxy-3-fluoro-beta-d-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modelling studies. 2043 Jun 29


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