Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of the protein kinase glycogen synthase kinase 3 (GSK-3) has been implicated in the development of type 2 diabetes mellitus. GSK-3 protein expression and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown promise as modulators of glucose metabolism and insulin sensitivity. There are two GSK-3 isoforms in mammals, GSK-3alpha and GSK-3beta. Mice engineered to lack GSK-3beta die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3alpha are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3beta in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3beta was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3beta knockout mice are viable and glucose and insulin tolerant and display "normal" metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3beta in skeletal muscle are also viable but, in contrast to the liver-deleted animals, display improved glucose tolerance that is coupled with enhanced insulin-stimulated glycogen synthase regulation and glycogen deposition. These data indicate that there are not only distinct roles for GSK-3alpha and GSK-3beta within the adult but also tissue-specific phenotypes associated with each of these isoforms.
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PMID:Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. 1869 57

Loss of retinal ganglion cells occurs in a variety of pathological conditions, including central retinal artery occlusion, diabetes and glaucoma. Using an experimental model of retinal ischemia induced by transiently raise the intraocular pressure (IOP), In this study, we report the original observation that ischemic retinal ganglion cells death is associated with the transient deactivation of the pro-survival kinase Akt and activation of GSK-3beta followed, during reperfusion, by a longer lasting, PI3K-dependent, activation of Akt and phosphorylation of GSK-3beta. Under these experimental conditions, retinal ischemia induced the expression of Bad, a pro-apoptotic protein, member of the Bcl-2 family. The detrimental effects yielded by the ischemic stimulus were minimized by intravitreal administration of the NMDA receptor antagonist, MK801, that reduced the expression of Bad and significantly increased Akt phosphorylation. In conclusion, our present results contribute to unravel the mechanisms underlying retinal damage by high IOP-induced transient ischemia in rat. In addition, these data implicate the pro-survival PI3K/Akt pathway and the observed reduced expression of Bad in the neuroprotection afforded by MK801.
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PMID:Modulation of pro-survival and death-associated pathways under retinal ischemia/reperfusion: effects of NMDA receptor blockade. 1880 92

Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3'-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3' showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation.
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PMID:Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period. 1881 10

Based on extensive preclinical data, glycogen synthase kinase-3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b(-/-) embryoid bodies. While GSK-3alpha-deficient mice were born without a cardiac phenotype, no live-born Gsk3b(-/-) pups were recovered. The Gsk3b(-/-) embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation - GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3alpha and GSK-3beta in the heart using loss-of-function approaches, implicate GSK-3beta as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age.
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PMID:Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. 1883 Apr 17

Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta. Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB. Furthermore, GSK-3beta-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-kappaB transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3beta and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3beta activity can dictate how cells will ultimately respond to glucocorticoids.
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PMID:Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. 1883 40

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.
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PMID:Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking. 1883 67

Glycogen Synthase Kinase 3beta is one of the important targets in the treatment of type II diabetes and Alzheimer's disease. Currently this target is in pursuit for type II diabetes and a few GSK-3beta inhibitors have been now advanced to Phases I and II of clinical trials. The best validated HypoGen model consists of four pharmacophore features; 1) two hydrogen bond acceptors, 2) one hydrogen bond donor and 3) one hydrophobic. This pharmacophore model correlates well with the docking model, one hydrogen bond acceptor is necessary for the H-bond interaction with VAL135, and second hydrogen bond acceptor is important for the H-bond interactions with ARG141 and the hydrophobic feature may be required for the weak H-bond interactions with ASP133. The comparative model was developed from analogue and structure-based models like Catalyst, Glide SP & XP, Gold Fitness & ChemScore and Ligand Fit using multiple linear regression analysis. A virtual library of 10,000 molecules was generated employing fragment and knowledge-based approach and the comparative model was used to predict the activities of these molecules. The H-bond with ARG141 appears to be unique to GSK-3beta and explains the high GSK-3beta selectivity observed for 1H-Quinazolin-4-ones and Benzo[e][1,3]oxazin-4-ones. This understanding of protein-ligand interactions and molecular recognition increases the rapid development of potent and selective inhibitors, and also helps to eliminate the increase in number of false positives and negatives.
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PMID:Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models. 1892 33

As a serine-threonine protein kinase, glycogen synthase kinase-3 (GSK-3) regulates the synthesis of glycogen and plays important roles in several signaling pathways. It is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimer's disease and chronic inflammation. The conserved Lys85 is important to GSK-3beta activity and in this paper we illustrate the significant role of Lys85 using dynamic simulation. We find that when Lys85 is mutated to Arg, one of the two conserved hydrogen bonds between Lys85 and ATP disappears, the salt bridge between Lys85 and Glu97 cannot form, and conformational changes of Phe93, Arg96 and Glu211 occur. These will cause conformational changes of the substrate binding groove that would inhibit the activity of GSK-3beta. MM-GBSA calculations reveal that the K85R mutation could lead to a less energy-favorable complex, which is consistent with the structural analysis.
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PMID:Effect of mutation K85R on GSK-3beta: Molecular dynamics simulation. 1895 29

Type 2 diabetes recently has been identified as a risk factor for developing Alzheimer's disease (AD). The main reason for this appears to be insulin signaling failure in the brain. Furthermore, cholinergic neurons are particularly affected in the brains of AD patients. The aim of the present study is to investigate if insulin signaling-related proteins are co-located with cholinergic neuron in the CA1 region of hippocampus of mice, which could explain the early loss of cholinergic neurons in AD. Using immunohistochemistry, the insulin signaling-related proteins, such as insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), protein kinase B (PKB, also named Akt), glycogen synthase kinase-3beta (GSK-3beta) and insulin-degrading enzyme (IDE) were analysed. Choline acetyltransferase (ChAT) was selected as a marker of cholinergic neurons. In the CA1 region of hippocampus of mice, several of the insulin signaling-related proteins we had chosen are co-located with ChAT, and most double immunoreactive positive cells were pyramidal cells. The coexistences indicated that the insulin signaling may play an important part in the activities of cholinergic neurons, and the impairment of the pathway may be important in the mechanisms that underlie neurodegeneration in AD.
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PMID:Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. 1901 38

Glycogen synthase kinase-3beta (GSK-3beta) is involved in glycogen metabolism, neuronal cell development, osteoblast differentiation. Small molecule inhibitors of GSK-3beta have various therapeutic potential for the treatment of diabetes type II, bipolar disorders, stroke and chronic inflammatory disease. To identify GSK-3beta inhibitors with novel scaffold from chemical library, we primarily screened out putative inhibitors through computer modeling and subsequently evaluated the inhibitory activity of selected compounds against GSK-3beta by in vitro Z'-LYTEtrade mark assay. A series of compound KRMs strongly inhibited phosphorylation of its substrate with IC(50) value of approximately 0.5microM. Also, we demonstrated that KRM-189 and KRM-191 competed with ATP for GSK-3beta, leading to decreased Vmax and constant Km with increasing concentrations of ATP as determined from Lineweaver-Berk equation. Moreover, they showed the selectivity for GSK-3beta over other kinases with IC(50) values of 2 to 10microM or more Incubation of cells with KRM-191 with highly selective and potent inhibitory activity caused accumulation of beta-catenin, downstream of GSK-3beta signaling pathway, indicating that small molecule can prevent degradation of beta-catenin via GSK-3beta inhibition. Our results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors.
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PMID:Identification of small molecules that inhibit GSK-3beta through virtual screening. 1908 Dec 48


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