A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective <i>N</i>-Acetyl-β-<scp>d</scp> Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans

Lehman, Donna M.; Fu, Dong Jing; Freeman, Angela B.; Hunt, Kelly J.; Leach, Robin J.; Johnson‐Pais, Teresa L.; Hamlington, Jeanette; Dyer, Thomas D.; Arya, Rector; Abboud, Hanna E.; Göring, Harald H.H.; Duggirala, Ravindranath; Blangero, John; Konrad, Robert J.; Stern, Michael P.

doi:10.2337/diabetes.54.4.1214

Cited by 155 publications

(112 citation statements)

References 40 publications

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“…These findings, coupled with our previous findings that OGT overexpression produces insulin resistance in mice (17), demonstrate a role for O-GlcNAc cycling in metabolism and insulin signaling. Consistent with these findings, the human O-GlcNAcase gene, MGEA5, was shown to be a type 2 diabetes susceptibility locus in the Mexican-American population (43).…”

supporting

confidence: 68%

“…Resistance to insulin is associated with increased flux through the hexosamine biosynthetic pathway (28)(29)(30)(31)(32)(33) as well as with inhibition of OGA (34)(35)(36)(37)(38)(39)(40)(41)(42). The link between hexosamine signaling and human diabetes mellitus was more directly shown by the finding that a single nucleotide polymorphism in the MGEA5 gene encoding OGA is associated with diabetes mellitus and age of onset in the Mexican-American population (43).…”

mentioning

confidence: 85%

“…A single nucleotide polymorphism in intron 10 of the MGEA5 gene is associated with type 2 diabetes and age of onset in the Mexican-American population. This polymorphism may interfere with OGA activity in the susceptible population (43). This important finding links the human disease to a large body of literature implicating the hexosamine-signaling pathway and O-GlcNAc cycling to insulin resistance and diabetes mellitus (reviewed in refs.…”

Section: A Genetic Model Of Insulin Resistance and Type 2 Diabetes Mementioning

confidence: 99%

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Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Forsythe

Love²,

Lazarus³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

147

206

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A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven ''hexosamine-signaling pathway.'' A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates OGlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser-and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3␤ (GSK-3␤) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C. elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling ''finetune'' insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C. elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.hexosamine ͉ insulin signaling ͉ nutrients ͉ obesity O -linked N-acetylglucosamine (O-GlcNAc) is a dynamic modification of nuclear pore complexes, transcription complexes, and kinases (1-4). Because of the diverse targets modified by O-GlcNAc, deciphering its role in cell physiology has proven challenging. Two enzymes regulate the cycling of O-GlcNAc: the O-linked GlcNAc transferase (OGT) and the glycosidase, OGlcNAcase (OGA) (1-4). In mammals, the two enzymes of OGlcNAc cycling are products of single genes; alternative splicing produces isoforms differing in subcellular location and substrate specificity (1,(5)(6)(7)(8)(9). The O-GlcNAc cycling enzymes act like kinases and phosphatases to modify Ser and Thr residues of target proteins. In addition, the hexosamine biosynthetic pathway giving rise to the O-GlcNAc donor, UDP-GlcNAc, is highly regulated and responsive to nutrient availability (4,(10)(11)(12)(13)(14).OGA, originally identified as a meningioma auto antigen and termed MGEA5 (8), is a member of the family 84 glycoside hydrolase {Carbohydrate-Active Enzymes [CAZy] database [GH 84 (caz, a)]}. OGA is highly conserved in eukaryotic evolution from Drosophila melanogaster and Caenorhabditis elegans to rodents and man. In mammals, the MGEA5 gene produces at least two isoforms differing ...

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supporting

confidence: 68%

mentioning

confidence: 85%

Section: A Genetic Model Of Insulin Resistance and Type 2 Diabetes Mementioning

confidence: 99%

See 1 more Smart Citation

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Forsythe

Love²,

Lazarus³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

147

206

View full text Add to dashboard Cite

show abstract

“…An animal experiment using high-fat diet-fed mice and genetically obese and insulin-resistant db/db mice demonstrates that hepatic overexpression of OGA ameliorates the elevated plasma glucose level and promotes O-GlcNAc removal from the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2 (CRTC2), indicating that OGA improves glucose tolerance and insulin sensitivity via the reduction of OGlcNAc levels on the insulin signaling protein 45) . In addition, a single nucleotide polymorphism (SNP) of the human MGEA5 gene, encoding OGA, is suggested to be a potential risk factor for type 2 diabetes in Mexican Americans 46) .…”

Section: Ogamentioning

confidence: 99%

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

Shirato

Kizaki

Ohno

et al. 2012

JPFSM

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Minor amounts of glucose incorporated into the cells is metabolized via the hexosamine biosynthetic pathway, resulting in the production of uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is utilized as a donor substrate for the N-and O-linked glycosylation of extracellular and membrane proteins in the Golgi apparatus, or for the O-linked GlcNAc modification (O-GlcNAcylation) of intracellular proteins in the cytosol. In particular, O-GlcNAcylation, the addition of GlcNAc to serine/threonine residues, is reversibly regulated by the enzymatic activities of O-GlcNAc transferase (OGT) and O-GlcNAcase. Since OGT activity is sensitive to the intracellular UDP-GlcNAc level, flux via the hexosamine pathway influences O-GlcNAcylation. Actually, excess flux via the hexosamine pathway and resultant increased O-GlcNAcylation are associated with several pathophysiological conditions, including insulin resistance. To date, there are several studies addressing the effects of exercise on the hexosamine pathway and O-GlcNAcylation. Thus, this short review focuses on the relationships among exercise, the hexosamine pathway, O-GlcNAcylation, and insulin resistance.

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“…Le gène codant pour l'enzyme O-GlcNAcase a d'ailleurs été montré comme étant un locus de susceptibilité pour le diabète de type 2 dans une population d'Américains d'origine mexicaine [23].…”

Section: O-glcnacylation Et Pathologies Humainesunclassified

O-GlcNAc glycosylation et régulation de la signalisation cellulaire

Issad

2010

Med Sci (Paris)

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Le séquençage du génome humain, au début des années 2000, a révélé que notre patrimoine génétique comprenait moins de 40 000 gènes (20-25 000 gènes codant pour des protéines selon des estimations plus récentes [1]) alors que les cellules vivantes sont des systèmes sophistiqués comprenant un nombre très important d'activités biologiques complexes. Cette grande diversité des activités cellulaires, surprenante au regard du faible nombre de gènes qui codent pour les protéines, peut en partie s'expliquer par les nombreuses modifications post-traductionnelles (phosphorylation, glycosylation, sumoylation, acétylation, ubiquitinylation, nitrosylation, palmitoylation, farnésylation, méthyla-tion, ADP-ribosylation, hydroxylation, oxydation, etc.) qui augmentent de façon importante les potentialités fonctionnelles des protéines. Ces modifications contrô-lent en particulier leur localisation dans différents compartiments cellulaires et leur interaction avec différents partenaires au sein d'assemblages multimoléculaires, permettant la mise en place de réseaux de signalisation complexes. Les phosphorylations et glycosylations constituent les modifications post-traductionnelles les plus abondantes et les mieux connues. Cependant, alors que les phosphorylations sont généralement considérées comme étant des modifications rapides et réversibles, permettant à la cellule de répondre à divers stimulus et de s'adapter aux variations de son environnement, les glycosylations ont longtemps été considérées comme des modifications stables, impliquant l'ajout de chaî-nes complexes d'hydrates de carbone, qui généralement restent présentes sur la protéine mature tout au long de son existence. Ces glycosylations complexes, sur des résidus sérine/thréonine (O-glycosylations) ou asparagine (N-glycosylations), ne se rencontrent que dans certains compartiments cellulaires (réticulum endoplasmique, appareil de Golgi, face externe de la membrane plasmique) et concernent essentiellement les protéines membranaires ou sécrétées. Cependant, en 1984, en étudiant la distribution des résidus N-Acétyl-glucosamine terminaux à la surface des lymphocytes T, G. W. Hart [2] a découvert un type de glycosylation original, la O-N-Acétylglucosaminylation (O-GlcNAcylation), qui consiste en l'addition d'un monosaccharide, la N-acétyl-glucosamine, sur le groupement hydroxyl d'acides aminés sérine ou thréonine (Figure 1). Il s'est ensuite rendu compte que, contrairement aux glycosylations « classiques », cette modification était observée essentiellement dans le cytoplasme et le noyau de la cellule [3,4]. > La O-GlcNAcylation correspond à l'addition de N-Acétylglucosamine sur des résidus sérine/thréo-nine de protéines cytosoliques ou nucléaires. Elle constitue un mode de régulation post-traductionnel réversible, analogue aux phosphorylations, qui contrôle l'activité, la stabilité ou la localisation des protéines en fonction de la disponibilité en glucose. Des perturbations de la O-GlcNAcylation des protéines pourraient jouer un rôle important dans des pathologies humain...

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A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective N-Acetyl-β-d Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans

Cited by 155 publications

References 40 publications

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

O-GlcNAc glycosylation et régulation de la signalisation cellulaire

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