Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice

Parker, Glendon J.; Taylor, Rodrick P.; Jones, Deborah L.; McClain, Donald A.

doi:10.1074/jbc.m312139200

Cited by 68 publications

(40 citation statements)

References 61 publications

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“…Glucosamine infusion in vivo also results in skeletal muscle insulin resistance (118,158,159). In addition, hyperglycemia, hyperlipidemia, and/or hyperinsulinemia were all shown to produce increased O-GlcNAcylation disturbing signaling, transcription, and other cellular functions (105,117). Furthermore, a correlation between a polymorphism in the OGA gene and type 2 diabetes has been reported in MexicanAmericans (88).…”

Section: O-glcnacylation and Cardiovascular Diseasementioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Glycosylation with Olinked ␤-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET A and ETB receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed. endothelin receptor; vascular signaling; O-GlcNAc modification GLYCOSYLATION IS THE SITE-specific enzymatic addition of saccharides to proteins and lipids. There are many types of glycosylation, but great interest has been directed to O-GlcNAcylation, or glycosylation with O-linked ␤-N-acetylglucosamine or ␤-Olinked 2-acetamido-2-deoxy-D-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [␤-N-acetylglucosamine (O-GlcNAc)] is added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169).Considering that almost every functional class of proteins is subject to O-GlcNAcylation (55, 177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets for O-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca 2ϩ )-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (...

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Section: O-glcnacylation and Cardiovascular Diseasementioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Macronutrient storage occurs in the transition to dauer (diapause) in C. elegans in a process regulated by the insulin-like-signaling pathway (38). Furthermore, in mammals, the enzymes GSK-3␤ and glycogen synthase regulate glycogen stores downstream of insulinsignaling cascades (57)(58)(59). O-GlcNAc modification of glycogen synthase has been shown to inhibit the ability of the enzyme to catalyze glycogen formation.…”

Section: Ogt-1 Modulates Dauer Formation and Macronutrient Storagementioning

confidence: 99%

“…O-GlcNAc modification of glycogen synthase has been shown to inhibit the ability of the enzyme to catalyze glycogen formation. Several of the enzymes upstream of glycogen synthase, including GSK-3␤, are also substrates for OGT (57)(58)(59). The sugar trehalose may be important in the physiology of nematodes where it functions in sugar transport, energy storage, and protection against environmental stress.…”

Section: Ogt-1 Modulates Dauer Formation and Macronutrient Storagementioning

confidence: 99%

A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout

Hanover

Forsythe

Hennessey

et al. 2005

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

205

269

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O-linked N-acetylglucosamine (O-GlcNAc) is an evolutionarily conserved modification of nuclear pore proteins, signaling kinases, and transcription factors. The O-GlcNAc transferase (OGT) catalyzing O-GlcNAc addition is essential in mammals and mediates the last step in a nutrient-sensing ''hexosamine-signaling pathway.'' This pathway may be deregulated in diabetes and neurodegenerative disease. To examine the function of O-GlcNAc in a genetically amenable organism, we describe a putative null allele of OGT in Caenorhabditis elegans that is viable and fertile. We demonstrate that, whereas nuclear pore proteins of the homozygous deletion strain are devoid of O-GlcNAc, nuclear transport of transcription factors appears normal. However, the OGT mutant exhibits striking metabolic changes manifested in a Ϸ3-fold elevation in trehalose levels and glycogen stores with a concomitant Ϸ3-fold decrease in triglycerides levels. In nematodes, a highly conserved insulin-like signaling cascade regulates macronutrient storage, longevity, and dauer formation. The OGT knockout suppresses dauer larvae formation induced by a temperature-sensitive allele of the insulin-like receptor gene daf-2. Our findings demonstrate that OGT modulates macronutrient storage and dauer formation in C. elegans, providing a unique genetic model for examining the role of O-GlcNAc in cellular signaling and insulin resistance.is a nucleocytoplasmic modification present throughout eukaryotic evolution with the possible exception of yeast (1, 2). Although many intracellular proteins such as nuclear pore components and transcription factors bear O-GlcNAc, the precise function of the modification is unknown. Evidence in mammals suggests a role for O-GlcNAc in the development of insulin resistance associated with noninsulindependent diabetes mellitus (3, 4). A number of lines of evidence also link O-GlcNAc to transcriptional regulation and neurodegeneration (1, 2). O-GlcNAc addition is partly driven by the levels of UDP-GlcNAc derived from the hexosamine biosynthetic pathway. This pathway is a nutrient-sensing pathway implicated in cellular signaling (1, 2). The uncertainty regarding the precise function of O-GlcNAc is perhaps to be expected given the many substrates modified by this glycan addition. Furthermore, O-GlcNAc is a dynamic modification; the levels of O-GlcNAc are maintained by the action of a glycosytransferase [O-linked GlcNAc transferase (OGT)] and a hexosaminidase (O-GlcNAcase) (1, 2). Mammalian O-GlcNAcase exists as two splice variants and is relatively specific for nucleocytoplasmic O-GlcNAc (1, 5, 6). The transferase, OGT, catalyzes the transfer of O-GlcNAc to Ser͞Thr residues. This enzyme has been identified from a number of sources, including plants, human, rat, mouse, and the nematode Caenorhabditis elegans (7,8). In plants, the OGT homolog Spindly is involved in plant-signaling pathways (9, 10). These evolutionarily conserved proteins share a similar overall structure; OGT is composed of multiple protein domains, including tetratricopepti...

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“…OGT localizes to the plasma membrane shortly after insulin binding to the insulin receptor, suggesting that relocation of OGT to the membrane suppresses insulin signaling by O-GlcNAcylating IRS1 (4 -7). Elevated glucose levels impair glycogen synthase function through increased OGlcNAcylation of glycogen synthase (8). Furthermore, chronic hyperglycemia causes an increase in O-GlcNAcylation of CRTC2 (cyclic adenosine monophosphate response elementbinding protein 2), thereby promoting increased gluconeogenesis through interactions with the CREB transcription factor (9).…”

mentioning

confidence: 99%

Altering O-Linked β-N-Acetylglucosamine Cycling Disrupts Mitochondrial Function

Tan¹,

Villar²,

Lezi³

et al. 2014

Journal of Biological Chemistry

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Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice

Cited by 68 publications

References 61 publications

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout

Altering O-Linked β-N-Acetylglucosamine Cycling Disrupts Mitochondrial Function

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