Elevated O-LinkedN-Acetylglucosamine Metabolism in Pancreatic β-Cells

Hanover, John A.; Lai, Zhennan; Lee, George; Lubas, William A.; Sato, Sheryl M.

doi:10.1006/abbi.1998.1016

Cited by 121 publications

(102 citation statements)

References 45 publications

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“…In particular, the adverse action of glucose on beta cells is much less well understood, being slower and more subtle than that of fatty acids, which cause strong ER stress and subsequent apoptosis. High glucose has been reported to cause generation of ROS [4,5], activation of ER stress [6][7][8] and increase in the HBP flux [9]. Under physiological conditions, only 1-3% of intracellular glucose enters the hexosamine pathway; however, the flux increases with glucose concentration [9].…”

Section: Discussionmentioning

confidence: 99%

“…High glucose has been reported to cause generation of ROS [4,5], activation of ER stress [6][7][8] and increase in the HBP flux [9]. Under physiological conditions, only 1-3% of intracellular glucose enters the hexosamine pathway; however, the flux increases with glucose concentration [9]. Increased HBP flux, in turn, causes hyper-O-GlcNAc of proteins [10], oxidative stress [11] and ER stress, although this last mechanism has been demonstrated in cells other than beta cells [12,29].…”

Section: Discussionmentioning

confidence: 99%

“…The other component of beta cell failure is beta cell dysfunction, represented by inhibition of glucose-stimulated insulin secretion (GSIS) and by downregulation of beta cellspecific genes resulting in beta cell dedifferentiation. Several mechanisms have been implicated in glucotoxicity: the generation of reactive oxygen species (ROS) [4,5], the activation of endoplasmic reticulum (ER) stress [6][7][8] and an increase in the hexosamine biosynthetic pathway (HBP) flux [9]. However, these mechanisms are greatly interconnected.…”

Section: Introductionmentioning

confidence: 99%

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Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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“…First, enrichment of OGT in the pancreatic ␤ cells and the physiologic increase in the levels of O-GlcNAc residues present in these cells suggested that OGT may participate in glucose sensing and͞or the regulation of insulin secretion (40). Second, transcription factor glycosylation appears to regulate gene expression.…”

Section: Figmentioning

confidence: 99%

Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia

McClain

Lubas

Cooksey

et al. 2002

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

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299

245

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Insulin resistance and ␤ cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDPhexosamine biosynthetic pathway leading to ''glucose toxicity.'' How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production.

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“…One of the striking features of type 2 diabetes mellitus is insulin resistance. 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: 99%

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.

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146

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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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Elevated O-LinkedN-Acetylglucosamine Metabolism in Pancreatic β-Cells

Cited by 121 publications

References 45 publications

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia

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

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