Insulin Resistance of Glycogen Synthase Mediated byO-Linked N-Acetylglucosamine

Parker, Glendon J.; Lund, Kelli C.; Taylor, Rodrick P.; McClain, Donald A.

doi:10.1074/jbc.m207787200

Cited by 150 publications

(133 citation statements)

References 68 publications

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“…*p<0.05 for clamp vs basal values. AU Arbitrary units decrease glycogen synthase activity without changes in the phosphorylation state [31]. However, in the light of fasting plasma glucose and HbA 1c levels within the normal range, it seems unlikely that O-linked glycosylation plays a role in the observed blunted activation of glycogen synthase in Arg1174Gln carriers.…”

Section: Discussionmentioning

confidence: 91%

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

et al. 2006

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Aims/hypothesis Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified. Subjects, materials and methods We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic-hyperinsulinaemic clamp.Results Impaired clearance of exogenous insulin caused four-fold higher clamp insulin levels in Arg1174Gln carriers compared with control subjects (p<0.05). In Arg1174Gln carriers insulin increased glucose disposal and non-oxidative glucose metabolism (p<0.05), but to a lower extent than in controls (p<0.05). Insulin increased Akt phosphorylation at Ser473 and Thr308, inhibited glycogen synthase kinase-3α activity, reduced phosphorylation of glycogen synthase at sites 3a+3b, and increased glycogen synthase activity in Arg1174Gln carriers (all p<0.05). In the insulin-stimulated state, Akt phosphorylation at Thr308 and glycogen synthase activity were reduced in Arg1174Gln carriers compared with controls (p<0.05), whereas glycogen synthase kinase-3α activity and phosphorylation of glycogen synthase at sites 3a+3b were similar in the two groups. Conclusions/interpretation In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin-stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance. Our data suggest that impaired insulin clearance in part rescues in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors.

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Section: Discussionmentioning

confidence: 91%

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

et al. 2006

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“…We and others have recently established that increased O-GlcNAc levels induce insulin resistance, the hallmark of type II diabetes (51,52). Furthermore, McClain and co-workers (53) have demonstrated that glycogen synthase is O-GlcNAc-modified. Interestingly, N-acetylglucosamine analogues have been shown to inhibit glycogen-bound PP1 (54).…”

Section: Ogt-pp1 a Yin-yang Complexmentioning

confidence: 99%

O-GlcNAc Transferase Is in a Functional Complex with Protein Phosphatase 1 Catalytic Subunits

Wells

Kreppel

Comer

et al. 2004

Journal of Biological Chemistry

127

113

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A hallmark of signal transduction is the dynamic and inducible post-translational modification of proteins. In addition to the well characterized phosphorylation of proteins, other modifications have been shown to be regulatory, including O-linked ␤-N-acetylglucosamine (O-GlcNAc). O-GlcNAc modifies serine and threonine residues on a myriad of nuclear and cytosolic proteins, and for several proteins there appears to be a reciprocal relationship between phosphorylation and O-GlcNAc modification. Here we report further evidence of this yin-yang relationship by demonstrating that O-GlcNAc transferase, the enzyme that adds O-GlcNAc to proteins, exists in stable and active complexes with the serine/ threonine phosphatases PP1␤ and PP1␥, enzymes that remove phosphate from proteins. The existence of this complex highlights the importance of understanding the dynamic relationship between O-GlcNAc and phosphate in modulating protein function in many cellular processes and disease states such as Alzheimer's disease and type II diabetes.Although there are only 21, counting selenocysteine, genomically encoded mammalian amino acids, post-translational modification results in proteins that contain more than 50 different amino acids (1). Thus, covalent modification of polypeptides plays a major role in the generation of functional polypeptides and adds an extra level of complexity in attempts to understand the proteome (2). While several protein modifications are static, a subset of post-translational modifications is both dynamic and inducible. It is the study of these "regulatory" posttranslational modifications and the enzymes that add and subtract them to proteins that comprises a significant portion of the signal transduction field (3).The most well studied and understood regulatory post-translational modification is phosphorylation (3). Accordingly, a significant body of literature has focused on the kinase superfamily, which makes up more than 2% of the proteins encoded by the human genome (4). Interestingly, in humans there appear to be only about 15 catalytic serine/threonine protein phosphatases (PPP subfamily) compared with literally hundreds of serine/threonine kinases (4). Thus, understanding how protein dephosphorylation is regulated has been an area of intense study for the last two decades (5, 6). One emerging theme is that the catalytic phosphatases have binding partners that regulate their localization and activity (7).Similar to phosphorylation, O-linked ␤-N-acetylglucosamine (O-GlcNAc) modification of nuclear and cytosolic proteins is an abundant, dynamic, and inducible post-translational modification (8 -10). However, unlike kinases, there appears to be only one O-GlcNAc transferase catalytic subunit (OGT, 1 the enzyme that adds O-GlcNAc to proteins) in mammals (11). Similar to phosphatases, it has been proposed that OGT is regulated by a multitude of binding partners as well as post-translational modification and alternative splicing (12, 13). It has been demonstrated recently that OGT interacts with sever...

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“…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%

“…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%

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.

204

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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Insulin Resistance of Glycogen Synthase Mediated byO-Linked N-Acetylglucosamine

Cited by 150 publications

References 68 publications

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

O-GlcNAc Transferase Is in a Functional Complex with Protein Phosphatase 1 Catalytic Subunits

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

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