O-GlcNAc modification is associated with insulin sensitivity in the whole blood of healthy young adult males

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Abstract

Background

Hemoglobin A1c (HbA1c) is the predominant diagnostic tool for diabetes diagnosis and progression. However, it has proven to be insensitive at pre-diabetic threshold values. O-linked- β- N-acetylglucosamine (O-GlcNAc) modification has emerged as a sensitive biomarker. The purpose of this study was to explore the sensitivity of O-GlcNAc expression as a potential marker of early metabolic dysfunction in a young adult population. Healthy, young males (18–35 y) from the Assessing Inherited Metabolic syndrome Markers in the Young study ( AIMMY), were divided into low (LH,0.60) or high (HH,1.61) homeostatic model assessment of insulin resistance (HOMA-IR) cohorts.

Findings

The relationships between a panel of anthropometric, metabolic measures and whole blood global protein O-GlcNAc was examined. O-GlcNAc and O-GlcNAc transferase (OGT) levels were quantified by immunoblotting and compared to anthropometric measures: body mass index (BMI), percentage body fat, aerobic fitness, blood glucose, triglycerides, HDL, insulin, and HbA1c. HOMA-IR cohorts showed no differences in BMI, blood glucose or HbA1c, but differed in percent body fat, plasma triglycerides, and circulating insulin. Greater O-GlcNAc expression was observed in the whole blood of HH compared to LH. Moreover, a positive association between HOMA-IR and O-GlcNAc emerged, while no relationship was found between HbA1c and HOMA-IR. This effect was not related to OGT expression.

Conclusions

Results indicate that O-GlcNAc has a greater sensitivity to metabolic status compared to HbA1c in this population. O-GlcNAc has the potential to serve as a screening tool for predicting future metabolic disturbances in a young healthy adult population free of any clinically relevant pathologies.

Electronic supplementary material

The online version of this article (doi:10.1186/1758-5996-6-96) contains supplementary material, which is available to authorized users.

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Most cited references 15

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Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.

Wei Tan, Z. Wang, Mark A. Lehrman … (2014)

The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress. Copyright © 2014 Elsevier Inc. All rights reserved.

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O-GlcNAc signaling: a metabolic link between diabetes and cancer?

C. Slawson, R.J. Copeland, G.W. Hart (2010)

O-linked β-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins. In many ways, O-GlcNAcylation is similar to phosphorylation because both post-translational modifications cycle rapidly in response to internal or environmental cues. O-GlcNAcylated proteins are involved in transcription, translation, cytoskeletal assembly, signal transduction, and many other cellular functions. O-GlcNAc signaling is intertwined with cellular metabolism; indeed, the donor sugar for O-GlcNAcylation (UDP-GlcNAc) is synthesized from glucose, glutamine, and UTP via the hexosamine biosynthetic pathway. Emerging research indicates that O-GlcNAc signaling and its crosstalk with phosphorylation are altered in metabolic diseases, such as diabetes and cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

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Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes.

Keith Vosseller, Lance Wells, M Daniel Lane … (2002)

Increased flux of glucose through the hexosamine biosynthetic pathway (HSP) is believed to mediate hyperglycemia-induced insulin resistance in diabetes. The end product of the HSP, UDP beta-N-acetylglucosamine (GlcNAc), is a donor sugar nucleotide for complex glycosylation in the secretory pathway and for O-linked GlcNAc (O-GlcNAc) addition to nucleocytoplasmic proteins. Cycling of the O-GlcNAc posttranslational modification was blocked by pharmacological inhibition of O-GlcNAcase, the enzyme that catalyzes O-GlcNAc removal from proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc). PUGNAc treatment increased levels of O-GlcNAc and caused insulin resistance in 3T3-L1 adipocytes. Insulin resistance induced through the HSP by glucosamine and chronic insulin treatment correlated with increased O-GlcNAc levels on nucleocytoplasmic proteins. Whereas insulin receptor autophosphorylation and insulin receptor substrate 2 tyrosine phosphorylation were not affected by PUGNAc inhibition of O-GlcNAcase, downstream phosphorylation of Akt at Thr-308 and glycogen synthase kinase 3 beta at Ser-9 was inhibited. PUGNAc-induced insulin resistance was associated with increased O-GlcNAc modification of several proteins including insulin receptor substrate 1 and beta-catenin, two important effectors of insulin signaling. These results suggest that elevation of O-GlcNAc levels attenuate insulin signaling and contribute to the mechanism by which increased flux through the HSP leads to insulin resistance in adipocytes.

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Author and article information

Contributors

Jason P Myslicki: jpmyslicki@ucalgary.ca

Jane Shearer: jshearer@ucalgary.ca

Dustin S Hittel: dhittel@ucalgary.ca

Curtis C Hughey: cchughey@ucalgary.ca

Darrell D Belke: dbelke@ucalgary.ca

Journal

Journal ID (nlm-ta): Diabetol Metab Syndr

Journal ID (iso-abbrev): Diabetol Metab Syndr

Title: Diabetology & Metabolic Syndrome

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-5996

Publication date (Electronic): 9 September 2014

Publication date PMC-release: 9 September 2014

Publication date Collection: 2014

Volume: 6

Issue: 1

Electronic Location Identifier: 96

Affiliations

[ ]Faculty of Kinesiology, University of Calgary, 3300 University Drive NW, Calgary, Alberta T2N 4N1 Canada

[ ]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 1N4 Canada

Article

Publisher ID: 357

DOI: 10.1186/1758-5996-6-96

PMC ID: 4164748

PubMed ID: 25228926

SO-VID: e8dad612-6d45-4b83-85ae-4c658613ba84

License:

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 April 2014

Date accepted : 27 August 2014

Custom metadata

ScienceOpen disciplines: Nutrition & Dietetics

Keywords: young adult,metabolism,homa-ir,obesity,insulin resistance

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ScienceOpen disciplines: Nutrition & Dietetics

Keywords: young adult, metabolism, homa-ir, obesity, insulin resistance

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O-GlcNAc modification is associated with insulin sensitivity in the whole blood of healthy young adult males

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Most cited references 15

Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.

O-GlcNAc signaling: a metabolic link between diabetes and cancer?

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes.

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