Plasma N-glycome shows continuous deterioration as the diagnosis of insulin resistance approaches

TY - JOUR

T1 - Plasma N-glycome shows continuous deterioration as the diagnosis of insulin resistance approaches

AU - Cvetko, Ana

AU - Mangino, Massimo

AU - Tijardović, Marko

AU - Kifer, Domagoj

AU - Falchi, Mario

AU - Keser, Toma

AU - Perola, Markus

AU - Spector, Tim D.

AU - Lauc, Gordan

AU - Menni, Cristina

AU - Gornik, Olga

N1 - Funding Information: Funding This work was supported by the Medical Research Council AimHy (MR/ M016560/1) project grant and by the Chronic Disease Research Foundation (grant numbers CDRF-18/2019 and CDRF-17/2019). TwinsUK receives funding from the Wellcome Trust (grant number 212904/Z/18/Z) and from European Commission H2020 grants SYSCID (contract #733100); and the National Institute for Health Research (NIHR) Clinical Research Facility and the Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust, in partnership with King’s College London. CM is funded by the Chronic Disease Research Foundation and by the Medical Research Council. MM is funded by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust, in partnership with King’s College London. This work was supported by the European Structural and Investment funding for the ‘Croatian National Centre of Research Excellence in Personalized Healthcare’ (contract #KK.01.1.1.01.0010), ‘Centre of Competences in Molecular Diagnostics’ (contract #KK.01.2.2.03.0006), and the European Regional Development Fund grant ‘CardioMetabolic’ agreement (#KK.01.2.1.02.0321). Competing interests GL declares that he is a founder and owner of Genos Glycoscience, which offers commercial service of glycomic analysis and has several patents in this field. Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/13

Y1 - 2021/9/13

N2 - Introduction Prediction of type 2 diabetes mellitus (T2DM) and its preceding factors, such as insulin resistance (IR), is of great importance as it may allow delay or prevention of onset of the disease. Plasma protein N-glycome has emerged as a promising predictive biomarker. In a prospective longitudinal study, we included patients with a first diagnosis of impaired glucose metabolism (IR or T2DM) to investigate the N-glycosylation's predictive value years before diabetes development. Research design and methods Plasma protein N-glycome was profiled by hydrophilic interaction ultra-performance liquid chromatography in 534 TwinsUK participants free from disease at baseline. This included 89 participants with incident diagnosis of IR or T2DM during the follow-up period (7.14±3.04 years) whose last sample prior to diagnosis was compared using general linear regression with 445 age-matched unrelated controls. Findings were replicated in an independent cohort. Changes in N-glycome have also been presented in connection with time to diagnosis. Results Eight groups of plasma N-glycans were different between incident IR or T2DM cases and controls (p<0.05) after adjusting for multiple testing using Benjamini-Hochberg correction. These differences were noticeable up to 10 years prior to diagnosis and are changing continuously as becoming more expressed toward the diagnosis. The prediction model was built using significant glycan traits, displaying a discriminative performance with an area under the receiver operating characteristic curve of 0.77. Conclusions In addition to previous studies, we showed the diagnostic potential of plasma N-glycome in the prediction of both IR and T2DM development years before the clinical manifestation and indicated the continuous deterioration of N-glycome toward the diagnosis.

AB - Introduction Prediction of type 2 diabetes mellitus (T2DM) and its preceding factors, such as insulin resistance (IR), is of great importance as it may allow delay or prevention of onset of the disease. Plasma protein N-glycome has emerged as a promising predictive biomarker. In a prospective longitudinal study, we included patients with a first diagnosis of impaired glucose metabolism (IR or T2DM) to investigate the N-glycosylation's predictive value years before diabetes development. Research design and methods Plasma protein N-glycome was profiled by hydrophilic interaction ultra-performance liquid chromatography in 534 TwinsUK participants free from disease at baseline. This included 89 participants with incident diagnosis of IR or T2DM during the follow-up period (7.14±3.04 years) whose last sample prior to diagnosis was compared using general linear regression with 445 age-matched unrelated controls. Findings were replicated in an independent cohort. Changes in N-glycome have also been presented in connection with time to diagnosis. Results Eight groups of plasma N-glycans were different between incident IR or T2DM cases and controls (p<0.05) after adjusting for multiple testing using Benjamini-Hochberg correction. These differences were noticeable up to 10 years prior to diagnosis and are changing continuously as becoming more expressed toward the diagnosis. The prediction model was built using significant glycan traits, displaying a discriminative performance with an area under the receiver operating characteristic curve of 0.77. Conclusions In addition to previous studies, we showed the diagnostic potential of plasma N-glycome in the prediction of both IR and T2DM development years before the clinical manifestation and indicated the continuous deterioration of N-glycome toward the diagnosis.

KW - diabetes mellitus

KW - glycosylation

KW - insulin resistance

KW - preventive medicine

KW - type 2

UR - http://www.scopus.com/inward/record.url?scp=85115060728&partnerID=8YFLogxK

U2 - 10.1136/bmjdrc-2021-002263

DO - 10.1136/bmjdrc-2021-002263

M3 - Article

AN - SCOPUS:85115060728

SN - 2052-4897

VL - 9

JO - BMJ Open Diabetes Research and Care

JF - BMJ Open Diabetes Research and Care

IS - 1

M1 - e002263

ER -