Identification of biomarkers for glycaemic deterioration in type 2 diabetes

被引：21

作者：

Slieker, Roderick C. ^{[1
,2
]}

Donnelly, Louise A. ^{[3
]}

Akalestou, Elina ^{[4
]}

Lopez-Noriega, Livia ^{[4
]}

Melhem, Rana ^{[5
,6
]}

Gunes, Aysim ^{[6
,7
]}

Abou Azar, Frederic ^{[5
,6
]}

Efanov, Alexander ^{[8
]}

Georgiadou, Eleni ^{[4
]}

Muniangi-Muhitu, Hermine ^{[4
]}

Sheikh, Mahsa ^{[4
]}

Giordano, Giuseppe N. ^{[9
]}

Akerlund, Mikael ^{[9
]}

Ahlqvist, Emma ^{[9
]}

Ali, Ashfaq ^{[10
]}

Banasik, Karina ^{[11
]}

Brunak, Soren ^{[11
]}

Barovic, Marko ^{[12
,13
]}

Bouland, Gerard A. ^{[2
]}

Burdet, Frederic ^{[14
]}

Canouil, Mickael ^{[15
]}

Dragan, Iulian ^{[14
]}

Elders, Petra J. M. ^{[16
]}

Fernandez, Celine ^{[9
]}

Festa, Andreas ^{[17
,18
]}

Fitipaldi, Hugo ^{[9
]}

Froguel, Phillippe ^{[15
,19
]}

Gudmundsdottir, Valborg ^{[20
,21
]}

Gudnason, Vilmundur ^{[20
,21
]}

Gerl, Mathias J. ^{[22
]}

van der Heijden, Amber A. ^{[16
]}

Jennings, Lori L. ^{[23
]}

Hansen, Michael K. ^{[24
]}

Kim, Min ^{[10
,25
]}

Leclerc, Isabelle ^{[4
,5
,6
]}

Klose, Christian ^{[22
]}

Kuznetsov, Dmitry ^{[14
]}

Aly, Dina Mansour ^{[9
]}

Mehl, Florence ^{[14
]}

Marek, Diana ^{[14
]}

Melander, Olle ^{[9
]}

Niknejad, Anne ^{[14
]}

Ottosson, Filip ^{[9
,26
]}

Pavo, Imre ^{[17
]}

Duffin, Kevin ^{[8
]}

Syed, Samreen K. ^{[8
]}

Shaw, Janice L. ^{[8
]}

Cabrera, Over ^{[8
]}

Pullen, Timothy J. ^{[4
,27
]}

Simons, Kai ^{[22
]}

机构：

[1] Amsterdam UMC, Amsterdam Publ Hlth Inst, Dept Epidemiol & Data Sci, Amsterdam Cardiovasc Sci,Locat VUMC, Amsterdam, Netherlands

[2] Leiden Univ, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands

[3] Univ Dundee, Sch Med, Populat Hlth & Genom, Dundee, Scotland

[4] Imperial Coll London, Dept Metab Digest & Reprod, Div Diabet Endocrinol & Metab, Sect Cell Biol & Funct Genom, London, England

[5] CHUM Res Ctr, Montreal, PQ, Canada

[6] Univ Montreal, Montreal, PQ, Canada

[7] IRCM, Montreal, PQ, Canada

[8] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN USA

[9] Lund Univ, Dept Clin Sci, Malmo, Sweden

[10] Steno Diabet Ctr Copenhagen, Gentofte, Denmark

[11] Novo Nord Fdn, Ctr Prot Res, Copenhagen, Denmark

[12] Univ Hosp Carl Gustav Carus, Paul Langerhans Inst Dresden PLID, Helmholtz Ctr Munich, Dresden, Germany

[13] Med Fac, Dresden, Germany

[14] SIB Swiss Inst Bioinformat, Vital IT Grp, Lausanne, Switzerland

[15] Univ Lille, Lille Univ Hosp, European Genom Inst Diabet EGID, Inst Pasteur Lille,CNRS,INSERM,U1283,UMR 8199, F-59000 Lille, France

[16] Amsterdam UMC Locat VUmc, Amsterdam Publ Hlth Res Inst, Dept Gen Practice & Elderly Care Med, Amsterdam, Netherlands

[17] Eli Lilly Reg Operat GmbH, Vienna, Austria

[18] LK Stockerau, Med Dept 1, Niederosterreich, Austria

[19] Imperial Coll London, Dept Diabet Endocrinol & Metab, Div Syst Biol, London, England

[20] Univ Iceland, Fac Med, Reykjavik, Iceland

[21] Iceland Heart Assoc, Kopavogur, Iceland

[22] Lipotype GmbH, Dresden, Germany

[23] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[24] Janssen Res & Dev, Cardiovasc & Metab Dis Res, Spring House, PA USA

[25] Kings Coll London, Inst Pharmaceut Sci, Fac Life Sci & Med, London, England

[26] Statens Serum Inst, Danish Ctr Neonatal Screening, Dept Congenital Disorders, Sect Clin Mass Spectrometry, Copenhagen, Denmark

[27] Guys Campus Kings Coll London, Dept Diabet, London, England

[28] Tech Univ Dresden, Univ Hosp, Mol Diabetol, Dresden, Germany

[29] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dresden, Germany

[30] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[31] Univ Bergen, Ctr Diabet Res, Dept Clin Sci, Bergen, Norway

[32] Lund Univ, Skane Univ Hosp, Dept Clin Sci Malmo, Genom Diabet & Endocrinol Unit,Diabet Ctr, Malmo, Sweden

[33] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland

[34] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland

[35] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA

[36] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[37] Leiden Univ, Dept Biomed Data Sci, Sect Mol Epidemiol, Med Ctr, Leiden, Netherlands

[38] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

英国惠康基金; 瑞典研究理事会;

关键词：

2-AMINOADIPIC ACID; OBESE WOMEN; WEIGHT-LOSS; PROTEIN; RECEPTOR; EXPRESSION; HOMOCITRULLINE; ASSOCIATION; DEFICIENCY; METABOLISM;

D O I：

10.1038/s41467-023-38148-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of similar to 1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2predict lowerprogression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fedmalemice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

引用

页数：18

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