Abbasi

AndrÃ©

Begg

Egger

Fraser

Giannini

Goessling

Hanley

Higgins

Jiamjarasrangsi

Kunutsor

Monami

Nakanishi

Nannipieri

Rahmioglu

Robins

Sato

Schneider

Tonelli

Whitfield

Wroblewski

English

PubMed

Setor K. Kunutsor

Ali Abbasi

Tanefa A. Apekey

Crossref

Frontiers in Endocrinology

Aspartate Aminotransferase â€“ Risk Marker for Type-2 Diabetes Mellitus or Red Herring?

Kunutsor, Setor K.

Abbasi, Ali

Apekey, Tanefa A.

University of Groningen

University of GroningenAspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?Kunutsor, Setor K.; Abbasi, Ali; Apekey, Tanefa A.Published in:Frontiers in endocrinologyDOI:10.3389/fendo.2014.00189IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2014Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kunutsor, S. K., Abbasi, A., & Apekey, T. A. (2014). Aspartate aminotransferase - risk marker for type-2diabetes mellitus or red herring? Frontiers in endocrinology, 5, Article 189.https://doi.org/10.3389/fendo.2014.00189CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-12-2025                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, Leeds Trinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:Soroku Yagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q. Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P < 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betes Metab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts. PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand. Diabetes Metab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

Aspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?

Frontiers - Publisher Connector

   University of GroningenAspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?Kunutsor, Setor K.; Abbasi, Ali; Apekey, Tanefa A.Published in:Frontiers in endocrinologyDOI:10.3389/fendo.2014.00189IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2014Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kunutsor, S. K., Abbasi, A., & Apekey, T. A. (2014). Aspartate aminotransferase - risk marker for type-2diabetes mellitus or red herring? Frontiers in endocrinology, 5, [189].https://doi.org/10.3389/fendo.2014.00189CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 28-04-2023                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, Leeds Trinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:Soroku Yagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q. Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P < 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betes Metab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts. PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand. Diabetes Metab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

Kunutsor, Setor K

Apekey, Tanefa A

Explore Bristol Research

   University of GroningenAspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?Kunutsor, Setor K.; Abbasi, Ali; Apekey, Tanefa A.Published in:Frontiers in endocrinologyDOI:10.3389/fendo.2014.00189IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2014Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kunutsor, S. K., Abbasi, A., & Apekey, T. A. (2014). Aspartate aminotransferase - risk marker for type-2diabetes mellitus or red herring? Frontiers in endocrinology, 5, [189].https://doi.org/10.3389/fendo.2014.00189CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, LeedsTrinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:SorokuYagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q.Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P< 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betesMetab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts.PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand.DiabetesMetab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

ARTS repository - University of Groningen

   University of GroningenAspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?Kunutsor, Setor K.; Abbasi, Ali; Apekey, Tanefa A.Published in:Frontiers in endocrinologyDOI:10.3389/fendo.2014.00189IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2014Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kunutsor, S. K., Abbasi, A., & Apekey, T. A. (2014). Aspartate aminotransferase - risk marker for type-2diabetes mellitus or red herring? Frontiers in endocrinology, 5, Article 189.https://doi.org/10.3389/fendo.2014.00189CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 01-11-2023                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, Leeds Trinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:Soroku Yagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q. Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P < 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betes Metab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts. PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand. Diabetes Metab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

Kunutsor, SK

Abbasi, A

Apekey, TA

Leeds Beckett Repository

                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, LeedsTrinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:SorokuYagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q.Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P< 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betesMetab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts.PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand.DiabetesMetab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British women’s heart and health study and meta-analysis. Diabetes Care

Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes,and cardiovascular disease. Gastroenterology

Bias in meta-analysis detected by a simple,graphical test. BMJ

Coresh J,Clark JM,et al. Liver enzymes,race,gender and diabetes risk: the atherosclerosis risk in communities (ARIC) study. Diabet Med

Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes

Epidemiology and genetic epidemiology of the liver function test proteins. PLoS One

Gamma glutamyl transferase. Crit Rev Clin Lab Sci

Genetic covariation between serum gammaglutamyltransferase activity and cardiovascular risk factors. Clin Chem

Hepatic markers and development of type 2 diabetes in middle aged men and women: a three-year follow-up study. The D.E.S.I.R. study (data from an epidemiological study on the insulin resistance syndrome).

Identiﬁability and exchangeability for direct and indirect effects. Epidemiology

Increased alanine aminotransferase level and future risk of type 2 diabetes andimpairedfastingglucoseamongtheemployees inauniversityhospitalinThailand.DiabetesMetab

Liver aminotransferases and risk of incident type 2 diabetes: a systematic review and meta-analysis.

Liver enzyme alteration: a guide for clinicians. CMAJ

Liver enzymes and risk of diabetes and cardiovascular disease: results of the ﬁrenze bagno a ripoli (FIBAR) study. Metabolism

Liver enzymes as a predictor for incident diabetes in a Japanese population: the Hisayama study. Obesity (Silver Spring)

Liver enzymes compared with alcohol consumption in predicting the risk of type 2 diabetes: the Kansai healthcare study. Diabetes Care

Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico city diabetes study. Diabetes Care

Liver function tests and risk prediction of incident type 2 diabetes:evaluationintwoindependentcohorts.PLoS One

Operating characteristics of a rank correlation test for publication bias. Biometrics

Quantifying heterogeneity in a meta-analysis. Stat Med

Serum gammaglutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care

Serum glutamic pyruvic transaminase in cardiac with hepatic disease.

Thadhani R,Melamed ML,et al. Relation between alkaline phosphatase, serum phosphate, and all-cause or cardiovascular mortality. Circulation

The association between liver enzymes and risk of type 2 diabetes: the Namwon study. Diabetol Metab Syndr

WroblewskiF,LadueJS.Serumglutamicoxalacetic aminopherase (transaminase) in hepatitis.

University of GroningenAspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?Kunutsor, Setor K.; Abbasi, Ali; Apekey, Tanefa A.Published in:Frontiers in endocrinologyDOI:10.3389/fendo.2014.00189IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2014Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kunutsor, S. K., Abbasi, A., & Apekey, T. A. (2014). Aspartate aminotransferase - risk marker for type-2diabetes mellitus or red herring? Frontiers in endocrinology, 5, Article 189.https://doi.org/10.3389/fendo.2014.00189CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 24-12-2025                                                         OPINION ARTICLEpublished: 04 November 2014doi: 10.3389/fendo.2014.00189Aspartate aminotransferase – risk marker for type-2diabetes mellitus or red herring?Setor K. Kunutsor 1*, Ali Abbasi 2,3,4 andTanefa A. Apekey 51 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK2 MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands5 Sport, Health and Nutrition Department, Leeds Trinity University, Leeds, UK*Correspondence: skk31@cantab.netEdited by:Soroku Yagihashi, Hirosaki University Graduate School of Medicine, JapanReviewed by:Hideyuki Sasaki, Wakayama Medical University, JapanToru Aizawa, Aizawa Hospital, JapanZhong Q. Wang, Pennington Biomedical Research Center, USAKeywords: aspartate aminotransferase, type-2 diabetes mellitus, liver enzymes, risk factors, meta-analysisINTRODUCTIONGamma glutamyltransferase (GGT), ala-nine aminotransferase (ALT), aspartateaminotransferase (AST), and alkalinephosphatase (ALP) are common liverenzymes. Abnormal serum circulating lev-els of these enzymes may signal liver orcholestatic damage (1). Circulating GGTis present on the external surfaces of mostcells, particularly hepatocytes, and is usedas a biological marker of excessive alco-hol intake (2). ALT and AST catalyze thetransfer of amino groups to generate prod-ucts in gluconeogenesis and amino acidmetabolism (3, 4). Elevated serum levelsof these aminotransferases signal acute orchronic liver injury (1). ALP is a hydrolaseenzyme that transports metabolites acrosscell membranes, with elevated serum lev-els commonly used in clinical practice as amarker of liver or bony disease (1, 5).In addition to their physiological func-tions, a growing body of evidence indicatesthat baseline serum levels of these enzymesmay be associated with the developmentof a wide range of disease outcomes. Sev-eral reports have indicated that amongthese enzymes, elevated baseline levels ofGGT and ALT are each associated withincreased risk of future type-2 diabetesmellitus (T2DM) (6, 7). Indeed, the asso-ciations are apparent even within normalranges of these enzymes. There is, how-ever, considerable uncertainty regardingthe association between AST level and riskof T2DM. In a recent review, we synthe-sized available prospective epidemiologicaldata on the association between AST andincident T2DM (7). The pooled analysesinvolving 1,912 incident T2DM cases didnot show a significant association betweenAST and risk of future T2DM. In contrast,a recently rigorously conducted prospec-tive study involving 2,182 incident T2DMcases, reported a multivariate adjusted rela-tive risk (RR) of 1.16 (1.02–1.31) for T2DMin a comparison of the highest to the low-est quartile of baseline AST levels (8). Theassociation was continuous and extendedwell within the normal range of AST lev-els. This large study adds to the growingbody of evidence that like GGT and ALT,elevated AST level may also be associatedwith increased risk for T2DM.The prospective evidence on the asso-ciation between AST and T2DM is incon-clusive and this may be attributed to sev-eral reasons including: lack of adequatepower, unmeasured confounding, or evenover-adjustment for potential intermedi-ates by previous studies. Given that lev-els of serum liver enzymes (GGT, ALT,and AST) (i) are strongly environmentallyand genetically correlated with one another(9), and (ii) have shared genetic variances(10), the evidence is suggestive of com-mon biological pathways affecting levels ofthese enzymes. There is therefore a pos-sibility that the association between ASTlevel and risk of T2DM might be medi-ated through the effects of the other liverenzymes. The potential impact of otherliver enzymes on the AST–T2DM associ-ation is unclear as it is uncertain whetheradjusting for such putative intermediatesis appropriate. There are indications thatfurther adjustment for other liver enzymesmay be responsible for the substantiallyattenuated or null associations observed inseveral studies. To help clarify the evidence,we report an updated review.METHODSWe searched MEDLINE, EMBASE, andWeb of Science electronic databases forpublished studies reporting on the asso-ciations between baseline AST levels andincident T2DM since the date of the pre-vious review (7). Details of the reviewmethodology and inclusion/exclusion cri-teria have been reported previously (7).Briefly, studies were only included if theyhad at least 1 year of follow-up, recruitedparticipants from approximately generalpopulations (i.e., did not select participantson the basis of pre-existing diabetes orknown liver disease), and excluded partici-pants with marked elevations in AST levels.Data were abstracted on several study char-acteristics including degree of adjustmentfor potential confounders (defined as “+”when RRs were adjusted for age and/or sex;“++” further adjustment for establisheddiabetes risk factors; and “+++” addi-tional adjustment for liver enzymes). Weseparately extracted estimates from mod-els adjusting for established and potentialdiabetes risk factors and models with addi-tional adjustment for other liver enzymes.We contacted authors of eligible studieswhere the published data were insufficient,www.frontiersin.org November 2014 | Volume 5 | Article 189 | 1                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskAdjusted for diabetes risk factorsMonami, 2008Jiamjarasrangsi, 2008Andre, 2005Nannipieri, 2005Doi, 2007Hanley, 2004Goessling, 2008Nakanishi, 2004Abbasi, 2012Ahn, 2014Sato, 2008Abbasi, 2012Schneider, 2013Total  Adjusted for liver enzymesJiamjarasrangsi, 2008Doi, 2007Nakanishi, 2004Abbasi, 2012Sato, 2008Abbasi, 2012Total Author, year of publication36488994135148208276503548878924218248135276503878924CasesNo. of+++++++++++++++++++++++++++++++++++++++++++Degree of adjustment1.00 (0.98, 1.02)1.01 (0.99, 1.02)1.29 (0.76, 2.19)1.55 (1.05, 2.30)1.68 (1.03, 2.73)1.71 (1.11, 2.64)1.63 (1.18, 2.24)1.40 (1.00, 1.96)1.14 (0.87, 1.51)1.00 (0.79, 1.27)1.41 (1.15, 1.72)0.96 (0.81, 1.13)1.14 (1.02, 1.26)1.09 (1.03, 1.14)1.01 (0.99, 1.03)1.43 (0.85, 2.41)0.80 (0.50, 1.28)1.07 (0.81, 1.42)0.97 (0.73, 1.27)0.88 (0.74, 1.05)1.00 (0.96, 1.05)RR (95% CI)1.25 .5 2.5 5Relative risk (95% CI) top versus bottom third of AST levelFIGURE 1 | Prospective studies of aspartate aminotransferaselevels and type-2 diabetes mellitus risk, grouped according tocovariate adjustment levels. The summary estimates presentedwere calculated using random-effects models; degree ofadjustment: +, adjusted for age and/sex; ++, additionally adjustedfor diabetes risk factors; +++, further adjusted for other liverenzymes; AST, aspartate aminotransferase; bars, 95% CI; RR,relative risk.to provide relevant missing information.Risk estimates were transformed to involvecomparisons between the top third andbottom third of the study population’sbaseline distribution of AST levels. Consis-tency of findings across studies was assessedby standard χ2 and I 2 statistics (11). Pre-specified sources of potential heterogene-ity were explored by using random-effectsmeta-regression. Evidence of publicationbias was assessed using Begg’s funnel plotsand Egger’s asymmetry test (12, 13). Allanalyses were performed using Stata release12 (StataCorp, College Station, TX, USA).RESULTSData were available on 90,975 participantsfrom 13 unique prospective cohort studies(14–24) (of which, 9 were included in theprevious review) (Table S1 in Supplemen-tary Material). The cumulative analysisinvolved 6,069 incident T2DM cases, col-lected over average follow-up periods rang-ing from 3 to 20 years. The pooled random-effects RR (95% CI) for T2DM in a com-parison of extreme thirds of AST level was1.09 (1.03–1.14) in studies that adjusted forpotential diabetes risk factors. The corre-sponding RR was 1.00 (0.96–1.05) in stud-ies that additionally adjusted for other liverenzymes (P for meta-regression= 0.05;Figure 1). There was substantial hetero-geneity among the studies that adjustedfor diabetes risk factors (I 2= 73%: 54–85%, P < 0.001). The inconsistency wasto a large part explained by duration offollow-up (P for meta-regression= 0.004),with combined estimates from studies withfollow-up duration≥5 years (1.28, 95% CI:1.11–1.49) being stronger than those withshorter follow-up duration (1.02, 95% CI:0.98–1.05). Egger’s test was not significant(P= 0.92), consistent with observed funnelplot symmetry.DISCUSSIONThe pattern of findings from the avail-able evidence suggest that elevated AST isassociated with increased risk of T2DMafter controlling for potential confounding.Stronger associations were demonstratedfor studies with longer duration of follow-up, findings, which confirm the specula-tive suggestion that duration of follow-upplays a role in the association between liveraminotransferases and T2DM (7). Thisfinding may, however, require replicationin further studies. The association of ASTwith T2DM was, however, abrogated byfurther adjustment for other liver enzymes.These results must be interpreted with cau-tion given potential limitations such aseffects of residual confounding, variablyFrontiers in Endocrinology | Diabetes November 2014 | Volume 5 | Article 189 | 2                                                         Kunutsor et al. Aspartate aminotransferase and diabetes riskadjusted data, and the possibility for biaswhen attempting to assess the impact ofputative intermediates (25) such as otherliver enzymes (GGT and ALT). If other liverenzymes mediate the association, then cor-rection for these enzymes may be an over-adjustment by the studies concerned. Therelationship between these liver enzymesand T2DM may be more complex thangenerally appreciated. Future studies arewarranted to help provide insight into thenature of these processes and determinethe joint role of these liver enzymes in thepathophysiology of T2DM.ACKNOWLEDGMENTSWe thank the following authors for provid-ing additional data on request: Dr. Soo Lim,Division of Endocrinology and Metabo-lism, Seoul National University Collegeof Medicine; Dr. Wiroj Jiamjarasrangsi,Department of Preventive and Social Med-icine, Faculty of Medicine, ChulalongkornUniversity; and Dr. Kyoko Kogawa Sato,Preventive Medicine and EnvironmentalHealth, Osaka City University GraduateSchool of Medicine. This work was sup-ported by the Netherlands Organizationfor Scientific Research project (NWO)and the Medical Research Council UK(grant reference no. MC_U106179471).Ali Abbasi is supported by a Rubicon grantfrom the Netherlands Organization forScientific Research (NWO). The NWO andMRC had no role in study design; in datacollection, analysis, or interpretation; inwriting the report; or in the decision tosubmit for publication.SUPPLEMENTARY MATERIALThe Supplementary Material for thisarticle can be found online at http://www.frontiersin.org/Journal/10.3389/fendo.2014.00189/fullREFERENCES1. Giannini EG, Testa R, Savarino V. Liver enzymealteration: a guide for clinicians. CMAJ (2005)172:367–79. doi:10.1503/cmaj.10407522. Whitfield JB. Gamma glutamyl transferase. CritRev Clin Lab Sci (2001) 38:263–355. doi:10.1080/200140910842273. Wroblewski F, Ladue JS. Serum glutamic pyruvictransaminase in cardiac with hepatic disease. ProcSoc Exp Biol Med (1956) 91:569–71. doi:10.3181/00379727-91-223304. Wroblewski F, Ladue JS. Serum glutamic oxalaceticaminopherase (transaminase) in hepatitis. J AmMed Assoc (1956) 160:1130–4. doi:10.1001/jama.1956.02960480030008a5. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thad-hani R, Melamed ML, et al. Relation between alka-line phosphatase, serum phosphate, and all-causeor cardiovascular mortality. Circulation (2009)120:1784–92. doi:10.1161/CIRCULATIONAHA.109.8518736. Fraser A, Harris R, Sattar N, Ebrahim S, DaveySmithG, Lawlor DA. Alanine aminotransferase,gamma-glutamyltransferase, and incident dia-betes: the British women’s heart and healthstudy and meta-analysis. Diabetes Care (2009)32:741–50. doi:10.2337/dc08-18707. Kunutsor SK, Apekey TA, Walley J. Liver amino-transferases and risk of incident type 2 dia-betes: a systematic review and meta-analysis. AmJ Epidemiol (2013) 178:159–71. doi:10.1093/aje/kws4698. Schneider AL, Lazo M, Ndumele CE, Pankow JS,Coresh J, Clark JM, et al. Liver enzymes, race, gen-der and diabetes risk: the atherosclerosis risk incommunities (ARIC) study. Diabet Med (2013)30:926–33. doi:10.1111/dme.121879. Whitfield JB, Zhu G, Nestler JE, Heath AC, MartinNG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascularrisk factors. Clin Chem (2002) 48:1426–31.10. Rahmioglu N, Andrew T, Cherkas L, SurdulescuG, Swaminathan R, Spector T, et al. Epidemiologyand genetic epidemiology of the liver function testproteins. PLoS One (2009) 4:e4435. doi:10.1371/journal.pone.000443511. Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med (2002)21:1539–58. doi:10.1002/sim.118612. Begg CB, Mazumdar M. Operating characteristicsof a rank correlation test for publication bias. Bio-metrics (1994) 50:1088–101. doi:10.2307/253344613. Egger M, Davey Smith G, Schneider M, Minder C.Bias in meta-analysis detected by a simple, graphi-cal test. BMJ (1997) 315:629–34. doi:10.1136/bmj.315.7109.62914. André P, Balkau B, Born C, Royer B, Wilpart E,Charles MA, et al. Hepatic markers and devel-opment of type 2 diabetes in middle aged menand women: a three-year follow-up study. TheD.E.S.I.R. study (data from an epidemiologicalstudy on the insulin resistance syndrome). Dia-betes Metab (2005) 31:542–50. doi:10.1016/S1262-3636(07)70229-X15. Abbasi A, Bakker SJ, Corpeleijn E, van derADL,Gansevoort RT, Gans RO, et al. Liver functiontests and risk prediction of incident type 2 dia-betes: evaluation in two independent cohorts. PLoSOne (2012) 7:e51496. doi:10.1371/journal.pone.005149616. Goessling W, Massaro JM, Vasan RS, D’AgostinoRB Sr, Ellison RC, Fox CS. Aminotransferase lev-els and 20-year risk of metabolic syndrome, dia-betes, and cardiovascular disease. Gastroenterology(2008) 135(1935–44):44e1. doi:10.1053/j.gastro.2008.09.01817. Monami M, Bardini G, Lamanna C, Pala L, CresciB, Francesconi P, et al. Liver enzymes and risk ofdiabetes and cardiovascular disease: results of thefirenze bagno a ripoli (FIBAR) study. Metabolism(2008) 57:387–92. doi:10.1016/j.metabol.2007.10.01518. Doi Y, Kubo M, Yonemoto K, Ninomiya T, IwaseM, Tanizaki Y, et al. Liver enzymes as a predic-tor for incident diabetes in a Japanese population:the Hisayama study. Obesity (Silver Spring) (2007)15:1841–50. doi:10.1038/oby.2007.21819. Hanley AJ, Williams K, Festa A, Wagenknecht LE,D’Agostino RB Jr, Kempf J, et al. Elevations inmarkers of liver injury and risk of type 2 diabetes:the insulin resistance atherosclerosis study. Dia-betes (2004) 53:2623–32. doi:10.2337/diabetes.53.10.262320. Sato KK, Hayashi T, Nakamura Y, Harita N, YonedaT, Endo G, et al. Liver enzymes compared withalcohol consumption in predicting the risk of type2 diabetes: the Kansai healthcare study. DiabetesCare (2008) 31:1230–6. doi:10.2337/dc07-218421. Nannipieri M, Gonzales C, Baldi S, Posadas R,Williams K, Haffner SM, et al. Liver enzymes, themetabolic syndrome, and incident diabetes: theMexico city diabetes study. Diabetes Care (2005)28:1757–62. doi:10.2337/diacare.28.7.175722. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syn-drome and type 2 diabetes in middle-aged Japan-ese men. Diabetes Care (2004) 27:1427–32. doi:10.2337/diacare.27.6.142723. Jiamjarasrangsi W, Sangwatanaroj S, Lohsoon-thorn V, Lertmaharit S. Increased alanine amino-transferase level and future risk of type 2 diabetesand impaired fasting glucose among the employeesin a university hospital in Thailand. Diabetes Metab(2008) 34:283–9. doi:10.1016/j.diabet.2008.01.00924. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH,Jeong SK, et al. The association between liverenzymes and risk of type 2 diabetes: the Nam-won study. Diabetol Metab Syndr (2014) 6:14.doi:10.1186/1758-5996-6-1425. Robins JM, Greenland S. Identifiabilityand exchangeability for direct and indi-rect effects. Epidemiology (1992) 3:143–55.doi:10.1097/00001648-199203000-00013Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 27 August 2014; accepted: 17 October 2014;published online: 04 November 2014.Citation: Kunutsor SK, Abbasi A and Apekey TA (2014)Aspartate aminotransferase – risk marker for type-2 dia-betes mellitus or red herring? Front. Endocrinol. 5:189.doi: 10.3389/fendo.2014.00189This article was submitted to Diabetes, a section of thejournal Frontiers in Endocrinology.Copyright © 2014 Kunutsor, Abbasi and Apekey. This isan open-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org November 2014 | Volume 5 | Article 189 | 3

NARCIS 

Aspartate aminotransferase - risk marker for type-2 diabetes mellitus or red herring?

Abstract

Similar works

Full text

Available Versions

Crossref

University of Groningen

Frontiers - Publisher Connector

University of Groningen

Explore Bristol Research

University of Groningen

ARTS repository - University of Groningen

Leeds Beckett Repository

ARTS repository - University of Groningen

NARCIS