Association Between Liver Enzymes and Incident Type 2 Diabetes in Singapore Chinese Men and Women

Open Access Research BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2016-000296 on 19 September 2016. Downloaded from Association between liver enzymes and incident type 2 diabetes in Singapore Chinese men and women Ye-Li Wang,1 Woon-Puay Koh,1,2 Jian-Min Yuan,3,4 An Pan5 To cite: Wang Y-L, Koh W-P, ABSTRACT et al Key messages Yuan J-M, . Association Aims: To assess the association between liver between liver enzymes and enzymes and the risk of type 2 diabetes (T2D) in a incident type 2 diabetes in ▪ Increased levels of γ-glutamyltransferase (GGT) Chinese population. Singapore Chinese men and and alanine aminotransferase (ALT), even within – women. BMJ Open Diabetes Methods: A nested case control study comprising the normal range, are associated with increased Research and Care 2016;4: 571 T2D cases and 571 matched controls was risk of incident type 2 diabetes independent of e000296. doi:10.1136/ conducted within the Singapore Chinese Health Study. other diabetes risk factors in this Chinese bmjdrc-2016-000296 Alanine aminotransferase (ALT), aspartate population. aminotransferase (AST), alkaline phosphatase (ALP), ▪ GGT and ALT are useful markers for identifying and lactate dehydrogenase (LDH) were quantified in people at higher risk of T2D, and the best baseline plasma collected from them, while γ- cut-offs were 23 and 21 IU/L in this Chinese glutamyltransferase (GGT) was assayed among 255 population. ▸ Additional material is T2D cases with baseline hemoglobin A1c <6.5% and ▪ The other liver enzymes (aspartate aminotrans- available. To view please visit 255 matched controls. Participants were free of ferase, alkaline phosphatase, and lactate the journal (http://dx.doi.org/ diagnosed diabetes, cardiovascular disease, and cancer dehydrogenase) were not significantly associated 10.1136/bmjdrc-2016- at blood collections (1999–2004). Incident self- 000296). with diabetes risk in the Chinese adults. reported T2D cases were identified at follow-up II – Received 8 July 2016 interview (2006 2010). Controls were matched to copyright. Revised 23 August 2016 cases on age, sex, dialect group, and date of blood the liver, and associated with hepatic insulin collection. Accepted 30 August 2016 resistance2 and type 2 diabetes (T2D) risk.3 Results: Higher levels of ALT and GGT were ALT, found predominately in the liver, has significantly associated with increased risk of T2D been considered the most specific marker (p for trend <0.001 for ALT, p for trend=0.03 for GGT), 4 and the ORs (95% CIs) comparing highest versus for liver injury, while GGT is present on the lowest tertiles of ALT and GGT were 2.00 (1.01 to surface of most cell types and highly active in 5 3.96) and 2.38 (1.21 to 4.66), respectively. A null liver, kidney, and pancreas. GGT is respon- association was observed for AST, ALP, and LDH sible for catabolism of extracellular glutathi- with T2D risk. Adding GGT (<23 vs ≥23 IU/L) or ALT one and may be linked to oxidative stress6 (<21 vs ≥21 IU/L) to a prediction model resulted in fl 7 and chronic in ammation, which are also http://drc.bmj.com/ significant gain in net reclassification improvement and important pathways for T2D development. integrated discrimination improvement of T2D Thus, ALT and GGT may be underlying bio- prediction (all p<0.001). logical markers linking between liver disease Conclusions: Higher levels of GGT and ALT are and T2D. Previous studies on ALT/GGT and associated with increased T2D risk. GGT ≥23 IU/L and – T2D risk were conducted in Western2815 ALT ≥21 IU/L may identify people at higher risk of – and Asian populations such as Japanese,16 18 developing T2D in this Chinese population. on September 24, 2021 by guest. Protected South Koreans,19 20 Thai,21 and Iranians,22 but not in a Chinese population. The measurement of GGT and ALT involves well-standardized, simple, inexpensive, and INTRODUCTION routine tests with no requirement for fasting Liver, a vital organ in metabolism, plays an prior to venipuncture;23 therefore, it is of clin- important role in maintaining glucose ical interest to explore whether these conveni- homeostasis.1 Markers of liver injury, such as ent biomarkers can help identify people at alanine aminotransferase (ALT) and higher risk of developing T2D. However, exist- For numbered affiliations see γ fi end of article. -glutamyltransferase (GGT), have been ing studies found inconsistent ndings: some shown to be good surrogate measures of studies showed that GGT and/or ALT – non-alcoholic fatty liver disease (NAFLD), improved T2D prediction significantly,16 24 27 Correspondence to 22 28–30 Professor An Pan; the most common chronic liver conditions while others did not. Additionally, a [email protected] characterized by excess deposition of fat in recent study in a white and African-American BMJ Open Diabetes Research and Care 2016;4:e000296. doi:10.1136/bmjdrc-2016-000296 1 Epidemiology/health services research BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2016-000296 on 19 September 2016. Downloaded from population found that ALT ≥26 IU/L increased diabetes Case and control selection prediction substantially;27 while a Japanese study has For the current analysis, we established a case–control identified a much lower cut-off value for ALT (13 IU/ study nested within SCHS of 571 cases and 571 matched L).16 Since Asians develop T2D at lower body mass index controls. Cases and controls were free of physician- (BMI) compared to western populations, the observed diagnosed diabetes, cardiovascular disease, and cancer difference indicates that liver may play a more important at baseline interview and blood collection (1999–2004). role in T2D development in relatively lean Asian popula- Cases were those who reported to be diagnosed with tions. However, evidence is limited to confirm this T2D during follow-up II (2006–2010). Controls were assumption. Moreover, to the best of our knowledge, no selected from the remaining participants who were free study has examined the association of GGT, ALT with of T2D at follow-up II, and were matched for age T2D risk, and their potential cut-off levels for T2D pre- (±3 years), date (±6 months) of blood collection, sex, diction in a Chinese population yet. and dialect group with cases on a 1:1 ratio. Moreover, To address these issues, we conducted a nested case– the selected controls were screened for the presence of control study within the Singapore Chinese Health undiagnosed T2D at the time of blood donation by Study (SCHS) to examine the relationship between liver measuring hemoglobin A1c (HbA1c) level. Controls enzymes and incident T2D risk in Chinese adults. with HbA1c ≥42 mmol/mol (6.0%) were ineligible for Moreover, we evaluated the predictive utility of liver the study and excluded, and a replacement control with enzymes and identified appropriate cut-off values for the same matching criteria was randomly chosen among T2D prediction. the remaining eligible controls. RESEARCH AND METHODS Laboratory procedures Study population Twenty milliliters of peripheral blood were collected from The design of SCHS was described previously.31 Briefly, consenting participants, and transported to the laboratory SCHS was established between 1993 and 1998, and immediately. All specimens were separated into plasma, − recruited 63 257 Chinese adults aged 45–74 years. At serum, red blood cells, and buffy coat, and stored in 80° recruitment, an in-person interview was conducted using C freezers. For the current study, one aliquot of frozen a structured questionnaire to collect health-related infor- plasma for each of study subjects were retrieved from the copyright. – mation. Follow-up I (1999–2004) was conducted via tele- bioreposity. The plasma samples of matched case control phone to update selected lifestyle habit and medical pairs were randomly placed next to each other with the history. We recontacted 52 322 participants successfully, case/control status blinded to the laboratory personnel, and among them, 32 535 participants donated their and processed and tested in the same batch. Plasma con- biospecimens during the follow-up I visit. Follow-up II centrations of ALT, aspartate aminotransferase (AST), (2006–2010) was conducted via telephone, and 39 528 alkaline phosphatase (ALP), lactate dehydrogenase participants were recontacted successfully. The study (LDH), total cholesterol (TC), triglycerides (TG), high- protocol was approved by the Institutional Review density lipoprotein cholesterol (HDL-C), and high- Boards at the National University of Singapore and the sensitivity C reactive protein (CRP) were measured via col- University of Pittsburgh. orimetric method on a chemistry analyzer (AU5800 http://drc.bmj.com/ Analyzer, Beckman Coulter, Brea, California, USA). Adiponectin levels were measured by ELISA (Bio-Rad Ascertainment of diabetes Laboratories, Hercules, California, USA). HbA1c levels History of physician-diagnosed T2D risk was asked at were measured by HPLC method using Bio-Rad Variant II baseline and both follow-ups by the question: “Have you System (Bio-Rad Laboratories) in red blood cells. All bio- been told by a doctor that you have diabetes?” If the chemical measurements were conducted at the National on September 24, 2021 by guest. Protected answer was ‘yes’, participants were also asked for the age University Hospital Reference Laboratory. at which they were first diagnosed. The robustness and Among 571 case–control pairs, although 279 cases accuracy of the self-reported diabetes data was con- had baseline HbA1c ≥48 mmol/mol (6.5%) and may be firmed in a validation study: among 1651 cohort partici- considered to have T2D according to current diagnostic pants who reported prior diagnosis of diabetes either at criteria,33 they were not considered to have T2D baseline or at follow-up I interview, 98.9% were con- because this was not used as criterion for diagnosis firmed by medical records (hospital-based discharge during the period of blood collection (1999–2004) and summary database) or a supplementary questionnaire follow-up (2006–2010).

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