Abnormal Liver Function Test Predicts Type 2 Diabetes: A community-based prospective study

doi:10.2337/dc07-0106

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Epidemiology/Health Services Research
Brief Report

Abnormal Liver Function Test Predicts Type 2 Diabetes

A community-based prospective study

Nam H. Cho, MD, PHD¹, Hak C. Jang, MD², Sung Hee Choi, MD², Hyung R. Kim, MD³, Hong Kyu Lee, MD², Juliana C.N. Chan, MD⁴ and Soo Lim, MD²

¹ Preventive Medicine, Ajou University, Suwon, Korea
² Internal Medicine, Seoul National University, Seoul, Korea
³ Korean National Genome Institute, Korean Center for Disease Control and Prevention, Seoul, Korea
⁴ Therapeutics, Chinese University of Hong Kong, Hong Kong, China

Address correspondence and reprint requests to Soo Lim, MD, PHD, Internal Medicine, Seoul National University, 300, Gumi-dong, Bundang-gu, Seongnam-city, South Korea. E-mail: limsoo{at}snu.ac.kr

Abbreviations: ALT, alanine aminotransferase • AST, aspartate aminotransferase • GGT, ${gamma}$ -glutamyltranspeptidase • HOMA-ß, homeostasis model assessment of pancreatic ß-cell function • HOMA-IR, homeostastis model assessment of insulin resistance • QUICKI, quantitative insulin sensitivity check index

INTRODUCTION

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

Increased activities of liver enzymes such as aspartate aminotransferase(AST), alanine aminotransferase (ALT), and ${gamma}$ -glutamyltranspeptidase(GGT) are indicators of hepatocellular injury. Increased activityof these markers is associated with insulin resistance (1),metabolic syndrome, and type 2 diabetes (2–9). However,most of these studies were performed in Western countries (2–5,7,9),and the two studies from Japan and Korea were not communitybased (6,8). In this prospective community-based study, we evaluatedthe relationships between markers of liver function and theonset of type 2 diabetes after adjusting for potential riskfactors including inflammatory markers.

RESEARCH DESIGN AND METHODS—

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

In 2001, the Korean government funded a large community-basedepidemiological survey to investigate the trends in diabetesand the associated risk factors (10). For this study, two communities,one from a rural Ansung and the other from an urban Ansan community,were selected. The baseline examination was performed in 2001–2002,and biennial follow-up examinations will continue through 2010.The age range for eligibility was 40–69 years. Of the7,192 eligible individuals in Ansung, 5,018 were surveyed (70%response rate) using a cluster sampling method. A total of 15,580individuals were eligible in Ansan, and we successfully recruited5,020 (32.4%) using a random sampling method of the local telephonedirectory. The study protocol was approved by the ethics committeeof the Korean Health and Genome Study.

Anthropometric parameters and blood pressure were measured bystandard methods. Fasting plasma glucose, lipid profiles, insulin,high-sensitivity C-reactive protein, and the activities of hepaticenzymes were measured in a central laboratory.

All participants except those on oral hypoglycemic medicationsor insulin therapy underwent a 2-h 75-g oral glucose tolerancetest at baseline and at each follow-up visit. Pancreatic ß-cellfunction and insulin resistance were calculated using the homeostasismodel assessment (HOMA-ß and HOMA-IR, respectively)and quantitative insulin sensitivity check index (QUICKI) (11,12).

All data are presented as means ± SD. Statistical analyseswere conducted using t tests, Pearson’s correlation, andlogistic regression models by using SPSS (version 12.0; SPSS,Chicago, IL). P < 0.05 was considered significant.

RESULTS—

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INTRODUCTION
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RESULTS--
CONCLUSIONS--
References

At baseline, 594 (5.9%) of 10,038 participants were being treatedfor diabetes and 542 (5.4%) were newly diagnosed with type 2diabetes by oral glucose tolerance testing. The clinical andbiochemical features of men (n = 4,075) and women (n = 4,675)were investigated after excluding those with a known historyof diabetes and those positive for hepatitis B or C by antibodytesting. Mean ± SD age was 51.4 ± 8.7 and 52.1± 8.9 years in men and women, respectively. Regardingalcohol drinking, the proportion of current drinkers in menwas much higher than that in women (71.0 vs. 26.5%, P < 0.01).Mean levels of liver enzyme activities were higher in men thanthose in women (30.8 ± 20.1 vs. 25.3 ± 13.1 IU/lin AST, 31.0 ± 24.8 vs. 21.4 ± 16.0 IU/l in ALT,and 50.4 ± 30.7 vs. 18.8 ± 20.4 IU/l in GGT, respectively;all P < 0.05).

Of the three liver enzymes, ALT activity correlated better withBMI than AST or GGT (r = 0.203 vs. r = 0.023 or r = 0.016 inmen; r = 0.174 vs. r = 0.058 or r = 0.126 in women, respectively).In the correlation with HOMA-IR, ALT showed a stronger relationshipthan either AST or GGT (r = 0.104 vs. r = 0.044 or r = 0.025in men; r = 0.082 vs. r = 0.061 or r = 0.074 in women). Whendivided into drinkers and nondrinkers, a similar pattern wasfound in both sexes. Accordingly, ALT was used as the markerfor liver function in all subsequent analyses.

We stratified participants into quartiles according to ALT activityin each sex. In the percentage of participants who had obesity,bad lipid profiles, and high glucose, insulin and HOMA-IR increasedprogressively with ALT quartile in both sexes (Table 1). Incontrast, increasing quartiles of ALT were associated with decliningQUICKI, HOMA-ß, and HDL cholesterol concentrationafter adjusting for age and alcohol status. The percentage ofalcohol drinkers increased with ALT only in men.

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Table 1— Clinical and biochemical characteristics of male and female participants, stratified by ALT quartiles, and relative risk (RR) of ALT quartiles in logistic regression models for incidence of diabetes

At the 2-year follow-up, we found that the highest quartileof ALT level was a predictor of the incidence of type 2 diabetesin both sexes (Table 1). We also found similar results whenGGT was used, although the relative risk was lower than thatfor ALT. However, we found no relationships when we used AST.

CONCLUSIONS—

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

In this study, we found that the highest quartile of ALT activitywas associated with risk of type 2 diabetes both cross-sectionallyat baseline and prospectively at the 2-year follow-up period,as well as before and after adjusting for alcohol intake. Wealso demonstrated the independent predictive value of ALT activityon the incidence of type 2 diabetes after controlling for potentialrisk factors including age, family history, BMI, alcohol intake,and insulin resistance in both sexes. This result supports theprevious studies reporting an association between abnormal liverfunction and type 2 diabetes, conducted mainly in Caucasianpopulations (2–5,7,9).

The liver is an important site for insulin clearance (13) andproduction of inflammatory cytokines (4,9). A large body ofclinical and experimental data shows that increased flux offree fatty acids from increased visceral adipose tissue canlead to hepatic steatosis and insulin resistance (5). Otherresearchers have reported an association between elevated ALTactivity and fatty liver (7,14) in obesity, insulin resistance,and type 2 diabetes (1). Another study has shown that ALT activityeven within the normal range correlates with increasing hepaticfat infiltration (15). In contrast, elevated AST and GGT activitiesare not related to hepatic or whole-body insulin sensitivity(4). Although we did not confirm the presence of fatty liverby imaging, we showed a continuous relationship between ALTactivity, lipid and glucose concentrations, HOMA-IR, HOMA-ß,and QUICKI—all of which were independent predictors oftype 2 diabetes.

Elevated liver enzyme activity may also reflect inflammation,which impairs insulin signaling (4). In agreement with otherstudies (16–18), our data show that individuals in thetop ALT quartile have the highest levels of high-sensitivityC-reactive protein, which is also an independent predictor fortype 2 diabetes (19).

In conclusion, in this population-based survey, increased activityof liver enzymes, notably ALT, was associated with a twofoldincrease in the risk of type 2 diabetes independently of conventionalrisk factors. Because the measurement of ALT activity is internationallystandardized and often part of the routine clinical assessment,this marker may serve as a useful marker to identify individualsat high risk of type 2 diabetes in Asian populations.

Acknowledgments

This study was supported by the National Genome Research Institute,Seoul, Korea (2001-347-6111-221, 2002-347-6111-221, 2003-347-6111-221,2004-347-6111-213, and 2005-347-24002-440-215).

Footnotes

Published ahead of print at http://care.diabetesjournals.orgon 12 July 2007. DOI: 10.2337/dc07-0106.

A table elsewhere in this issue shows conventional and SystèmeInternational (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.

Received for publication January 17, 2007. Accepted for publication July 4, 2007.

References

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