Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study

Naveed Sattar; Olga Scherbakova; Ian Ford; Denis St. J. O'Reilly; Adrian Stanley; Ewan Forrest; Peter W. MacFarlane; Chris J. Packard; Stuart M. Cobbe; James Shepherd

Disclosures

Diabetes. 2004;53(11) 

In This Article

Abstract and Introduction

Abstract

We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men in the West of Scotland Coronary Prevention Study. A total of 139 men developed new diabetes over 4.9 years of follow-up. ALT, but not aspartate aminotransferase, levels increased progressively with the increasing number of metabolic syndrome abnormalities from (means ± SD) 20.9 ± 7.6 units/l in those with none to 28.1 ± 10.1 units/l in those with four or more (P < 0.001). In a univariate analysis, men with ALT in the top quartile (ALT ≥29 units/l) had an elevated risk for diabetes (hazard ratio 3.38 [95% CI 1.99-5.73]) versus those in the bottom quartile (<17 units/l). ALT remained a predictor with adjustment for age, BMI, triglycerides, HDL cholesterol, systolic blood pressure, glucose, and alcohol intake (2.04 [1.16-3.58] for the fourth versus first quartile). In stepwise regression, incorporating ALT and C-reactive protein (CRP) together with metabolic syndrome criteria, elevated ALT (≥29 units/l), and CRP (≥3 mg/l) predicted incident diabetes, but low HDL cholesterol and hypertension did not. Thus, elevated ALT levels within the "normal" range predict incident diabetes. The simplicity of ALT measurement and its availability in routine clinical practice suggest that this enzyme activity could be included in future diabetes prediction algorithms.

Introduction

The role of the liver in the pathogenesis of type 2 diabetes is attracting increasing interest. In a recent study,[1] directly determined liver fat content was shown to correlate with several features of insulin resistance in normal weight and moderately overweight subjects independent of BMI and intra-abdominal or overall obesity. However, direct measurements of liver fat require ultrasound, computed tomography scan, or proton spectroscopy, and such techniques are unlikely to be recommended for this purpose in routine clinical practice. Fortunately, circulating concentrations of a number of variables appear to give insight into the extent of liver fat accumulation. Among these are γ-glutamyltransferase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Of these three, ALT is the most specific marker of liver pathology and appears to be the best marker for liver fat accumulation.[2] In addition, circulating concentrations of plasminogen activator inhibitor-1 may give insight into the extent of liver fat content[3] but, unlike ALT, its measurement is perhaps not as simple, standardized, or routinely available in laboratories.

In light of the above observations, it is of interest that ALT has been shown to predict incident type 2 diabetes in two prospective studies.[4,5] Ohlson et al.[4] determined risk factors for diabetes in 766 men, 47 of whom developed diabetes over 13.5 years of follow-up. They reported that elevated ALT predicted diabetes independently of classical predictors inclusive of BMI, blood pressure, triglycerides, and family history. However, diabetes ascertainment was not uniform in their study, and the potential utility of ALT to predict diabetes was not examined in any detail. Vozarovoa et al.[5] examined the ALT levels in a cohort of 370 Pima Indians with normal glucose tolerance, 63 of whom developed diabetes over an average follow-up of 6.9 years. In their analyses, individuals in the top decile for ALT (≥70 units/l) had a relative risk of 2.5 (95% CI 1.7-3.7) for diabetes compared with those in the bottom decile (ALT ≤12 units/l), with adjustment for age, sex, percentage body fat, clamp-derived insulin resistance, and acute insulin response. The only minor weaknesses in that study were the absence of data on alcohol consumption and routine clinical measures known to predict diabetes, namely fasting lipids and blood pressure. Moreover, they were not able to incorporate markers of inflammation in their prospective analyses, and the authors themselves suggested that inflammatory cytokines, via their ability to enhance de novo hepatic fatty acid synthesis, may contribute to both elevated ALT and diabetes. We and others[6,7,8] have previously shown elevated C-reactive protein (CRP) to be an independent predictor of incident diabetes.

We had the opportunity to address the predictive power of ALT for new-onset diabetes in the West of Scotland Coronary Prevention Study (WOSCOPS) in more detail and attempted to address many of the above issues in this study. In particular, we were able to examine whether ALT predicts new-onset diabetes independently of classical predictors, alcohol intake, and markers of inflammation. We were also able to address whether elevated ALT predicts new-onset diabetes independently of the metabolic syndrome, previously shown to predict new-onset diabetes in WOSCOPS.[9] Finally, due to the larger size of WOSCOPS, it was possible to better approximate the level of ALT above which increased risk for diabetes is evident. We believe our study enhances knowledge on the prediction of incident diabetes by ALT, with potential implications for clinical practice and the development of future algorithms to predict diabetes.

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