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

Discussion

Our study adds new information to the concept of ALT as a predictor of diabetes. First, a large sample size allowed us to identify the level of ALT above which the risk of diabetes is evident. Men with baseline ALT levels 29 units/l had more than three times the risk for diabetes than men with ALT <17 units/l. Second, we were able to exclude alcohol intake and CRP, a robust biomarker of low-grade inflammation, as potential confounders. Finally, we had prior data on metatolic syndrome in this population and again were able to adjust for this in our analysis. Significantly, ALT continued to predict type 2 diabetes independently of all the above factors whether we compared risk in the fourth versus the first quartile or examined risk in those above or below the 75th percentile for ALT (i.e., ≥ 29 units). Moreover, elevated ALT and CRP continued to predict, quite independently, incident diabetes, whereas low HDL cholesterol and blood pressure did not in a stepwise regression analysis that considered all individual metabolic syndrome criteria. Given the simplicity of ALT measurement and its universal standardization and availability in routine clinical practice, these novel observations indicate the potential for an ALT cutoff to be considered in diabetes prediction algorithms. Our observations perhaps also add further support for the role of the liver in the pathogenesis of type 2 diabetes.

Why should elevated ALT predict type 2 diabetes? There is now good evidence that elevated ALT, even within the normal range, correlates with increasing liver fat.[2] Moreover, the condition of nonalcoholic fatty liver disease is now well recognized, and an elevated ALT is a principal diagnostic feature.[14,15] With respect to diabetes risk, it is therefore likely that elevated liver fat is part of the pathogenic mechanism. In line with this, Seppala-Lindross et al.[1] elegantly demonstrated that elevated liver fat in nondiabetic men with average BMI is linked to insulin resistance independently of total adiposity. These prior observations in turn explain why elevated ALT predicted decreasing hepatic insulin sensitivity independent of total adiposity and an increase in hepatic glucose output in a study of Pima Indians.[5] Of more recent interest, an inverse correlation between ALT levels and adiponectin concentrations has been demonstrated.[16] This observation is relevant since low adiponectin predicts incident diabetes in prospective studies[17,18,19] and may do so in part by enhancing hepatic fatty acid oxidation and thereby lessening fat accumulation and ALT levels. It would be clinically important in future studies, therefore, to compare ALT and adiponectin as predictors of diabetes in prospective cohorts.

Why then does the liver accumulate fat? One possibility is simply excess flux of fatty acids to liver from abdominal or visceral fat depots.[20] However, others[2] suggest that increased liver fat content may relate better to dietary fat intake. Further possibilities include excessive intravascular lipolysis of triglyceride-rich lipoproteins or indeed impaired free fatty acid clearance. Whether acquired or genetic defects in hepatic β-oxidation are involved in liver fat accumulation requires direct examination.

Regardless of the mechanisms for fat accumulation, our results offer some potential clinical interest. Firstly, our data suggest that levels of ALT, even within the currently acceptable normal range, may indeed be prognostic with respect to the development of diabetes. A level of ~28-29 units/l (around the mean level of those developing diabetes and the approximate cutoff for the top quartile) is well within the current normal range in all laboratories and populations. This suggests that perhaps even modest degrees of hepatic fat accumulation may be relevant for the development of diabetes.

Given the increasing incidence of obesity and therefore the likelihood for diabetes worldwide, there is great interest in the development of predictive algorithms for type 2 diabetes. In this respect, it is of interest that the National Cholesterol Education Program-defined metabolic syndrome criteria have been shown to predict incident diabetes in different populations.[9,21] However, we previously suggested that the National Cholesterol Education Program criteria could be modified to improve its prediction of diabetes and that differing definitions are likely to better predict risk for coronary heart disease.[9] Our findings that elevated ALT and CRP continued to predict incident diabetes in stepwise regression analyses, whereas low HDL cholesterol and blood pressure did not, perhaps indicate the potential future use of ALT cutoffs in this respect. Future studies in other populations should address this potential in greater detail.

The strengths of our study have been indicated above and include its larger sample size and inclusion of alcohol intake, CRP, and metabolic syndrome in analyses. Moreover, our definition of diabetes used the American Diabetes Association criteria and was consistent and validated in prior analyses.[6,9,13] We acknowledge that the current study represents a post hoc analysis of men with elevated cholesterol and that men with levels of ALT >70 units/l were excluded from WOSCOPS. However, since cholesterol and LDL cholesterol are not predictive of diabetes and since others have shown higher ALT levels to predict diabetes, we feel such limitations are not significant concerns. Clearly, our results were obtained in a cohort of men and are not applicable to women. We also acknowledge that we used a modified version of the American Diabetes Association criteria to predict diabetes but feel that our conservative approach (which may have contributed to only 2.33% developing diabetes) increased rather than decreased our confidence in the diagnosis of new-onset type 2 diabetes. Finally, although these results were conducted in the context of a statin trial, and statins can transiently raise transaminases, it is important to note that ALT and AST concentrations used herein were measured before randomization and treatment allocation and that further statistical analysis indicated no heterogeneity in the ALT-incident diabetes findings dependent on treatment allocation.

In conclusion, we have shown that elevated ALT within the "normal" range predicts diabetes independently of classical predictors, CRP, and the metabolic syndrome in middle-aged Caucasian men of average BMI. In this respect, it is noteworthy that ALT measurement is automated, internationally standardized, and universally available, unlike many other proposed novel markers of diabetes. Therefore, we believe that the results of our study have potential implications for clinical practice or development of future algorithms to predict diabetes. The results may also add some support for the notion that liver fat accumulation is important in the pathogenesis of type 2 diabetes.

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