We read with great interest the article by Nannipieri et al. (1), which reported no association between aspartate aminotransferase, alanine aminotransferase (ALT), or alkaline phosphatase and the 7-year incidence of impaired glucose tolerance and type 2 diabetes. Interestingly, γ-glutamyltransferase was, but ALT was not, a significant predictor of impaired glucose tolerance or type 2 diabetes. This is, as the authors stated, in contrast to previously published papers that found significant prospective associations of ALT with incident type 2 diabetes after adjustment for obesity, insulin sensitivity, or inflammation (C-reactive protein) (2–4). We studied the baseline ALT enzyme activity in relation to 6-year incident type 2 diabetes in the Hoorn Study, a population-based cohort study of glucose tolerance among Caucasian men and women (5). Glucose tolerance was assessed by oral glucose tolerance test at baseline and after 6.4 years of follow-up. The study methods were similar to the Mexico City Diabetes Study described by Nannipieri et al. (1), with the exception that the participants of the Hoorn Study were ∼15 years older at baseline (5). Of the 1,289 subjects free of type 2 diabetes at baseline, 123 developed type 2 diabetes during follow-up. We found that ALT was a significant predictor of type 2 diabetes only in the models adjusted for age, sex, and follow-up duration, with an odds ratio of 2.18 (95% CI 1.29–3.69) for subjects in the upper tertile versus those in the lower tertile. However, after additional adjustment for waist circumference, BMI, alcohol consumption, fasting plasma insulin levels, and 2-h postload glucose levels, the association attenuated and lost significance (1.18 [0.66–2.11]). The other liver enzymes were not determined in the Hoorn Study.
Thus, in accordance with the report by Nannipieri et al. (1), but in contrast to the findings by others, we found that ALT was not an independent predictor of incident type 2 diabetes in the Hoorn study. We think it is important to report these findings, since we cannot exclude the possibility of publication bias leading to overrepresentation of studies showing an independent relationship between liver enzymes and risk of type 2 diabetes. The observed association between ALT and incident type 2 diabetes in several published reports may be explained by the fact that these studies were performed in selected populations, i.e., in high-risk populations and may not be representative for the general population. An alternative explanation is that the applied models overadjust for potential mediating variables such as insulin and 2-h glucose, factors that might be directly related to liver fat. To increase the insight into the role of liver fat in the pathophysiology of the metabolic syndrome and type 2 diabetes, further studies are needed to assess the underlying mechanisms. The role of oxidative stress, as hypothesized by Nannipieri et al. (1), as well as the contribution of inflammation should be explored in large-scaled prospective studies.
