This is the first report in a Middle Eastern population which adds to the information regarding the role of hepatic markers in development of type 2 diabetes. It demonstrates that among hepatic markers only ALT is significantly associated with development of type 2 diabetes independent of classic risk factors as well as markers of whole body insulin resistance (HOMA-IR) and sub-clinical inflammation (CRP). However, addition of ALT to the previously known risk factors does not improve their predictive power for type 2 diabetes.
In the current study ALT and GGT showed significant correlation with WC, WHR, FPG 2hPG, and TGs which is consistent with the results of the studies that have shown a strong association between hepatic enzymes and various factors related to insulin resistance and the metabolic syndrome [2, 3].
A number of prospective studies have investigated the association of liver markers with incident type 2 diabetes. Although most of these studies showed that GGT was an independent predictor of diabetes [7, 8, 12, 18, 19], few of them adjusted for the full range of classic diabetes risk factors [12] and none adjusted for baseline 2-hour glucose, a strong and consistent risk factor for type 2 diabetes. In a study in Pima Indians, in which AST, ALT and GGT were measured at baseline, only ALT predicted diabetes after adjustment for age, sex, percent body fat and insulin sensitivity [9]. In the west of Scotland coronary prevention study [10], high ALT but not AST predicted diabetes after adjustment for BMI, SBP, TC/HDL-C ratio, TGs and FPG. In the Insulin resistance Atherosclerosis study (IRAS) [11], both high ALT and AST were associated with incident diabetes after adjustment for full range of diabetes risk factors in addition to the markers of insulin sensitivity. On the other hand, in 3 recent population-based studies [7, 20, 21], ALT lost its association with incident diabetes after adjustment for either a minimum [7] or full range of diabetes risk factors [20, 21]. One possible explanation for the variability of these observations may be explained both in terms of insufficient understanding of the biology of the liver enzymes and incomplete capture of their correlates and confounders [1]. Ethnicity could also have some role in this regard since separate analysis of the Hispanic and black subjects in the IRAS showed a non-significant association of liver markers with diabetes risk [11].
In the current study, GGT predicted diabetes after adjustment for family history of diabetes as well as anthropometric and blood pressure factors including BMI, WC, WHR, SBP and DBP; However it lost its association with diabetes after further adjustment for metabolic factors including FPG, 2hPG, TGs and HDL-C, which are some of the major components of the metabolic syndrome and might be directly related to liver fat [1]. In fact, elevated liver enzymes even within their normal range correlate well with increasing hepatic fat and NAFLD [22], which is in turn related to visceral fat deposition and general body insulin resistance [2]. However, the fact that in the current study both ALT and GGT were significantly associated with incident type 2 diabetes independent of markers of abdominal obesity and HOMA-IR (a sensitive marker of whole body insulin resistance) may highlight the role of hepatic insulin resistance and decline in hepatic insulin sensitivity in the association between hepatic markers, especially ALT, and incident type 2 diabetes [11].
It has been suggested that inflammatory markers, via their ability to enhance de novo hepatic fatty acid synthesis and fat accumulation, may contribute to both elevated liver enzymes and diabetes [9, 23]. Significant correlation between GGT and CRP in the current study supports this finding. However, the fact that adjustment for CRP had minor effect on the association of GGT with incident type 2 diabetes may indicate that GGT might also be involved in the pathogenesis of type 2 diabetes through non-inflammatory mechanisms related to oxidative stress [24].
In the current study, ALT was predictive of diabetes after adjustment for all of the classic risk factors. However, it has been suggested that making decision about the predictive utility of a particular variable for diabetes risk would be more accurate if based on its additional utility over traditional risk factors rather than its independent association and relative risk [25]. Hence, the conclusion that hepatic enzymes may be useful additional measures in identifying the population at risk of diabetes, as several authors have said [10, 26], must rely on appropriate statistical tests like calculation of AUC of the models with and without the particular variable. In this regards, the current study showed that ALT does not add to the predictive power of the model based on classic diabetes risk factors.
Our study has some limitations the first of which is small sample size. We compensated for this limitation by reducing the number of covariates in the logistic regression models by using factor analysis to justify the variable to outcome ratio and to reduce the statistical bias [14, 15]. The second limitation is that we did not measure baseline markers of hepatitis B and C infection which considering the high prevalence of these infections in Iran [27], could have resulted in elevated liver enzymes. Alcohol consumption, a known cause of the elevated enzymes, is an unlikely confounder because of religious believes in the Iranian population. Definition of diabetes based on FPG and 2hPG measurement to identify undiagnosed cases, adjusting for all of the classic diabetes risk factors and using AUC as a measure of model discrimination are some of the strength of the current study.
The current study suggests that although serum ALT is a strong and independent predictor and might be involved in the pathogenesis of type 2 diabetes, its measurement in order to strengthen the predictive power of the classic risk factors for development of diabetes may not be justified.