Aspartate Aminotransferase – Risk Marker for Type-2 Diabetes Mellitus or Red Herring?

Abstract

Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) are common liver enzymes. Abnormal serum circulating levels of these enzymes may signal liver or cholestatic damage (1). Circulating GGT is present on the external surfaces of most cells, particularly hepatocytes, and is used as a biological marker of excessive alcohol intake (2). ALT and AST catalyze the transfer of amino groups to generate products in gluconeogenesis and amino acid metabolism (3, 4). Elevated serum levels of these aminotransferases signal acute or chronic liver injury (1). ALP is a hydrolase enzyme that transports metabolites across cell membranes, with elevated serum levels commonly used in clinical practice as a marker of liver or bony disease (1, 5). In addition to their physiological functions, a growing body of evidence indicates that baseline serum levels of these enzymes may be associated with the development of a wide range of disease outcomes. Several reports have indicated that among these enzymes, elevated baseline levels of GGT and ALT are each associated with increased risk of future type-2 diabetes mellitus (T2DM) (6, 7). Indeed, the associations are apparent even within normal ranges of these enzymes. There is, however, considerable uncertainty regarding the association between AST level and risk of T2DM. In a recent review, we synthesized available prospective epidemiological data on the association between AST and incident T2DM (7). The pooled analyses involving 1,912 incident T2DM cases did not show a significant association between AST and risk of future T2DM. In contrast, a recently rigorously conducted prospective study involving 2,182 incident T2DM cases, reported a multivariate adjusted relative risk (RR) of 1.16 (1.02–1.31) for T2DM in a comparison of the highest to the lowest quartile of baseline AST levels (8). The association was continuous and extended well within the normal range of AST levels. This large study adds to the growing body of evidence that like GGT and ALT, elevated AST level may also be associated with increased risk for T2DM. The prospective evidence on the association between AST and T2DM is inconclusive and this may be attributed to several reasons including: lack of adequate power, unmeasured confounding, or even over-adjustment for potential intermediates by previous studies. Given that levels of serum liver enzymes (GGT, ALT, and AST) (i) are strongly environmentally and genetically correlated with one another (9), and (ii) have shared genetic variances (10), the evidence is suggestive of common biological pathways affecting levels of these enzymes. There is therefore a possibility that the association between AST level and risk of T2DM might be mediated through the effects of the other liver enzymes. The potential impact of other liver enzymes on the AST–T2DM association is unclear as it is uncertain whether adjusting for such putative intermediates is appropriate. There are indications that further adjustment for other liver enzymes may be responsible for the substantially attenuated or null associations observed in several studies. To help clarify the evidence, we report an updated review.