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Letters to the Editor |
1 Department of Preventive Medicine and Health Promotion Research Center, School of Medicine, Kyungpook National University, Daegu, Korea
2 Department of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN
3 Department of Nutrition, University of Oslo, Oslo, Norway
aAddress correspondence to this author at: Department of Epidemiology, School of Public Health, University of Minnesota, 1300 South 2nd St., Suite 300, Minneapolis, MN 55454-1015. Fax 612-624-0315; e-mail jacobs{at}epi.umn.edu.
To the Editor:
We read with interest the 2 letters addressing our recent article on the interactive effects of obesity and serum 
-glutamyltransferase (GGT) on the risk of type 2 diabetes. We reported that obesity, a well-established risk factor of type 2 diabetes, was not associated with type 2 diabetes among the approximately 50% of participants with low-normal serum GGT, whereas obesity was associated with risk of diabetes in the other half of participants who had high-normal serum GGT.
Targher et al.’s cross-sectional findings among type 2 diabetes patients, reported above, appear to support our findings, despite a study purpose and population that differed from ours. Targher et al. reported that associations between obesity and the risk of dyslipidemia and poor glycemic control were observed only among type 2 diabetic patients with high-normal and abnormal GGT, although the association between obesity and hypertension was seen at all GGT concentrations. Lippi et al., in a methodologically more limited study restricted to hospital laboratory values, failed to find any difference in the relation of hypertriglyceridemia to increased fasting plasma glucose across concentrations of serum GGT, although serum GGT itself was associated with both type 2 diabetes and hypertriglyceridemia. No measure of adiposity was available. Because the interaction of serum GGT with obesity may have a specific meaning in terms of cause and/or pathophysiology of type 2 diabetes (see below), Lippi et al.’s study of the interaction between serum GGT and hypertriglyceridemia in predicting concurrent type 2 diabetes may not be pertinent to our findings.
The authors of both letters interpreted serum GGT largely as a marker of fatty liver or oxidative stress. Although both these correlates of serum GGT could be involved, our current thinking is that a more important consideration may be the role of serum GGT as a cumulative biomarker of exposure to xenobiotics. Cellular GGT is necessary to metabolize certain xenobiotics (1). We have recently reported dose-response relations of serum or urinary concentrations of environmental pollutants [such as lead or cadmium(2) or persistent organic pollutants (POPs)(3)] with serum GGT within its reference interval in the general population. Among various xenobiotics, in relation to type 2 diabetes, POPs stored in adipose tissues may be the most relevant. Parallel to the interaction between obesity and serum GGT on the risk of type 2 diabetes and insulin resistance, there were interactions between obesity and serum concentrations of POPs associated with the risk of type 2 diabetes(4). Thus, we hypothesized that the risk of type 2 diabetes would be increased among obese persons with substantial amounts of POPs in their adipose tissue, which are reflected as high-normal serum GGT, but that the risk of type 2 diabetes might not be increased among obese persons without substantial amounts of POPs in their adipose tissue, reflected as low-normal serum GGT.
Broadly speaking, this interpretation may not contradict the prevailing concept of serum GGT as a marker of fatty liver, because POP exposure may increase the risk of fatty liver as well as type 2 diabetes; in fact, serum concentrations of POPs were also associated with the prevalence of metabolic syndrome in the US general population (5). Etiologically, however, it may be important to determine whether serum GGT predicts clinical outcomes as an exposure marker of xenobiotics such as POPs or as a marker of fatty liver itself. In fact, components related to metabolic syndrome, such as dyslipidemia and/or fatty liver, may be regarded as outcomes consequent to POP exposure(5), similar to type 2 diabetes. In this sense, it is questionable whether the interaction between serum GGT and triglycerides on the risk of type 2 diabetes, which was tested in Lippi et al.’s laboratory data set, reflects the same biological mechanism as does the interaction of serum GGT with obesity. However, in Targher et al.’s work we do not rule out serum GGT as, in part, a marker for the existence of fatty liver because the associations of obesity with dyslipidemia and poor glycemic control were observed among individuals with substantially increased serum GGT (
44 U/L).
In terms of clinical application, whatever the mechanism, the findings of Targher et al. and our findings support use of serum GGT to detect a primary target population for early intervention for prevention of type 2 diabetes and its complications.
Acknowledgments
Grant/funding support: None declared.
Financial disclosures: None declared.
References
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