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Letters to the Editor |
1 Section of Endocrinology, Department of Biomedical and Surgical Sciences
2 Section of Clinical Chemistry, Department of Biomedical and Morphological Sciences, University Hospital of Verona, Verona, Italy
aAddress correspondence to this author at: Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona, Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126 Verona, Italy. Fax 0039-045-917374; e-mail giovanni.targher{at}univr.it.
To the Editor:
We read with interest the article by Lim et al. (1) regarding a strong interaction between serum gamma-glutamyltransferase (GGT) activity and body mass index (BMI) and their effect on the risk of prevalent diabetes. The authors found that BMI is associated with prevalent diabetes only among individuals with high-normal GGT, suggesting that GGT determination can be useful in clinical settings for identifying individuals at high risk for diabetes.
Given the scientific and clinical importance of an interaction between obesity and GGT in predicting diabetes, we investigated possible interactions between BMI and GGT in predicting poor glycemic control and common comorbidities of diabetes. Therefore, we assessed whether the association of BMI with hypertension, dyslipidemia, and poor glycemic control differed according to serum GGT activities in a type 2 diabetic population.
Study participants were enrolled in the Verona Diabetes Study, a prospective observational study designed primarily to evaluate associations between type 2 diabetes and incidence of cardiovascular complications (2). In this analysis, we included 2929 type 2 diabetic outpatients [56% males; mean (SD) age 68 (10) years] who regularly attended our clinic and who had complete data for analysis. Fasting serum GGT and lipid values were determined by standard laboratory procedures (Roche Diagnostics). Hemoglobin A1c was measured with an HPLC analyzer (Bio-Rad Diamat); the upper limit of the reference interval for the laboratory was 5.9%. LDL-cholesterol was calculated with the Friedewald’s equation. Patients were considered to have hypertension if they had blood pressure values 
140/90 mmHg or were on treatment, and to have atherogenic dyslipidemia if they had high triglycerides (>1.7 mmol/L) and/or low HDL cholesterol (<1.04 mmol/L) or were on treatment(3). Poor glycemic control was defined as hemoglobin A1c >7%(3). We used separate multivariable logistic regression analyses to examine the interaction relationships with hypertension, dyslipidemia, or glycemic control as the dependent variables, predicted from BMI (categorized as <25, 25–29.9, 30–34.9, and 35 kg/m2) within the quartiles of GGT (<16, 16–25, 26–43, and 44 U/L). Adjusting variables were sex, age, and diabetes duration and treatment (diet, oral agents, or insulin).
Overall, 2332 (79.6%) patients had hypertension, 1999 (68.2%) had dyslipidemia, and 1756 (59.9%) had poor glycemic control. Mean (SD) GGT and BMI values were 45.6 (90) U/L and 28.7 (5) kg/m2, respectively. Most participants were overweight or obese (approximately 75% had BMI 25 kg/m2). Although the associations of BMI with different outcome measures were significant, the associations varied remarkably by serum GGT activity (Table 1
). As serum GGT activity increased, the association of BMI with dyslipidemia and glycemic control strengthened (P value for interaction <0.001); in contrast, the association between BMI and hypertension did not substantially change across GGT categories. For example, within the lowest GGT quartile, BMI was not associated with dyslipidemia or worse glycemic control, in contrast to the highest GGT quartile, wherein the prevalence rates were 60%–78.5% for dyslipidemia and 50.4%–72.4% for glycemic control, respectively. Notably, these results were observed after adjustment for sex, age, and diabetes duration and treatment.
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Our findings suggest that in people with type 2 diabetes, BMI is associated with worse glycemic control and dyslipidemia only among those with high-normal GGT, but not in those with low-normal GGT. These findings, although only correlative in nature, complement the cross-sectional observations by Lim et al. (1), suggesting that the association of BMI with type 2 diabetes and its related metabolic disorders remarkably varied with serum GGT activity, and that obesity itself may not be a sufficient risk factor for developing diabetes, dyslipidemia, or worse glycemic control.
The associations between GGT activity and diabetes and its related comorbidities may possibly be explained by some underlying biological mechanisms such as enhanced oxidative stress, insulin resistance, and fatty liver.
Markers of liver fat such as serum GGT activity have been shown in prospective studies to predict type 2 diabetes, insulin resistance, dyslipidemia, and cardiovascular disease independent of obesity (4). Moreover, obesity appears to be unnecessary to the occurrence of insulin resistance in humans, because severe insulin resistance also characterizes patients lacking subcutaneous fat, such as those with lipodystrophy. A close linear relationship exists between liver fat content and direct measures of hepatic insulin resistance(4). The fatty liver thus might help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant and thereby at risk of developing type 2 diabetes and its related metabolic disorders. To further complicate the intertwined biological links between obesity and diabetes, it has been shown that obesity does not increase the prevalence of diabetes among those with undetectable serum concentrations of persistent organic pollutants(5).
Acknowledgments
Grant/funding support: None declared.
Financial disclosures: None declared.
References
-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem 2007;53:1092-1098.
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