AIMS/HYPOTHESIS: Among hepatic markers, gamma-glutamyltransferase (GGT) is the main predictor for development of type 2 diabetes, but there are no data to date on changes in GGT and type 2 diabetes incidence. METHODS: Data at baseline and at 3 years from the D.E.S.I.R. cohort were used, comprising 2,071 men and 2,130 women without baseline diabetes. RESULTS: Changes in GGT level were correlated with changes in markers of insulin resistance (fasting insulin, homeostasis model assessment of insulin resistance), as well as with the following elements of the metabolic syndrome: central obesity, and increased fasting glucose, triglycerides and blood pressure (systolic and diastolic). The 3-year increase in GGT was associated with incident type 2 diabetes in both sexes, after adjusting for age and baseline GGT. After further adjustment for baseline confounding factors, including alanine-aminotransferase, alcohol intake, obesity and fasting insulin, the odds ratios (95% CI) for an association between incident type 2 diabetes and unchanged or increased (as opposed to decreased) GGT levels were 2.54 (1.38-4.68) in men (p=0.003) and 2.78 (1.20-6.42) in women (p=0.02). These associations were slightly attenuated after adjusting for the 3-year change in BMI, alcohol consumption and fasting insulin, the odds ratios being 2.49 (1.28-4.86) in men and 2.53 (1.01-6.40) in women. This relationship was not dependent on intra-individual variability. CONCLUSIONS/INTERPRETATION: An unchanged or increased GGT level over time, even when GGT is in the normal range, is correlated with increasing insulin resistance and is associated with a risk of incident type 2 diabetes in both sexes, independently of baseline GGT, which is itself a diabetes risk factor.