The Dose-Response Relationship between Gamma-Glutamyl Transferase and Risk of Diabetes Mellitus Using Publicly Available Data: A Longitudinal Study in Japan

PURPOSE: The purpose of this study was to examine the association between baseline serum gamma-glutamyl transferase (GGT) and incident diabetes mellitus and to explore their dose-response relationship in a cohort of Japanese adults. Patients and Methods. Data were drawn from the NAGALA (NAfld in the Gifu Area, Longitudinal Analysis) study between 2004 and 2015, including hierarchical information on participants ≥18 years of age without diabetes mellitus, preexisting diabetes mellitus, heavy alcohol drinking, or other liver diseases (e.g., hepatitis B/C). The final analytic sample included 15464 participants, 373 of who were diagnosed as diabetes mellitus with a maximum 13-year follow-up. The risk of incident diabetes mellitus according to baseline serum GGT was estimated using multivariable Cox proportional hazards models and a two-piecewise linear regression model was developed to find out the threshold effect. RESULTS: Being in the highest quintile versus the lowest quintile of GGT levels was associated with an almost twofold increased risk of incident diabetes mellitus (hazard ratio 1.83 (95% CI 1.06, 3.15)), independent of age, gender, smoking status, alcohol intake, BMI, SBP, triglycerides, fatty liver, ALT, AST, and fasting plasma glucose. Further analysis revealed a positive curvilinear association between GGT and incident diabetes mellitus, with a saturation effect predicted at 24 IU/L. When serum GGT level was less than 24 IU/L, the risk of developing diabetes mellitus increased significantly with an increase in serum GGT levels (HR 1.04 (1.02, 1.07), P=0.0017). Besides, the association was more significant in nonsmoking participants than ex- or current-smokers (P=0.0017). Besides, the association was more significant in nonsmoking participants than ex- or current-smokers (P for interaction = 0.0378). CONCLUSION: Serum GGT level was a significant predictor of subsequent risk of diabetes mellitus, which increased by 4% for every 1 IU/L increase in GGT when GGT was less than 24 IU/L.