Aims/hypothesis: The aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance. Subjects and methods: We conducted a case-cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA. Results: In proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6-5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23-0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32-1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both). Conclusions/interpretation: High leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin's described protective effects against diabetes.
Bibliographical noteFunding Information:
Acknowledgements The authors thank the staff and participants in the ARIC study for their important contributions. The National Institute of Diabetes, Digestive and Kidney Diseases Grant R01-DK056918; National Heart, Lung, and Blood Institute Contracts N01-HC -55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022 provided support for this study. B. B. Duncan and M. I. Schmidt received support from a Centers of Excellence Grant from the CNPq (National Council for Scientific and Technological Development).
- Inflammatory markers
- Leptin resistance
- Risk factors
- Type 2 diabetes