High plasma glutamate and low glutamine-to-glutamate ratio are associated with Type 2 Diabetes: case-cohort study within the PREDIMED trial

Abstract Background Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. Aims To examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD). Methods The present study was built within the PREDIMED study using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Results Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43-5.42, P for trend= 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.84-2.31; P for trend= 0.04) and glutamine-to-glutamate ratio (HR: 0.30, 95% CI, 0.16-0.57; P for trend= 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet+EVOO and MedDiet+mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigate the positive association between higher baseline plasma glutamate and T2D risk (P for interaction=0.01). Conclusion Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com , ISRCTN35739639.