High plasma glutamate and low glutamine-to-glutamate ratio are associated with type 2 diabetes: Case-cohort study within the PREDIMED trial
Graphical abstract
Introduction
Globally, the prevalence of Type-2 Diabetes (T2D) is projected to affect 591.9 million people by 2035, which is equivalent to a 55% increase from 2013 [1]. In the US, an estimate of 30.3 million people had T2D in 2015 [2].The pathophysiology of T2D is beyond simple disorders in carbohydrate metabolism [3]. Amino acid metabolites are also disturbed in conditions of insulin resistance and T2D. Unfavorable changes in energy metabolism accompanied by insulin resistance and dysfunctional pancreatic β-cell are present years before the disease is clinically diagnosed by elevated blood glucose levels [4], [5]. Therefore, early diagnosis of T2D is extremely important as early intervention may delay or prevent the onset of complications.
Recent metabolomics technology provides new tools for identifying metabolites involved in metabolic pathways related to T2D. Imbalance of metabolic regulatory systems is the basis for many metabolic disorders, including diabetes. Elevated levels of branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) have been associated with an increased risk of prediabetes and T2D [6], [7].
A key function of the BCAAs is to provide nitrogen needed to maintain glutamate, alanine and glutamine pools in skeletal muscle [8]. Glutamine is the most abundant nonessential amino acid in human biology and is involved in regulation of pancreatic β-cell function and insulin secretion [9]. Previous studies have reported associations of glutamine and glutamate metabolites with T2D risk in healthy individuals and in subjects with metabolic syndrome [6], [10]. Among participants who were free of diabetes and cardiovascular disease, plasmatic glutamate levels were associated with insulin resistance traits (glucose, insulin and HOMA), and with an increased risk of T2D incidence [6]. Glutamate was able to increase transamination of pyruvate to alanine and promote gluconeogenesis [11] which is commonly seen in obese individuals [12]. Glutamate is also a precursor to α-ketoglutarate, an intermediate in the Krebs cycle that has a crucial role in cellular energy metabolism [13].
The ability of glutamate and glutamine in predicting T2D risk in individuals at high risk of cardiovascular disease (CVD) remains uninvestigated [14]. This question needs to be addressed as these high-risk individuals are those who will benefit the most from early diagnosis and lifestyle interventions to delay the onset of T2D.
Mediterranean diet has demonstrated protective effects in T2D through modifying metabolites related to T2D risk [15]. However, the underlying mechanisms of how Mediterranean diet influences metabolites involved in energy metabolism is not fully understood. Therefore, in the present study, we examined the following hypotheses using a case-cohort study design nested within the PREvención con DIeta Mediterránea (PREDIMED) trial in non-diabetic participants at high risk for CVD 1) baseline plasma levels of glutamate were positively associated with increased risk of incident T2D whereas, glutamine level is inversed associated with risk of incident T2D; 2) increases in these amino acids at 1 year are associated with a higher subsequent risk of T2D; (3) a Mediterranean style diet (MedDiet) can attenuate the association between glutamate, glutamine-to-glutamate ratio and T2D.
Section snippets
Study population
Design and protocol of the PREDIMED (www.predimed.es) study have been published in details elsewhere [16]. The PREDIMED study is an Spanish primary CVD prevention trial using a Mediterranean diet as the main intervention. In brief, 7447 participants were randomly allocated to three groups to examine the effects of two Mediterranean enriched diets with 1) extra virgin olive oil or 2) mixed nuts compared to a low-fat diet (control diet) on the primary prevention of CVD. Male and female
Results
We examined associations of baseline glutamine, glutamate, and their ratio (Gln/Glu) with incident T2D in 892 participants from the PREDIMED study. Participants had a mean age of 66 years, BMI of 30 kg/m2 and majority of them had dyslipidemia and hypertension (Table 1). Participants with T2D were more likely to be obese (30.8 ± 3.3), hypertensive (96%), current smoker (25.1%) with higher baseline glucose level (118.6 ± 18.0 mg/dL). The proportion of women was lower in diabetic participants.
Discussion
In this case-cohort study, we found that higher baseline plasma glutamate levels were associated with increased risk of incident T2D in a population at high risk of CVD. An imbalance between glutamine and glutamate may contribute to the development of T2D. We propose that abnormal glutamate homeostasis, could cause elevated extracellular glutamate concentrations that may participate in β-cell death, possibly in combination with increased FFA and glucose concentrations [13]. The two
Conclusion
In conclusion, we provide evidence of associations between glutamate and the glutamine-to-glutamate ratio and risk of incident T2D in a population at high-risk for CVD. Our findings support a role for these metabolites in the pathophysiology of T2D and the need to explore their potential predictive ability of disease risk. A Mediterranean-style dietary pattern appeared to modify risk of T2D associated with glutamate and the overall balance between glutamine and glutamate.
Sources of support
This study was supported by research grant NIDDK-R01DK 102896 from the National Institutes of Health.
Conflicts of interest
Dr. Emilio Ros has received funds for research through his institution and personal fees for lecture presentation from the California Walnut Commission and is a nonpaid member of its Scientific Advisory Committee.Dr. Jordi Salas-Salvadó has have received grants from the International Nut and Dried Fruit Foundation and is a non-paid member of the scientific advisory board of the International Nut and Dried Fruit Foundation.
Liu, Zheng, Ruiz-Canela, Toledo, Clish, Liang, Corella, Estruch, Fito,
Authors' contributions to manuscript
Conception or design of the work: JSS, FBH, MAM-G.
Coordinators of subject recruitment and clinical data collection: JSS, MAM-G, DC, RE, MF, ER, FA, EG-G, JL, MF, LS-M.
Metabolomics data analysis: CC, LL.
Statistical analysis: LX, YZ, MG-F.
Data interpretation: JSS, FBH, MAM-G, LX, YZ, MG-F, MR-C, ET, CR.
Drafting the paper: LX, YZ.
JSS takes full responsibility for the work as a whole, the study design, access to data, and the decision to submit and publish the manuscript.
All authors have read and
Acknowledgments
We express our gratitude to the participants for making this study possible. We also gratefully acknowledge the clinical coordinators and nurses for their assistance.
Dr. Marta Guasch-Ferré was supported by a postdoctoral fellowship granted by the Lilly Foundation European Association of Diabetes (EASD) through the Institut d’Investigacions Sanitàries Pere i Virgili (IISPV), Spain, Tarragona, Spain.
Dr. Christopher Papandreou was supported by a postdoctoral fellowship granted by the Autonomous
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