A Translational In Vivo and In Vitro Metabolomic Study Reveals Altered Metabolic Pathways in Red Blood Cells of Type 2 Diabetes

Abstract

Clinical parameters used in type 2 diabetes mellitus (T2D) diagnosis and monitoring such as glycosylated haemoglobin (HbA1c) are often unable to capture important information related to diabetic control and chronic complications. In order to search for additional biomarkers, we performed a pilot study comparing T2D patients with healthy controls matched by age, gender, and weight. By using 1H-nuclear magnetic resonance (NMR) based metabolomics profiling of red blood cells (RBCs), we found that the metabolic signature of RBCs in T2D subjects differed significantly from non-diabetic controls. Affected metabolites included glutathione, 2,3-bisphophoglycerate, inosinic acid, lactate, 6-phosphogluconate, creatine and adenosine triphosphate (ATP) and several amino acids such as leucine, glycine, alanine, lysine, aspartate, phenylalanine and tyrosine. These results were validated by an independent cohort of T2D and control patients. An analysis of the pathways in which these metabolites were involved showed that energetic and redox metabolism in RBCs were altered in T2D, as well as metabolites transported by RBCs. Taken together, our results revealed that the metabolic profile of RBCs can discriminate healthy controls from T2D patients. Further research is needed to determine whether metabolic fingerprint in RBC could be useful to complement the information obtained from HbA1c and glycemic variability as well as its potential role in the diabetes management.

Potential of Creatine in Glucose Management and Diabetes

“…Recent evidence has suggested that T2DM individuals display altered creatine metabolism [26,27]. In a prospective cohort study including more than 4700 participants, Post et al [27] observed that higher plasma creatine concentration was associated with increased incidence of T2DM.…”

Plasma creatine and incident type 2 diabetes in a general population‐based cohort: The PREVEND study

“…Additionally, plasma creatine itself was strongly associated with an increased risk of incident type 2 diabetes in males, but not in females. In a recent metabolomic study of human erythrocytes, it was shown that the creatine content of erythrocytes in patients with type 2 diabetes was also higher than that of healthy controls 57 . Unfortunately, no sex‐stratified analyses were performed in this study.…”

The Relationship between Erythrocytes and Diabetes Mellitus

“…They only conserve a few metabolic pathways for obtaining energy and reduce the energy consumption for the key functions they need to fulfil. This makes erythrocytes highly sensitive to any disorder [ 77 ]. Glucose metabolism disorders in patients with diabetes profoundly affect the morphological structure and physiological functions of erythrocytes ( Figure 2 ) and result in insufficient microcirculation perfusion, hypoxia, and OS, which promoting the occurrence of diabetic complications and reducing the quality of life of diabetic patients.…”

“…They only conserve a few metabolic pathways for obtaining energy and reduce the energy consumption for the key functions they need to fulfil. This makes erythrocytes highly sensitive to any disorder [77]. Glucose…”