Non‐invasive metabolic biomarkers in initial cognitive impairment in patients with diabetes: A systematic review and meta‐analysis

Abstract Aim Diabetic cognitive impairment (DCI), considered one of the most severe and commonly overlooked complications of diabetes, has shown inconsistent findings regarding the metabolic profiles in DCI patients. This systematic review and meta‐analysis aimed to identify dysregulated metabolites as potential biomarkers for early DCI, providing valuable insights into the underlying pathophysiological mechanisms. Materials and Methods A systematic search of four databases, namely PubMed, Embase, Web of Science and Cochrane, was conducted up to March 2024. Subsequently, a qualitative review of clinical studies was performed followed by a meta‐analysis of metabolite markers. Finally, the sources of heterogeneity were explored through subgroup and sensitivity analyses. Results A total of 774 unique publications involving 4357 participants and the identification of multiple metabolites were retrieved. Of these, 13 clinical studies reported metabolite differences between the DCI and control groups. Meta‐analysis was conducted for six brain metabolites and two metabolite ratios. The results revealed a significant increase in myo‐inositol (MI) concentration and decreases in glutamate (Glu), Glx (glutamate and glutamine) and N ‐acetylaspartate/creatine (NAA/Cr) ratios in DCI, which have been identified as the most sensitive metabolic biomarkers for evaluating DCI progression. Notably, brain metabolic changes associated with cognitive impairment are more pronounced in type 2 diabetes mellitus than in type 1 diabetes mellitus, and the hippocampus emerged as the most sensitive brain region regarding metabolic changes associated with DCI. Conclusions Our results suggest that MI, Glu, and Glx concentrations and NAA/Cr ratios within the hippocampus may serve as metabolic biomarkers for patients with early‐stage DCI.