IMI-DIRECT Study Reveals Key Plasma Metabolites Linked to Prediabetes and Type 2 Diabetes Risk

The research published in Diabetologia has identified not only well-known branched-chain amino acids (BCAAs) and lipids but also novel N-lactoyl-amino acid metabolites that are significantly linked to these conditions. These metabolites mediate the progression of diabetes over time, as observed during follow-ups at 18 and 48 months.

"Causal inference analysis using genetic variants indicates that lipid metabolism and n-3 fatty acids play a causal role in the relationship between metabolites and type 2 diabetes, while the total levels of hexoses contribute causally to the reverse relationship from type 2 diabetes to metabolites," the researchers wrote. "The identified metabolite markers are valuable for stratifying individuals by their risk of progression and could facilitate targeted interventions."

Type 2 diabetes is a chronic condition characterized by high blood sugar levels (hyperglycemia). In the study, Sapna Sharma, Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany, and colleagues aimed to analyze the metabolomics to identify their association with the glycemic spectrum and establish a causal relationship between metabolites and type 2 diabetes.

As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, the researchers analyzed 3,000 plasma samples using the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites—comprising 132 targeted and 779 untargeted metabolites—passed quality control. They performed multivariable linear and logistic regression analyses, using the concentration or peak areas of each metabolite as explanatory variables and glycemic status as the dependent variable.

The basic model was adjusted for age, sex, BMI, and study center, while the full model additionally accounted for alcohol consumption, smoking, blood pressure, fasting HDL-cholesterol, and fasting triacylglycerol levels. Statistical significance was maintained through Bonferroni correction. Beyond identifying associations, the researchers examined mediation and causal effects, employing causal mediation tests and two-sample Mendelian randomization (2SMR) methods for their analyses.

Based on the study, the researchers revealed the following findings:

• In the targeted metabolomics, the researchers observed four (15), 34 (99), and 50 (108) metabolites (the number of metabolites observed in untargeted metabolomics appears in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation versus type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively.
• Significant metabolites were mainly branched-chain amino acids, with some derivatized BCAAs, lipids, xenobiotics, and a few unknowns.
• Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up.
• 2SMR was used to estimate the causal effect of exposure on an outcome using summary statistics from UK Biobank genome-wide association studies.
• Type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate, and caproate [fatty acid (FA) 6:0]), whereas, lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3), as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3), potentially had a causal role in the development of type 2 diabetes.

The findings from the DIRECT study indicate that changes in blood plasma metabolites are linked to glycemic deterioration. The progression from prediabetes to diabetes is influenced by novel metabolites like picolinoylglycine and N-lactoyl-amino acids. Notably, N-lactoyl-amino acids, which are known to be induced by exercise, play a role in suppressing food intake and regulating glucose homeostasis.

According to the authors, further functional research and quantification are essential for enhancing the identification of early metabolic biomarkers, such as N-lactoyl-amino acids, which could help predict the onset of type 2 diabetes. Collectively, these findings emphasize the importance of novel metabolic signatures associated with glycemic decline.

Reference:

Sharma, S., Dong, Q., Haid, M. et al. Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study. Diabetologia (2024). https://doi.org/10.1007/s00125-024-06282-6